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Dihydric Alcohols or Glycols and their Derivatives
Chapter 12
Dihydric Alcohols or Glycols and their Derivatives E. S. WAIGHT
This chapter is concerned with the glycols, those compounds in which two hydroxyl groups are attached to different carbon atoms, and their derivatives in which one oi both of the hydroxyl groups are alkylated to form ethers, esterified with organic or inorganic acids, or replaced by thiol or amino groups. The hydroxyl groups in the glycols may be primary, secondary, or tertiary and can undergo reactions analogous to those of primary, secondary, and tertiary alcohols. Thus on oxidation those members with primary groups form first aldehydes and then carboxylic acids, while those with secondary groups yield ketones, in this way several classes of compounds containing two functional groups, other than two hydroxyl groups, can be obtained, namely, hydroxy-aldehydes and -ketones, dialdehydes, diketones, aldehydocarboxylic acids, ketocarboxylic acids, and dicarbox3~lic acids. These classes will be dealt with in the following chapters. 1. Saturated aliphatic glycols; alkanediols,
Cni-I2n+202
The first dihydric alcohol, HOCH~-CH,OH, was discovered by A. Wurtz (Compt. rend., 1856, 43, 199) who named it ethylene glycol as it was intermediate between the monohydric ethyl alcohol on one hand and the trihydric glycerol on the other. Subsequently, other glycols became known having hydroxyl groups attached to adjacent (1,2-) or other (I,3-, 1,4-, 1,5-, etc.) carbon atoms. Compounds with two hydroxyl groups attached to the same carbon atom are unstable and readily lose water with the formation of aldehydes and ketones (see Vol. IC, p. I). The systematic names of glycols are derived by adding the suffix diol to the name of the parent hydrocarbon, so that ethylene glycol is correctly named ethane-I,2-diol. As indicated above either or both hydroxyl groups of a glycol may be
2
GLYCOLS
I2
converted to some other functional group so that, in the case of ethylene glycol, the following can be obtained: CHg.0H
CH~0CgH 5
I
[
CHg.0COCH3
I
CHgOH
CHzOH
CHz0H
Glycol
Glycol mono-ethyl ether
Glycol mono-acetate
Such compounds behave as monohydric alcohols. On the other hand, the following behave as simple ethers and esters" CHg0COCH 3
CH,0C2H 5
I
[
CH~.OCzH5
CH 20COCH s
Glycol diethyl ether
Glycol diacetate
Replacement of the hydroxyl groups by halogen, thiol and amino groups produces the corresponding halides, thiols and amines, thus: CH2C1
CH2C1
CH,NH~
I
I
I
CH2NH ~
I
CHg.0H
CHg.C1
CHg.OH
CHzNH 2
Ethylene chlorohydrin
Ethylene dichloride
2-Aminoethanol ethanolamine
Ethylenediamine
CH2SH
CHgSH
;
i
CHg0H
CH~SH
2-Mercaptoethanol
Ethane-I,2dithiol
Ethylene chlorohydrin and ethylene dichloride have already been discussed in Vol. IB, p. 36 and Vol. IA, p. 497, respectively. Glycols form characteristic cyclic derivatives, for example, cyclic ethers such as: CH2- ~
I
o
CH~ "/
Ethylene oxide
CH~--O--CH 2
;
[
CH~--O--CHg.
Dioxan (diethylene oxide)
Ethylene oxide and its homologues are discussed in this chapter, although they are cyclic compounds, because of their importance in the chemistry of glycols, but trimethylene oxide, dioxan and the sulphur and nitrogen analogues of all these systems are discussed in Vol. IV.
ALKANEDIOLS
I
3
Stereoisomerism may be observed in glycols containing secondary or tertiary hydroxyl groups, and in several cases racemic mixtures have been resolved to give pure optical isomers. Apart from this any glycol more complex than ethylene glycol has structural isomers (e.g. propane-I,2-diol, CHs.CHOH.CH~OH , and propane-I,3-diol, HOCH2.CH2.CH,OH ) the number of which becomes very large in the case of a high molecular weight glycol ( c . f . H . R . Henze and C. M. Blair, J. Amer. chem. Soc., 1934, 56, 157). (i) Methods of formation Glycols m a y be obtained by applying to bifunctional compounds m e t h o d s used for forming monohydric alcohols. (I) Dihalogenoalkanes give glycols directly on hydrolysis under mild conditions. Although prolonged t r e a t m e n t with water under pressure is satisfactory, less direct methods are more convenient; that of A. Wurtz (1859) is frequently employed. This consists in converting the dihalide to the diacetate, by warming either with a solution of silver or lead acetate in acetic acid or with a methanolic solution of an alkali metal acetate, followed by hydrolysis of the diester. With methanolic sodium formate the dihalide is converted in one operation into the glycol, the intermediate diformate being very easily hydrolysed. Conditions must be chosen to avoid side reactions such as elimination of hydrogen halide or formation of carbonyl compounds. Thus hydrolysis of 1,2-dibromo-2-methylpropane may give isobutanal (A. Elteko~, Bet., 1878, x x, 989; C. M. Surer and H. D. Zook, J. Amer. chem. Soc., 1944, 66, 738), while t r e a t m e n t with sodium acetate in acetic acid leads to the formation of 2-methylallyl acetate (K. Krassuski and F. Schenderowitsch, Chem. Ztbl., 1926, II, 183). The mechanism of replacement of bromine by acetate in 1,2-dibromoalkanes has been investigated by S. Winstein and R. E. Buckles (J. Amer. chem. Soc., 1942, 64, 2787). (2) Halogenohydrins, or their mono-esters, give glycols on hydrolysis
(H. D. Cowan, C. L. McCabe and J. C. Warner, J. Amer. chem. Soc., 195o, 72, 1194). 1,2-Halogenohydrins react considerably more slowly under neutral conditions than the analogous alkyl halides, but in the presence of strong bases form the epoxide [see s(b) below]. Tetramethylene chlorohydrin reacts rapidly with water to give tetrahydrofuran (H. W. Heine et al., ibid., 1953, 75, 4778), but this may be avoided by protecting the hydroxyl group, for example, by formation of a 2-pyranyl ether, before carrying out the hydrolysis (C. Croisan, Ann. chim., I956, [I 3 ], 1,436). Carbonyl compounds may be formed; thus 2-chloro-2-methylpropanol gives isobutanal with aqueous sodium hydroxide, and pinacolone is formed from 3-iodo-2,3-dimethylbutan-2-ol (M. T i ~ e ~ a u and J. Ldvy, Bull. Soc. chim. Fr., I93I, [iv], 49, I8O6):
4
GLYCOLS
12
heat
(CHs),C(OH) 9C(CH~),I ~ or AgOH ~- CHa. CO. C(CHa)a While the above two methods are applicable to the formation of any dihydric alcohol, they are particularly useful for 1,2-glycols as the relevant dihalide or halogenohydrin is readily available from the olefin. (3) 1,2-Glycols, specifically, m a y be obtained by the oxidation of olefins. For a review see F. D. Gunstone, "Advances in Org. Chem." Methods and Results", Vol. I, Interscience, New York, 196o, p. lO3. (a) Alkaline or neutral permanganate, alkaline manganate (W. Rigby, J. chem. Soc., 1956, 2452), or permanganate and magnesium sulphate (C. J. Maan, Rec. Tray. chim., 1929, 48, 332) give diols by cis-addition, although yields are often poor. Osmium tetroxide adds to olefins giving stable osmate esters, which on hydrolysis in the presence of sodium sulphite or chlorate give the vicinal diols. (b) Alkenes are readily converted by peracids to epoxides (see p. x9) which, can be hydrolysed by dilute acid to the 1,2-diols (D. Swern, Chem. Reviews, 1949, 45, 16). Peracetic and performic acids give glycol mono-esters which are readily converted by hydrolysis to the diols in excellent yield. Peroxytrifluoroacetic acid in the presence of trifluoroacetate ions (W. D. Emmons, A. S. Pagano and J. P. Freeman, J. Amer. chem. Soc., I954, 75, 3472) is more reactive than performic acid. The glycol monotrifluoroacetate may be converted to the glycol by treatment with methanolic hydrogen chloride. (c) Hydrogen peroxide hydroxylates double bonds in the presence of metallic oxide catalysts (M. Mugdan and D. P. Young, J. chem. Soc., I949, 2988), water, dioxan, or tert-butanol being employed as a solvent. Osmium tetroxide leads to cis-addition, but pertungstic acid, permolybdic acid, and selenium dioxide, which are rather less efficient catalysts, give trans-addition. (d) Iodine-silver benzoate complex, C6HsCO,Ag.CeHsCOI, (C. Prdvost, Compt. rend., 1933, I96, II29; I97, 1661; for a review see C. V. Wilson, Org. Reactions, 1957, 9, 332), gives with olefins dibenzoates by trans-addition; but iodine-silver acetate in wet acetic acid gives diacetates by cis-addition (R. B. Woodward and F. V. Brutcher, J. Amer. chem. Soc., 1958, 80, 209, but see C..4. Bunton and M. D. Cart, J. chem. Soc., 1963, 77o). The diesters are readily hydrolysed to 1,2-diols. (4) Diamines or amino-alcohols give diols on t r e a t m e n t with nitrous acid. Pinacolic deamination (see p. 36) m a y be observed with 1,2-diamines or amino-alcohols in which one amino group is tertiary (F. Feist and H. Arnstein, Ber., 1895, 28, 3169; F. R. Japp and J. Moir, J. chem. Soc., 19oo, 77, 642; A. McKenzie and W. S. Dennler, ibid., 1924, I25, 21o5; J. Kenyon et al., ibid., 193o, 421).. Choline is decomposed to glycol by heating: o
CH~OH.CH~N(CHa)3OHe
> (CH~OH)~ + H,O + (CHa)aN
I
ALKANEDIOLS
5
(5) Paraffin glycols can be obtained by hydrogenation of ethylenic and acetylenic glycols (W. Reppe et al., Ann., I955, 596, 38). (6) Reduction of carboxylic acids and their derivatives m a y give diols. (a) Diesters may be reduced with sodium and an alcohol under vigorous conditions. The method is best suited to the higher homologues (G. M. Bennett and A. N. Mosses, J. chem. Soc., 1931, 1697; Org. Synth., Coll. Vol. II, 1943, p. 154). Diesters can be hydrogenated over copper chromite catalysts at high temperature and pressure (see Org. Synth., Coll. Vol. II, 1943, P. 325; H. Adkins, "Reactions of Hydrogen", University of Wisconsin Press, Madison, Wisconsin, 1946, p. lO3 et seq.; A. Guyer, A. Bider and M. Sommaruga, Helv., 1955, 38, 976). Dicarboxylic acids, particularly the higher members, may be reduced under rather similar conditions (Guyer et al., loc. cit.). (b) Diamides are reduced by sodium and alcohol (R. Scheuble and E. Loebl, Monatsh., 19o4, 25, 341) or sodium in liquid ammonia a t - - 5 o~ (E. Chablay, Ann. chim., 1917, 8, 216) to diprimary glycols. (7) Diols m a y be prepared b y the hydrogenation of dialdehydes, diketones, aldols, and ketols. Sodium and alcohol or wet ether may be used. The selective reduction of carbonyl groups with aluminium isopropoxide (T. Bersin, "Newer Methods of Prep. Org. Chem.", Interscience, l~ew York, 1948, p. 125) allows diols to be obtained from substituted ketones and ketols. Carbonyl compounds, especially those unstable to alkali, such as 1,2- and 1,3-dicarbonyl compounds, may be hydrogenated catalytically (c.f.G.F. Hennion and E. J. Watson, J. org. Chem., 1958, 23, 656, 658), a method used to prepare very high members of the 1,2-glycol series (V. L. Hansley, J. Amer. chem. Soc., 1935, 57, 23o3; U.S.P., 2,o79,4o3/ 1937; F. Bouquet and C. Paquot, Bull. Soc. chim. Ft., 1948, 15, II65), or reduced with sodium borohydride (J. Dale, J. chem. Soc., 1961, 91o). Lithium aluminium hydride may be employed to obtain diols from a wide variety of bifunctional compounds, for example, diketones, keto-esters, aldols, ketols, and lactones (N. G. Gaylord, "Reduction with Complex Metal Hydrides", Interscience, New York, I956), as well as dicarboxylic acids and their esters. (8) Reduction of epoxy-alcohols can give diols. The reaction is of wide scope. Alcohols containing 1,2- (A. K6tz and F. Richter, J. pr. Chem., 1925, xxx, 373), 1,4- (R. Adams et al., J. Amer. chem. Soc., 1923, 45, 3o29; 1925, 47, lO98; R. Connor and H. Adkins, ibid., 1932, 54, 4678) and 1,5-oxide rings (R. Paul, Bull. Soc. chim. Fr., 1934, Iv], x, 978) have all been reduced to the corresponding diols. Thus 2,3-epoxypropan-i-ol is catalytically hydrogenated over palladium to propane-i,2-diol (K6tz and Richter, loc. cit.): CHz--CH. CHgOH --H-L+ CH3- CHOH. CH~OH Furyl alcohol and its derivatives yield mainly pentane-I,2-diol together with a little of the 1,5-dioI (jr. Pierce and R. Adams, J. Amer. chem. Soc., 1925, 47, lO98).
6
GLYCOLS
12
(9) 1,2-Glycols (including pinacols, see p. 13) are formed by bimolecular reduction of carbonyl compounds" 2 RCHO + 2H:
.~CHR(OH).CH(OH)R
2 RCOR' + 2H---~ CRR'(OH).C(0H)RR" A pinacol
Unsymmetrical glycols of this latter type may be obtained if a mixture of ketones is used (G. Lande and J. Wiemann, Bull. Soc. chim. Fr., 1946, 256). Suitable reducing agents are: sodium or sodium amalgam, preferably in acetic acid (J. B~eseken and G. H. van Senden, Rec. Tray. chim., 1913, 32, 26); sodium in moist ether (J. Bredt and W. H. Perkin, J. chem. Soc., 1913, xo3, 2213); magnesium amalgam (Org. Synth., Coll. Vol. I, 1941, p. 459); magnesium in aqueous acetic acid (M. Kolobielski, Ann. Chim., 1955, xo, 271); a mixture of magnesium and magnesium iodide (R. C. Fuson et al., J. Amer. chem. Soc., 1942, 64, 3o) ; chromous chloride or vanadous sulphate (J. B. Conant and H. B. Cutter, ibid., 1926, 48, lO16); the zinc-copper couple, which is particularly good for the bimolecular reduction of unsaturated carbonyl compounds (J. Wiemann, Ann. Chim., 1936, 5, 287)- Pinacols are produced in the electrolytic reduction of ketones but the method is not satisfactory for the preparation of aliphatic pinacols (M. J. Allen, "Organic Electrode Processes", Chapman and Hall Ltd., London, 1958, p. 61). For a discussion of the mechanism of pinacol formation see A. J. Birch, Quart. Reviews, 195o, 4, 79. The following offer general methods of carbon chain extension with the formation of glycols of all types. (IO) Syntheses with Grignard reagents. (a) Dialdehydes and diketones yield disecondary and ditertiary glycols respectively" HCO. (CH~)n.CHO + 2RMgX----+ CHR(OH). (CH~)n.CH(OH)R RC0. (CHg)n.COR' + 2 R ' M g X ~
CRR'(0H). (CH,)n.C(OH)R'R*
The method is of very wide application (see M . S . Kharasch and 0. Reinmuth, "Grignard Reactions of Nonmetallic Substances", Prentice Hall Inc., New York, 1954). Diesters, keto-esters, hydroxy-esters, lactones, aldols, ketols, and glycides may also be employed. Lithium alkyls have some advantages over Grignard reagents (W. J. Hickinbottom, A. A. Hyatt and M. B. S~arke, J. chem. Soc., 1954, 2533). (b) The Grignard reagents from dihalides react with carbonyl compounds to form glycols" thus formaldehyde gives diprimary products (J. yon Braun and W. Sobecki, Bet., 1911 , 44, 1918):
I
ALKANEDIOLS
7
XMg(CH~)nMgX + 2CH~O---+ HO.(CH2)n+9. OH Other aldehydes and ketones give secondary and tertiary glycols. AlkoxyGrignard reagents give mono-ethers of glycols (M. H. Palomaa and A. A. Erikowski, ibid., 1938, 7I, 574). The reaction of alkoxy-Grignard reagents with ethylene oxide can be used to extend the carbon chain by two units (Palomaa and R. Jansson, ibid., 1931, 54, 16o6) thus: /O.~ ROCHz. CH2MgC1 + CH2mCHl ~ ROCHI. CHg.CHg. CH~OH (c) Dimagnesium compounds with aft-unsaturated aldehydes give diallylic glycols. Acrolein reacts as follows (J. Cologne and R. Davis, Compt. rend., 1958, 247, 88I): BrMg.(CH2)n-MgBr + 2CHB:CH-CHO~
>
CH~ CH. CHOH. (CHg)n-CHOH. CH CHs PBr, .
.
_
r
BrCH~. CH: CH. (CH2)n"CH: CH. CH,Br Conversion of the above dibromide to the diacetate followed by hydrogenation and hydrolysis leads to diprimary glycols, HO. (CH2) 2n+6-OH. (II) Dialkyl ethers of glycols are also prepared by subjecting alkoxyalkyl halides to a Wurtz reaction. This method is useful for the higher diprimary glycols (J. Hamonet, ibid., 19o3, I36, 96; 19o4, 138, 975): 2R0. (CH,).. I
Na
> [R0. (CHz)n] ,
> H 0 . (CH,)... O H
(12) 1,3-Glycols may be obtained from olefins by hydrolysis of 1,3-dioxan derivatives produced in the Prins reaction (see Houben-Weyl, "Methoden der org. Chemie", 1955, 4/2, 45)" /CHz~ CH~--CH CH2 CH$ 9CH: CH~ + 2CH20
H,SO4-->
[
I
--+ CH 3- C H O H . CH z. CHaOH
o o ~CH~ / (13) The hydroboronation of dienes can lead to diols. The reaction a t - - I O ~ of diborane with conjugated or unconjugated dienes gives organoboranes which are decomposed by alkaline hydrogen peroxide
8
GLYCOLS
12
affording diols; the method in effect involves "anti-Markownikoff" hydration of the carbon-carbon double bonds. Thus butane-I,4-diol is obtained from butax,3-diene, and hexalxe-I,6-diol from hexa-I,5-diene (H. C. Brown and G. Zweifel, J. Amer. chem. Soc., 1959, 8I, 5832; K. A. Saegebarth, ibid., 196o, 82, 2o81). Isomerization of the organoborane may occur on heating. (14) 1,2-Glycols are formed, a m o n g other products, when m o n o h y d r i c alcohols are exposed to ionizing radiations (E. Collinson a n d A. J. Swallow, Chem. Reviews, 1956, 56, 471). Ethylene glycol can be prepared by neutron-irradiation of a suspension of methanol and uranium dioxide (Hercules Powder Co., B.P., 77o,594/I955).
(if) Industrial manufacture and uses of the glycols The huge demand for glycols is met by four main methods (see G. Machell. Mfg. Chemist., I96O, 3 x, 2o, I i I). (I) The hydrolysis of epoxides and of halogenohydrins, obtained from olefins. (2) The fermentation of molasses (giving butane-2,3-diol). (3) The hydrogenation of sucrose and glucose (giving propane-I,2-diol). (4) The reduction of aldols and ketols. An efficient process for ethylene glycol, now little used, involves the reaction of water gas with formaldehyde at 20o o under 7oo at. pressure. The glycollic acid thus formed is esterified and the ester hydrogenated at 2oo o using a copper chromite catalyst. The glycols have a variety of uses. Ethylene glycol has major outlets in automobile "anti-freeze" solutions, in the manufacture of polyester fibres, resins, and elastomers, and in the industries based on cellulose. Propylene glycol, less toxic than ethylene glycol, is extensively used as a humectant in foodstuffs, in hydraulic fluids, and in the production of polyester and polyurethane resins. Many other important glycol derivatives are obtained from ethylene oxide (see p. 21). Di- and poly-ethylene glycols, their esters and ethers, are used as solvents, rubber lubricants, hydraulic fluids, and in the cosmetics and pharmaceuticals industries. The butanediols are declining in importance as sources of butadiene, but butane-I,4-diol provides a useful route to tetrahydrofuran and is also used as a cross-linking agent for polyurethane rubbers.
(iii) Biochemical significance of the glycols The most important natural sources of glycols are fermentation liquors in which they occur along with ethanol. Glycols arise by anaerobic transformations of pyruvic acid to acetoin or other acyloins, which are reduced enzymatically to diols. The action of Acetobacter aerogenes on sugars yields a mixture of mesoand (+)-butane-2,3-diols. Fermentation of starches by Bacillus polymyxa yields the (--)-isomer (G. E. Ward et al., J. Amer. chem. Soc., 1944, 66, 541; A. C. Neish, Canad. J. Research, 1945, 23B, io). By enzymatic reduction glycolaldehyde may be converted to ethylene glycol (C. Neuberg and E. Schwenk, Biochem. Z.,
I
ALKANEDIOLS
9
19x5, 7x, IX4). For the metabolism of ethylene glycol, see C. J. Cart and J . C. Krantz, Adv. carbohydrate Chem., 1945, x, I76; G. Reif, Pharmazie, 195 o, 5, 276-
(iv) General properties and reactions The lower paraffin glycols are thick, neutral, high boiling liquids, having a sweetish taste. They show extensive hydrogen bonding (see G. C. Pimental and A. L. McClellan, "The Hydrogen Bond", W. H. Freeman & Co., San Francisco and London, I96O), are easily soluble in water but only slightly soluble in ether. The higher homologues may be obtained as crystalline solids and are often appreciably soluble in ether. Diols form the normal functional derivatives like ethers and esters by the usual methods applied to monohydric alcohols. Some polyesters with dibasic acids are of great commercial importance, e.g. poly(ethylene glycol terephthalate). Diols readily form acetals and ketals with aldehydes and ketones, which with 1,2- (and sometimes 1,3- ) diols are cyclic and thus provide means of protecting carbonyl groups during reactions involving other functional groups in the molecule. With 1,2-diols and acetone cyclic isopropylidene ethers are obtained, which are readily reconverted into the original starting materials on hydrolysis" CHgOH
CH,--O. ~- OC(CH3) 2 ----~ [ )C(CH3) 2 CH9OH CH~--O" Glycol isopropylidene ether
I
Glycols also undergo the following more specific reactions. (I) Action of alkali metals. At ordinary temperatures sodium forms with ethylene glycol a mono-sodium glycoxide from which the di-sodium salt can be obtained by heating with sodium at z 9o~ Solutions of sodium, potassium, and lithium in liquid ammonia give mono-metallic salts (E. Chablay, Compt. rend., I912, I54, I5o7). The di-metallic salts of pinacols may be obtained by treating ketones with alkali metals in ether or liquid ammonia (W. E. Bawl,mann, J. Amer. chem. Soc., I933, 55, II79; C. B. Wooster, ibid., I934, 56, 2436). (2) Action of dehydrating agents. Dehydration, with acid catalysts or by heating, of each class of glycol is summarized below. 1,2-Glycols. Ethylene glycol gives acetaldehyde" CH,OH. CH,OH -----> CHsCHO
Other 1,2-glycols give mixtures of carbonyl compounds" CHROH. CHR'OH
~ RCOCH~R' ~- CHgRCOR'
IO
GLYCOLS
12
(L. Bouveault and R. Locquin, Bull. Soc. chim. Fr., 19o6, [iii], 35, 643, 646). Tertiary 1,2-glycols undergo the pinacol-~inacolone rearrangement. The dehydration of pinacol, obtained by reduction of acetone, to tert-butyl methyl ketone by dilute acid was first observed by R. Fittig in 1859. The mechanism of the rearrangement has been extensively investigated, and involves formation of a carbonium ion from the conjugate acid as the rate-determining step, followed by migration of an alkyl group: (CHs)sC----C(CHs)s ,.
i
I
OH OH
(CHs)sC----C(CHs)s
I
I
*0H s OH
- - + (CHs)tG--C(OH) (CHs)s ---+ (CHs)sC--C(OH) .CHs # (CHs)sC.CO. CHs A number of closely related rearrangements are known; all proceed by similar mechanisms (see C. K. Ingold, "Structure and Mechanism in Organic Chemistry', Bell, London, 1953).
1,3-Gtycols. Butane-I,3-diol is dehydrated to butadiene at 200-24 ~ over a phosphate catalyst. With a zinc oxide catalyst at 4000 a mixture of methyl vinyl ketone and crotonaldehyde is obtained (E. Arundale and H. O. Mottern, U.S.P., 2,62o,357/1952). Saturated carbonyl compounds are also obtained (F. X. Schmalzhofer, Monatsh., 19oo, 21, 680" T. Hackhofer, ibid., 19Ol, 22, 95):
CHROH. CHR'. CHsOH ---+ CHsR. CHR'. CHO In 2,2-dialkyl-I,3-diols rearrangements similar to the pinacolic change m a y be observed, or oxide rings m a y be formed (M. A. Perry and R. E. de Busk, U.S.]~., 2,87o,214/1959): (CHs)sCH. CHOH. C(CH3)s. CHsOH i
l
(CHs)sCH. CHs. C(CHs)s. CHO + (CHs)sC.CH,. C(CHs)s. CH,O Rearrangements m a y also be observed in neopentyl systems (A. Fischer and
B. Winter, Monatsh., 19oo, 21, 3oi), thus: (CHs)sC(CHzOH)s ---+ (CHs)sC:CH. CHsOH ---+ (CH3)sCH. CHs. CHO Cleavage of ditertiary 1,3-glycols has been observed under acid conditions
(J. English and F. V. Brutcher, J. Amer. chem. Soc., 1952, 74, 4279), for example, 2,4-dimethylpentane-2,4-diol on treatment with sulphuric acid at room temperature forms acetone. 1,4-, 1,5-, z,6-etc. Glycols. The reactions of 1,4-diols have been investigated by T. A. Favorskaya and co-workers (J. gen. Chem. U.S.S.R.,
I
ALKANEDIOLS
II
1955, 25, 1459; 1956, 26, 447; 1957, 27, lO18). Tetrahydrofuran derivatives are formed through the intermediacy of unsaturated alcohols, which m a y themselves be isolated under favourable conditions. 2-Methylpentane-2,5-diol with dilute sulphuric acid yields a mixture of 2methylpent-2-en-5-ol and 2,2-dimethyltetrahydrofuran, whereas only the latter is obtained using a trace of acid as catalyst. Higher homologues, however, form derivatives of tetrahydrofuran and tetrahydropyran with 5o % sulphuric acid (A. Franke et al., Monatsh., 1929, 53-54, 577; Ber., 1932, 6o, lO6; 1936, 69, I67), but give alkenols on heating to 15o-3oo o with traces of acid (E. Ebel and H. Friederich, G.P., 8o3,354/I948). (3) Hydrogenation and dehydrogenation. Vigorous catalytic hydrogenation m a y result in carbon-carbon bond fission. Thus ethylene glycol gives ethanol or methanol, depending on the catalyst used (J. Mizuguchi and M. Ohashi, J. chem. Soc. Japan, Ind. Chem. Sec., I95O, 53, 93), and 2-methylpentane-2,4-diol gives isopropanol (H. Adkins et al., J. Amer. chem. Soc., 1932, 54, 4678, and later papers). Dehydrogenation of 1,4-diols has been studied extensively by W. Reppe (Ann., 1955, 596, 158). The most important products are ?-lactones, but diketones, ketols, and other compounds are also obtained. (4) Oxidation. Vigorous oxidation of diprimary glycols gives dibasic acids. Alkaline permanganate m a y cause carbon-carbon bond fission particularly in highly substituted glycols (Franke and M. Kohn, Monatsh., T9o7, 28, lO14). Cleavage of 1,2-diols to carbonyl compounds: CRR'(0H). C(0H)R'R" ---+ R R ' C 0 + R ' R " C 0
is conveniently brought about using lead tetra-acetate (R. Criegee et al., Ber., 1931, 64, 26o; I94 o, 73, 563; Ann., 1933, 5o7, I59), periodic acid (L. Malaprade, Bull. Soc. chim. Ft., 1928, [iv], 43, 683; Compt. rend., 1931, x86, 382), or sodium bismuthate (W. Rigby, J. chem. Soc., I95O, 19o7). Acyloins and x-dicarbonyl compounds are also cleaved by these reagents. Periodic acid is particularly valuable in quantitative analysis (see I. M. Koltho~ et al., "Volumetric Analysis", Vol. III, Interscience, New York, 1957, P. 475).
(a) 1,2-Glycols Ethylene glycol, ethane-I,2-diol, glycol, CH2OH.CHzOH, m.p. m I 3 ~ b.p. I97"2 ~ d~~ 1-1155, n~~ I "4316, is miscible with water and alcohol, and sparingly soluble in ether. It is best purified by distillation under reduced pressure (B. T. Brooks and I. Humphrey, Ind. Eng. Chem., 1917, 9, 75o). It is prepared industrially
GLYCOLS
12
12
from ethylene oxide and by other methods mentioned on p. 8 and in the laboratory by any of the relevant methods described on pp. 3-8. It dissolves inorganic compounds such as lq'aC1, ZnC1v K2CO 3, KOH and Ca(OH)~. Isopropylidene ether, b.p. 92-6~ ram.; bisphenylurethane, m.p. 157.5 ~ For physical constants of this and other common glycols, see G. O. Curme (Ed.), "Glycols", Reinhold, New York, 1952; (for patent literature, see H. Bahr and H. Zieler, Angew. Chem., I93 o, 43, 286; Ann. Report appl. Chem., 1932 and onwards; P. P. McClellan, Ind. Eng. Chem., I95 o, 42, 24o2). Oxidation. The stepwise oxidation of glycol may be represented as follows: CH~OH
[
CH~OH
~l
CHO
--+l
CHgOH Glycolaldehyde
C02H I
CHO
C09H
---~i
CHO CHO Glyoxal Glyoxylic acid
//
CO~H
---+J
C09H Oxalic acid
HCO~H
~ +
COs
CHz0H Glycoliic acid Under mild oxidizing conditions glycolaldehyde (see p. 45) is formed. Glyoxal may be obtained in good yield by vapour phase oxidation. Vigorous oxidation gives oxalic and formic acids and carbon dioxide. Biochemical oxidation leads to glycollic and oxalic acids (P. Mayer, Z. physiol. Chem., 19o 3, 38, 144; A. J. Brown, J. chem. Soc., 1887, 5 I, 638; A. Harden and D. Norris, Proc. roy. Soc., 1911, B84, 492; 1912, B85, 73)(+)-Propane-I,2-diol, propylene glycol, C H s . C H O H . C H z O H , b.p. 188.2 ~ d22o ~ I. o381, n~)~ i- 4326; bisphenylurethane, m.p. 152" 5-153" 5 ~ is miscible with water and sparingly soluble in ether. Its properties and methods of preparation are similar to those of ethylene glycol. It has been detected in fermentation liquors (A. J. Kluyver and C. Schellen, Enzymologia, 1937, 4, 7). Optical isomers. Both D- and L-forms, [x]~o + i5 o, are known. Resolution of the strychnine salt of the (+)-diol is possible (A. Gri~n, Bet., 1919, 52, 26o). L(+)-Propylene glycol is formed by the asymmetric reduction of acetol with yeast reductase (Org. Synth., Coll.Vol. II, I943, p. 545) and from D( +)-isopropylideneglycerol (E. Baer and H. O. L. Fischer, J. Amer. chem. Soc., 1948, 70, 6o9). Butans-I,2-diol, CzHs.CHOH. CHzOH , b.p. 191 ~ ( + )-Isomer, b.p. 91~ mm., [x]~2 + 12.40. (--)-isomer, b.p. 94~ ram., [x]~2 w 7 . 4 0 (P.A. Levene and H. L. Hallsr, J. biol. Chem., 1927, 74, 343). Butane-2,3-diol, C H s - C H O H . C H O H . C H 3 , is a product of the fermentation industry. (+)-Form, b.p. 177 ~ m.p. 7.6~ bisphenylurethane, m.p. 2Ol-2O2~ meso-]orm, b.p. 182 ~ m.p. 34.4 ~ bisphenylurethane, m.p. 175~ D(m)-buta~ce-
I
ALKANEDIOLS
13
2,3-diol, b.p. 178~ m.p. 18 ~ [x]~ --13.20 (H. J. Lucas and H. 14. Garner, J. Amer. chem. Soc., 1948, 7 O, 990)" L( + )-isomer, [x]~~ + 14"60 (J. B6esehen and R. Cohen, Rec. Tray. chim., 1928, 47, 839; cf. L. J. Rubin, H. A. Lardy and H. O. L. Fischer, J. Amer. chem. Soc., 1952, 74, 424) 9 When passed over a hot copper catalyst, butane-2,3-diol is dehydrogenated to 3-hydroxybutan-2-one, or, if oxygen is present, to diacetyl. 2-Methylpropane-I,2-diol, b.p. I97 ~ can be obtained from isobutene by hydroxylation or by hydrolysis of isobutylene oxide. Pentane-I,2-diol, b.p. 2o9 ~ is formed in the hydrogenation of furfuryl alcohol. Pentane-2,3-diol, b.p. 187 ~ 3-Methylbutane-I,2-diol, b.p. lO3~ mm. 2-Methylbutane-I,2-diol, b.p. 188 ~ 2-Methylbutane-2,B-diol, b.p. 178~ Pinacol, 2,3-dimethylbutane-2,3-diol, tetramahylethylene glycol, (CH3),C(OH) 9 C(OH)(CH3),, m.p. 4 I~ b.p. I72-8 ~ hexai~ydrate, m.p. 46-47 ~ (Org. Synth. Coll. Vol. I, 1941, p. 459). tert-Butyl methyl ketone is the chief product under many conditions of dehydration (see p. IO) but with hydrobromic acid or by passing pinacol vapour over alumina, 2,3-dimethylbuta-I,3-diene can be obtained.
(b) 1,3-Clycols Propane-l,3-diol, trimethylene, glycol, C H , O H . C H , . C H , O H , b.p. 2 I O - - 2 I I 0, "O554 " bisphenylurethane, m.p. 137.5 ~ is produced in the fermentation of glycerol (A. J. Rayner, J. Soc. Chem. Ind., I926, 45, 265, 287; C. H. Werkman et al., J. Bact., 1932, 23, I67; I94 o, 39, 7o9) 9 I t can also be obtained from acrolein by hydration followed by hydrogenation (L. F. Hatch and T. W. Evans, U.S.P., 2,434,IIO/I948 ) and is present in the products of the vigorous catalytic reduction of sucrose (T. Tanno, Bull. chem. Soc. Japan, I936, xz, 204). Butane-I,3-diol, CH 3 .CHOH .CH,. CH2OH, b.p. 2o7.5 ~ d~~ 1.oo59, is prepared by the reduction of aldol. Enzymatic reduction of acetoacetaldehyde or of I-hydroxybutan-3-one yields the (m)-isomer, [a]~5 - - 1 8 . 8 ~ (P. A. Levene and A. Walti, J. biol. Chem., 1931, 94, 361). The (+)-isomer, [~]~* 7.5 ~ has been obtained by reduction of D-methyl 3-hydroxybutyrate and by deamination of D-I-aminobutan-3-ol (Levene and H. L. Haller, ibid., 1926, 69, 165, 569). Pentane-2,4-diol, C H 3 . C H O H . C H , . C H O H . C H 3, b.p. I99 ~ m.p. 45 ~ is prepared by reduction of acetylacetone (H. Adkins et al., J. Amer. chem. Soc., I934, 56, 2669; 1939, 61, 33o3), or of the corresponding ketol (J. E. Dubois, Compt. rend., 1947, z24, 1234). Dehydration affords piperylene. 2-Mahylbutane2,4-diol, b.p. 2o3 ~ yields isoprene on dehydration. 2-Methylpentane-2,4-diol, hexylene glycol, b.p. 197.1 ~ d**o ~ o'9234, is manufactured by the hydrogenation of diacetone alcohol. Dehydration gives 2-methylpenta-I,3-diene together with some 4-methylpenta-I,3-diene (L. P. Kyriakides, J. Amer. chem. Soc., 1914, 36, 980; G. B. Bachman and C. G. Goebel, ibid., 1942, 64, 787). I t reacts specifically with aldehydes at pH 3 to give derivatives of 1,3-dioxan ill high yields (F. R. Fischer and C. W. Smith, J. org. Chem., 1963, z8, 594). 2,4-Dimethylpentane-2,4-diol, (CHs),C(OH) .CH,.C(OH)(CHs) ,, b.p. 98~
d~ ~ I
14
GLYCOLS
12
13 mm., is prepared by the action of methylmagnesium halides on diacetone alcohol; it loses water on distillation at ordinary pressure to give 2,4-dimethylpentI-en-4-ol, b.p. I28~ ram. 2,3,3,4-Tetramethylpentane-2,4-diol, (CHb)~C(OH) -C(CHb) 2"C(CHb)~OH, b.p. 2340/76o mm., m.p. 76 ~ is prepared by the reaction of methylmagnesium iodide and dimethylmalonic ester. 2-Ethylhexane-I,3-diol, CH 8 -CH 2 .CHi .CHOH. CH(C,Hs). CH ~OH, b.p. 244.2~ mm., d=2o ~ 0"9422, is manufactured by the reduction of butyraldol. It is one of the most effective insect repellents known.
2,2-Dimethylpropane-I,3-diol,
2,2-dimethyltrimethylene
glycol, pentaglycol,
(CHs) ,C(CH ~OH) ~, m.p. 129 ~ b.p. 2o6 ~ This and its homologues, RR'C(CH2OH ) 2, are prepared by reduction of the appropriate aldol or substituted malonic ester (H. L. Yale et al., ibid., 195o, 72, 3716). 2-Methyl-2-propylpropane-I,3-diol, m.p. 62-63 ~ is the parent of the important tranquilizing drug "Meprobamate". 2,2-Dimethylbutane-I,3-diol, CHzOH'C(CHs)~.CHOH.CH 8, m.p. IO~ b.p. 2o70/760 mm. 2,2-Dimethylpentane-I,3-diol, CH2OH'C(CHs) z'CHOH'C2Hs, m.p. 6o-63 ~ b.p. 213~ mm. 2,2,4-Trimethylpentane-I,3-diol , m.p. 52~ b.p. 223o/76o ram.
(c) 1,4-Glycols Butane-I,4-diol, tetramethylene glycol, HO(CH2)4OH, m.p. 16 ~ b.p. 23o0/ 76o mm., d~~ 1-020; bisphenylurethane, m.p. I8O ~ is prepared by the hydrogenation of but-2-yne-I,4-diol (Reppe et al., Ann., 1955, 596, 38). Dehydration may be controlled to give either butadiene or tetrahydrofuran, while dehydrogenation gives ~-butyrolactone (Reppe et al., ibid., p. 8o, 158 ). Pyrrolidine is formed by passing the diol and ammonia over alumina at 40o~ with hydrogen sulphide under similar conditions, tetrahydrothiophen is obtained (Y. K. Yur'ev and N. G. Medovshchikov, J. gen. Chem. U.S.S.R., 1939, 9, 628). A series of 2-alkylbutane-I,4-diols have been prepared by reducing diethyl 2-alkylsuccinates with lithium aluminium hydride (C. G. Overberger and C. W. Roberts, J. Amer. chem. Soc., 1949, 7I, 3618). Pentane-I,4-diol, CHb'CHOH'(CH~)3.OH, b.p. I23-I26~ ram., 2220/76o mm., with partial dehydration to the oxide (see R. M. Hill and H. Adkins, ibid., 1938, 6o, lO33 ). An optically active form is known (P. A. Levene et al., J. biol. Chem., 1927, 72, 591). 2-Methylpentane-2,5-diol, (CHb)zC(OH).(CH2)s.OH , b.p. IO7~ ram., 2220/ 76o mm. (L. Henry, Compt. rend., 19o6, x43, 1221; A. Franke and M. Kokn, Monatsh., I9O7, 28, IOO6). 3-Methylpentane-2,5-diol, CHs'CHOH-CH(CHb).CH2.CH~OH, b.p. I34~/ 2o mm. (C. D. Nenitzescu, Bet., 1937, 70, 277). Hexane-I,4-diol, b.p. i280/i3 mm. (C. Glacet, Compt. rend., 1944, 2z8, 283). Hexane-2,5-diol, b.p. 22o-8~ ram.; a solid form, m.p. 43 ~ is also known (G. Dupont, Ann. Chim., 1913, 30, 526; Y. S. Zal'kindandA. I. Nogaideli, J. gen. Chem., U.S.S.R., 1938, 8, 1816).
2
UNSATURATED
GLYCOLS
15
(d) 1,5-Glycols Pentane-x,5-diol, pentamethylene glycol, b.p. 239.40/760 mm., d22o ~ 0"994" bisphe~cylurethane,, m.p. I74 ~ is obtained by hydrogenation of 2-hydroxytetrahydrolyyran or of tetrahydrofurfuryl alcohol at high temperature and pressure (Org. Synth., 1946, 26, 83). Hexane-I,5-diol, b.p. 14o-141~ mm., may be prepared by reduction of x-hydroxyhexan-5-one, or of ethyl 5-oxohexanoate (R. M. Hill and H. Adkins, J. Amer. chem. Soc., 1938, 69, lO33). (e) 1,6-, 1,7-, 1,8-Glycols, etc. The higher diprimary glycols may be obtained by reduction of the dicarboxylic acids or their esters (Org. Synth., Coll. Vol. II, p. I54" R. F. Nystrom and W. G. Brown, J. Amer. chem. Soc., 1947, 69, 2548). Hexane-I,6-diol is also prepared by reduction of hexa-2,4-diyne-I,6-diol (Reppe et al., Ann., 1955, 596, 38). Certain of the higher glycols, in particular hexane-I,6-diol, decane-I,Io-diol, and octadecane-I, I2-diol (prepared from ricinoleic acid or castor oil, W. A. Lazier, U.S.P., 2,o94,6II/I937), are of some technical interest. The physical constants of some higher diprimary glycols are listed below. Hexane-I,6-diol, m.p. 42. 80, b.p. 243~ mm. Heptane-I,7-diol, m.p. 20.2 ~ b.p. 151~ mm. Octane-I,8diol, m.p. 62 ~ b.p. 154-156~ mm. Nonane-I,9-diot, m.p. 43 ~ b.p. I73~ mm. Decane-I,Io-diol, m.p. 72~ b.p. I79~ mm. Undecane-I,Ii-diol, m.p. 63 ~ Dodecane-I,I2-diol, m.p. 81 ~ Tridecane-I,I3-diol , m.p. 75-77 ~ Tetradecane-i,i 4diol, m.p. 85 ~ Octadecane-I,I8-diol, m.p. 97-98~
2. Unsaturated glycols (a) Olefinic glycols The simplest representatives, e.g. ethene-I,2-diol, H O C H : C H O H , are, like vinyl alcohol, not stable substances although derivatives such as esters and ethers are known. Preparation" Ethylenic diols are conveniently obtained from: (I) dienes by methods similar to those given on pp. 4 and 7. (2) acetylenic diols by partial hydrogenation (A. W. Johnson, "The Acetylenic Alcohols", Arnold & Co., London, 1946; cf. Re~bpe et al., loc. cit., p. 38) ; (3) unsaturated carbonyl compounds by bimolecular reduction or by reaction with the Grignard reagents from dihalogen compounds. Properties and reactions. The physical properties of olefinic glycols are similar to those of the analogous paraffinic glycols, and their chemical properties combine those of glycols and olefins. Thus they form crystalline dibromides which are converted to mono- and di-epoxides by the action
16
GLYCOLS
12
of potassium hydroxide. On hydrogenation they form saturated glycols and on hydroxylation saturated tetraols. Butene-3,4-diol, e~,ythrol, CH~:CH.CHOH-CH~OH, b.p. 196.5 ~ 91-92~ 12 mm., d 2~ 1-o47o3, **~o 1.4614 (C. Prdvost, Axln. Chim., 1928, 1o, 113, 356" A. Valette, ibid., 1948, 3, 644); bisphenylurethane, m.p. 125-126~ dibromide, m.p. 88-89 ~ But-2-ene-I,4-diol, CH,(OH).CH:CH.CHzOH. The cis-isomer b.p. I34-I35~ 15 mm., n~5 1.4716, is formed by hydrogenation of but-2-yne-I,4-diol (,4. W. Johnson, J. chem. Soc., 1946, lO14); dibenzoate, m.p. 69-70~ bis(3,5-dinitrobenzoate), m.p. 171-172~ The trans-isomer produced by the action of caustic soda on 1,4-dichloro- or 1,4-dibromo-but-2-ene , has m.p. 25.5~ b.p. i3i-5~ 12 mm." d~~ 1-o698" n~~ 1.4772; dibenzoate, m.p. IOI ~ (Prdvost, Compt. rend., 1926, I83, 1291; Valette, loc. cir.).
(b) Diolefinic glycols Hexa-I,5-diene-3,4-diol, CHz:CH.CHOH-CHOH.CH:CH~, b.p. 197-198~ 97~ mm., d~s 1.oo7, prepared by bimolecular reduction of acrolein, exists in meso-, m.p. 18 o and racemic-, m.p. 14 ~ forms (J. Wiemann, Ann. (;him., 1936, 5, 287; W. G. Young et al., J. Amer. chem. Soc., 1943, 65, 1245). The diols can be purified via the tetmbromides, m.p. 1740 and m.p. 90 ~ The (+)-isomer (3R, 4R) [x]~7 +82.60, is formed by treating the tetra-toluene-p-sulphonyl derivative of D-mannitol with sodium iodide ill acetone (P. Karrer and P. C. Davis, Helv., 1948, 31, 1611; R. Criegee et al., Ann., 1956, 599, 81). Dehydration by boiling with dilute sulphuric acid gives vinylcrotonaldehyde (M. Ti~eneau and P. Weill, Compt. rend., 1937, 2o4, 590).
(c) Acetylenic glycols The most important members of this class are the acetylenic-I,4-glycols , R R ' C ( O H ) . C i C . C ( O H ) R R ' , which are readily prepared by the reaction of acetylene and two equivalents of a carbonyl compound (Reppe et al., Ann., 1955, 596, I; see also A. W. Johnson, op. cir.; R. A. Raphael, "Acetylenic compounds in Organic Synthesis", Butterworths, London, 1955). Unsymmetrically substituted analogues m a y be obtained by reaction of ethynyl carbinols with carbonyl compounds. But-2-yne-I,4-diol CHeOH.CZC.CH2OH, m.p. 64 ~ b.p. I45~ ram., is prepared by the reaction of acetylene and formaldehyde in the presence of a copper acetylide catalyst containing bismuth to inhibit the formation of cuprene (Reppe et al., loc. dr.). It was prepared on a very large scale in Germany during the 1939-1945 war for conversion to buta-I,3-diene and synthetic rubbers. Its reactions have been discussed by A. W. Johnson (J. chem. Soc., 1946, lOO9
2
UNSATURATED GLYCOLS
17
lO14). It forms normal esters and ethers. On hydrogenation it yields successively but-2-ene-I,4-diol (p. 16) and butane-I,4-diol (p. 14). With bromine 2,3-dibromobut-2-ene-I,4-diol, m.p. 116-1170, is formed. With thionyl chloride and pyridine 1,4-dichlorobut-2-yne, b.p. 68-69~ mm., is obtained, which on treatment with IO% aqueous caustic soda gives diacetylene (Vol. IA, p. 467). Hex-3-yne-2,5-diol, CHs-CHOH.CiC.CHOH.CH s, exists in two forms, one of which has m.p. 7o~ The mixture has b.p. 122~ mm., n~3 I "4733, d~3 I-o23. 2,5-Dimethylhex-3-yne-2,5-diol, (CH3)2C(OH).CiC.C(OH)(CH3) 2, m.p. 95 ~ b.p. 2o5-2o6, is obtained from acetone and acetylene, via the dimagnesium derivative, or in the presence of caustic potash (e.g.C. Weizmann, B.P., 573,527/1941, 58o,921-2/I941). Dehydration gives dimethyldivinylacetylene, [CH,: C(CH 3) i C] 3; this reaction is typical of ditertiary acetylenic glycols. Hydrogenation yields successively either the ethylenic and saturated glycols, or tetramethyl-di- and -tetra-hydrofurans. Hydration in acid solution in the presence of mercuric salts gives a cyclic product:
C--C(0H) (CI-I,), C---C(OH) (CHs),
Hi0
CHa-C(CH,), CO--C(CH,)z
The diols are readily converted to the dihalides which undergo rearrangement to diene dihalides (W. Krestinsky, Ber., I926 , 59, 193 O) e.g.: (CH,) ~CBr. C i C. CBr(CH,) t
~ (CH,),C: CBr. CBr: C(CH,) ~
(d) Glycols of greater unsaturation A number of more complex acetylenic glycols occur in nature, e. g. octa2,6-dien-4-yne-I,8-diol, HOCH2CH" CH. C ! C- C H ' C H . CH~OH, trans-nona2-ene-4,6-diyne-I,9-diol, HOCH,. C H ' C H . (C" C)z" CH2" CH2OH, and deca-8ene-2,4,6-triyne-I,IO-diol, HOCH~-(CiC)a.CH:CH-CH~OH, are mould metabolites, and heptadeca-2,8,Io-triene-4,6-diyne-I,I4-diol , HOCH~. CH: CH(C i C) ~" (CH: CH) 3" (CHz) ~. CHOH. CHz" CH,. CH3, and octadeca-8,IO,I2triene-4,6-diyne-I,I5-diol, HO(CH2)3-(CiC),. (CH:CH)s.CH~-CHOH.CH~. CH2" CHs, are responsible for the toxicity of Umbelliferae (see E. R. H. Jones, Proc. chem. Soc., 196o, 199; R. C. Cambie et al., J. chem. Soc., 1963, 412o). Hexa-2,4-diyne-I,6-diol, CH2OH-(CiC),.CH,OH, m.p. I i i - I I 2 ~ is obtained by the oxidation of propargyl alcohol in the presence of cuprous chloride and ammonium chloride (Reppe et al., Ann., 1955, 596, 38). Hydrogenation gives hexane-I,6-diol. Octa-3,5-diyne-2,7-diol, CH3.CHOH. (C iC) ,-CHOH .CH v is similarly obtained from but-3-yn-2-ol. It occurs in meso- and DL-/orms, m.p. 67" 5-680 and lO8-1o9 ~ respectively. Hydrogenation gives octane-2,7-diol. A number of more complex unsaturated glycols are involved as intermediates in syntheses of members of the carotenoid group and will be discussed in Vol. II.
18
GLYCOLS
12
3. Derivatives of glycols
(a) O-Alkyl derivatives; alkoxyalkanols and bisalkoxyalkanes (i) Preparation The mono-alkyl ethers of the glycols i.e. the alkoxyalkanols, are prepared as follows. (I) By reacting a monometallic glycoxide with an alkylating agent: HOCH3. CH2ONa + C,HsI ~
NaI + HOCH2. CH2OCzH6
or from a halogenohydrin (or its ester) and an alkoxide. (2) By the action of alcohols or alkoxides on epoxides, frequently under increased pressure and temperature in the presence of a catalyst"
CHI. CHz + CzHsOH~ ~O j
HOCH~.CHzOC,H5
(L. H. Cretcher and W. H. Pittenger, J. Amer. chem. Soc., 1924, 46, 15o3; C. O. Young, U.S.P., 1,696,874/1928 ). The catalysts used include: nickel sulphate (W. Gibson and J. B. Payman, U.S.P., 1,774,o89/I93O), hydrosilicates (I.G., G.P., 558,6461193o), boron trifluoride (A. A. Parov, J. gen. Chem. U.S.S.R., 194o, IO, 98I), mineral acids (S. S. Al'tman and V. V. Kedrinskii, C.A., 1937, 3x, 6196; D. Swern, G. N. Billen and H. B. Knight, J. Amer. chem. Soc., 1949, 71, 1152" S. Searles and C. F. Butler, ibid., 1954, 76, 56), bases (H. M. Stanley and J. E. Youdl, B.P., 467,228/I935; Swern, Billen and Knight, loc. cir.). (3) By reduction of esters of the type ROCH,- CH,. CO~R' with sodium and alcohol. (4) From the reaction of alkoxy-derivatives of aldehydes, ketones, or esters with Grignard reagents. (5) By addition of a glycol to an olefin in the presence of sulphuric acid, e.g. ethylene glycol with isobutene forms mono- and di-tert-butyl ethers (T. W. Evans and K. R. Edlund, Ind. Eng. Chem., 1936, 28, 1186). The dialkyl ethers of the glycols i.e. bisalkoxyalkanes, are prepared as follows. (I) By the action of alkoxides on dihalogenoalkanes or on monohalogenoalkyl ethers. (2) From halogenoalkyl ethers by a Wurtz reaction or through a Grignard derivative (R. Dionneau, Ann. Chim., 1915, 3, 194; Compt. rend., 19o7, I45, 127; Bull. Soc. chim. Fr., 191o, [iv], 7, 327):
C~HsO(CH2)eMgI + ICH~OC2Hs----~CgHsO(CH2)~OC2H5
3
DERIVATIVES
19
(3) By alkylation of glycol monoalkyl ethers, e.g. with dialkyl sulphates.
(ii) Properties Glycol monoethers (alkoxyalkanols) undergo the normal reactions of monohydric alcohols, e.g. esterification, oxidation, dehydrogenation, dehydration, etc. They are typical ethers in forming peroxides on standing with air. Monoethers of 1,2-glycols in which the hydroxyl group is tertiary, on dehydration give aldehydes and ketones" R'R'C(OH). C H ( 0 R ) R "
~ R'R'CHCOR"
Diethers are relatively inert substances. Hydrobromic acid in the cold converts them to the bromides of glycol monoethers, (a, co-alkoxybromoalkanes) RO(CH,)nBr (J. Hamonet, Chem. Ztbl., 19o 4, I, 14oo). Raney nickel and hydrogen at 15o-2oo at. produces the glycol monoethers" thus ethylene glycol benzyl ethyl ether gives toluene, methylcyclohexane, and ethylene glycol monoethyl ether. The latter and the monomethyl ether are stable to hydrogen and Raney nickel at 200 o (E. M. Van Duzee and H. Adkins, J. Amer. chem. Soc., I935, 57, 147)-
Glycol monoethyl ether, 2-ethoxyethanol, Cellosolve, b.p. 135" I~ ram., d22~ o'9311, n~~ 1.4o76, is manufactured by the action of ethanol on ethylene oxide under pressure (see above). It is a colourless, almost odourless, mobile liquid, completely miscible with water and with many organic solvents. It is widely used as a solvent, e.g. for cellulose nitrate and acetate, resins, lacquers and enamels, leather dyestuffs and printing inks, and has a variety of other uses. Glycol monomethyl ether, Methylcellosolve, b.p. I24-5~ mm., d~o~ 0"9663, n~~ 1.4o21" monoisopropyl ether, b.p. I44 ~ dX~ o'9139, n~6 1"4o8o; monobutyl ether, b.p. I71.2 ~ d~ o-9o19, n~~ 1.4193. For urethane derivatives of the eellosolves see J. F. Manning and J. P. Mason, ibid., I94 o, 62, 3136. Ethylene glycol dimethyl ether, 1,2-dimethoxyethane, b.p. 85.2 ~ d~~ o.8692" diethyl ether, b.p. I2I-4~ d~O o.8417, n~~ 1.3922- dibutyl ether, b.p. 2o3.3~ d~~ o'8374, n~)~ 1.4131 (B. O. Field and C. J. Hardy, Chem. and Ind., 1962, 212). Ethylene glycol bis-2-chloroethyl ether, C1. (CH,) 2" O. (CH2) 0. O. (CH2) ~.C1, b.p. 23 o~ d~~ 1"197 (G. F. Zellhoeffer, Ind. Eng. Chem., 1937, 29, 548). The ethylene glycol diethers are useful as inert reaction media, e.g. in reactions involving lithium aluminium hydride. Ethers of higher glycols are useful industrial solvents, e.g. the monobutyl ether of butane-I,4-diol, 4-butoxybutan-i-ol, is a solvent for polyvinyl chloride.
(b) 1,2-Cyclic ethers. Alkylene oxides. Epoxides The cyclic ethers of 1,2-glycols, i.e. ethylene oxide and its homologues, are discussed here; for trimethylene oxide, dioxan, etc., see Vol. IV.
20
GLYCOLS
12
(i) Preparation The ethylene oxide (oxirane) ring is formed by the following methods. (I) By the action of alkali or a base on a halogenohydrin or the derived halogeno-ester, or on a glycol monotoluene-p-sulphonate. The method, first employed by A. Wurtz (Ann., 1859, 1io, I25), is still used in the manufacture of ethylene oxide and especially of propylene oxide: HOCH 2. CHIC1
Ca(0H)t
-+ C H 2 - - C H ~ + CaCI 2 + H 2 0
(2) The direct oxidation of olefins can give epoxides. In the presence of a silver catalyst at 25o-3000 ethylene vapour reacts with air to give ethylene oxide, together with carbon dioxide and water, the products of further oxidation. The process was discovered by T. E. Le]ort (F.P., 729,952] 1931 ) and is presently the basis of the most important industrial method for ethylene oxide. :Numerous descriptions of the analogous oxidation of propylene exist in the patent literature, but propylene oxide is not currently prepared by such a method. (3) Per-acids react with olefins to give epoxides directly:
I I --C=C--+
I RCOsH
->--C
; C---+ R C O ~ H
Perbenzoic, monoperphthalic, and peracetic acids (D. Swern, Org. Reactions, 1953, 7, 378; J. A. John and P. ]. Weymouth, Chem. and Ind., 1962, 62) have been employed. Peroxytrifluoroacetic acid in the presence of sodium carbonate is especially useful for the epoxidation of carbon-carbon double bonds deactivated by electron-withdrawing substituents such as C--O, C~-I~ (W. D. Emmons and A. S. Pagano, J. Amer. chem. Soc., 1955, 77, 89). In sufficiently acid conditions the oxide ring may be opened to give the glycol monoester. (4) The action of diazomethane on an aldehyde or ketone may give an epoxide (see B. Eistert, "Newer methods of Preparative Organic Chemistry", Interscience, 1948, pp. 521,527): RCOR"
+ CHgN 2
-> R R ' C
CH 2
(5) The Hofmann degration of alkylcholines produces epoxy compounds
(E. SJ)~th et al., Ber., 1933, 66, 591; 1941, 74, 599; C. E. Wilson and H. W. Lucas, J. Amer. chem. Soc., 1936, 58, 2396):
3
DERIVATIVES [CH s. (CH~) 5 9C H O H .
C H i N (CHa)a]eOH | ~
21 C H a. (CH~)5. C H - - C H
s
(ii) Properties and reactions Isomerization. In the vapour phase or in solution in the presence of mineral or Lewis acids, epoxides isomerize to aldehydes or ketones (V. Ipatiev and K. Leontovitsch, Ber., 19o 3, 36, 2o16; R. Lagrave, Ann. Chim., 1927, 8, 363; G. H. Twigg, Trans. F a r a d a y Soc., 1946, 42, 284, 657; E. L. Eliel and D. W. Delmonte, J. Amer. chem. Soc., 1958, 8o, 1744): RzC----CR i ~
RCO.
CR3
"~o/
Addition reactions. Alkylene oxides undergo ring-opening reactions with a wide variety of substances. Asymmetric oxides can form two products" R- C H ~ C H
2 + HA
> R.
CHOH. CHIA +
R. CH(A)-
CH2OH
~OJ Under basic or neutral conditions and when R is an electron-donating group, e.g. alkyl, the main product is that formed by attack at the least substituted carbon atom, namely R-CHOH.CHtA. Under acid conditions mixtures are likely to be produced: R.CH CHI ~OHeJ
slow
* Ae > R. CHCH2OH fast > R-CH(A).CHIOH
R. CHOH. CHI*
A|
fast
"-> R. CHOH. CHIA
There is evidence that A e attacks before the CmO bond is completely broken; thus cis-2,3-epoxybutane on acid hydrolysis gives the DL-glyco1, whereas the trans-isomer forms the meso-glycol (see p. 23). For a discussion of the mechanism of epoxide reactions, see R. E. Parker and N. S. Isaacs, Chem. Reviews, 1959, 59, 737. (I) With water epoxides give glycols or polyglycols (see pp. 3, 4, 28). (2) Alcohols and phenols give hydroxyethers; thiols react similarly to give hydroxy-thioethers. (3) Hydrogen halides and certain metallic halides, e.g. magnesium chloride, form halogenohydr ins. (4) Ammonia gives mono-, di-, and tri-alkanolamines; primary and secondary amines react similarly. (5) Hydrogen cyanide and metallic cyanides yield cyanohydrins. Thus
22
GLYCOLS
12
ethylene oxide gives 2-hydroxyacetonitrile which is readily dehydrated to give acrylonitrile. (6) Carboxylic acids and anhydrides react to give glycol mono- and diesters, respectively; thioacids react similarly. (7) With aldehydes and ketones, cyclic acetals and ketals (i.e. 1,3-dioxolane derivatives) may be isolated. Polymeric products are also formed. (8) Grignard reagents give alcohols: R C H ~ C H 2 + R'MgX
~ RCHOH-CHgR'
Two equivalents of the oxide must be employed to avoid formation of the halogenohydrin, R C H O H . C H , X ; the latter is always the main product when tert-alkylmagnesium halides are employed (N. G. Gaylord and E. I. Becker, ibid., 1951, 49, 413) 9 (9) Sodio-derivatives of malonic ester and acetoacetic ester react normally to give 2-hydroxyalkyl derivatives which may be converted to lactones. (IO) Sodium acetylides give acetylenic alcohols. (II) Sodium bisulphite forms hydroxy-sulphonic acids, RCHOH. CH,S03 H. (12) Thiourea and a variety of other thioamides react with epoxides to produce alkylene sulphides (cf. Rodd, C.C.C., Ist Edn., 1957, Vol. IVa, p. ~2). The products of many of these additions reactions are themselves capable of reacting with epoxides, thus polymeric materials may also be obtained in amounts depending on the reaction conditions employed. Reduction. Hydrogenation with nickel or platinum catalysts leads to an alcohol with the hydroxyl group attached to the least substituted carbon atom. The isomeric product is obtained by the use of lithium aluminium hydride. Olefins are obtained by heating epoxides with triethyl phosphite at 15o-1750 (C. B. Scott, J. org. Chem., 1957, 22, 1118).
Ethylene oxide, 1,2-epoxyethane, oxirane, CH,PCH 2, b.p. IO.7~
mm., crit.
temp. 195" 8~ d22~o'8711 (for physical constants, see G. O. Curme and F. Johnston, "Glycols", i~ew York, 1952, p. 88), is manufactured by the direct oxidation of ethylene, and also from ethylene chlorohydrin (R. P. Van Oosten, J. Inst. Petroleum, 196o, 46, 347)- It is miscible with water, alcohol, and ether, and forms a hexahydrate, m.p. 12 ~ It gives a positive iodoform reaction and precipitates silver from Tollen's reagent. Ethylene oxide is manufactured on a very large scale, for conversion into ethylene glycol and its ethers, non-ionic detergents, ethanolamines, polyethylene glycols and ethers, and acrylic polymers. It is also employed as a fumigant, being capable of destroying insects, moulds and bacteria. Structure. The bond lengths and angles in ethylene oxide have been computed
3
DERIVATIVES
23
from the microwave s p e c t r u m and confirmed b y electron diffraction (G. L.
Cunningham et al., J. chem. Phys., 1949, x7, 211; I95I, x9, 676; T. E. Turner and J. A. Howe, ibid., I956, 24, 924; M. Igarashi, Bull. chem. Soc. Japan, 1953, 26, 330). The r e p r e s e n t a t i o n of ethylene oxide as a ~-complex (A. D. Walsh, Nature, I947, x59, 165, 712" Trans. F a r a d a y Soc., 1949, 45, 179)" C H , ~ C H s , O has some advantages in explaining its properties (see Parker and Isaacs, loc. cir.) Propylene oxide, 1,2-epoxypropane, C H 3 . C H - - C H t, DL-/Orf~, b.p. 33"9~ 76o mm., d~~ o.83o 4, n~~ 1-3657" L(+)-/orm, [x]~x +150 (C. C. Price and M. Osgan, J. Amer. chem. Soc., 1956, 78, 4787) . D(--)-/orm, [~]~8 __8.260 (E. Abderhalden and E. Eichwald, Ber., 1918, 5z, 1312). Propylene oxide, manufactured from propylene chlorhydrin, is converted mainly to propane-I,2-diol and propanolamines. I t is also useful as a low boiling solvent and as a fumigant. 2,3-Epoxybutane, C H s ' C H ' C H - C H s, trans-(DL)-isomer, b.p. 53.5~ mm., -,O / d~5 o . 8 o l o , n~5 1.37o5 . D( + )-isomer, b.p. 53-5-53.7~ ram., [~]~5 + 5 9 . o 5 0 . cis-(meso)-isomer, b.p. 59.7~ ram., d~5 0.8226, n~s 1.38o2 (F. H. Dickey, et al., J. Amer. chem. Soc., 1952, 74, 944). The stereochemical relationships between the but-2-enes and their diols, chlorohydrins, and oxides are indicated in the schemes given below (cf. Dickey et al., loc. cir., and references therein): CH a
CH a
H 0 - - --H
Ac0-- --H
H
CH a
I ActO
pyridine
H-- ~ 0 H
HC1
HO---
H-- --0Ac
C1--- H
D(+)-
Ac0-- - - H
Act0
HCI o
Meso-
I H--C II H--C
HO-- --H
CH~
CH s
CI-Is
Cis-
CH 3
KOH O _+
-I'b
H__ --C1
Threo-
0___>.
CHs
CH s
H-- - - O H
H,O ~ 0
-.>.
H0-- --H
I
Cis-
CH s
D L-Threo-
CH 3 HOC1
D( +)-Trans
H-- --C1
CH s
CH s
CH s
I
CH a
HO-- --H
Ac0-- ~ H
Meso-
H--I/
CH s
pyridine H0-- --H
HC1
L( +)-ErythroCH s
CH s
<-'-O
CH a
CH s
CH s
H0-- --H
KOH0_> CHs--]%]
O
>
D(--)-
H
CI-Is
Cis-
CHa
Threo-
24
GLYCOLS CH 3
H--C
'
I2
CH8
HOC1 HO-- - - H
CHs--C
1
CH 8
KOH
H--
1
CHs-- J
I H
Trans-
CH 8
Erythro-
H
Trans-
CH 3 HtO ~
H0--
~H
H0--
~H
_._.D__..~
CH3
Meso-
(-Q--+ signifies inversion)
3,4-Epoxybut-I-ene, butadiene monoxide, CH~-CH.CH :CH v b.p. 66-66.5 ~ d "~ o.872o, n~~ 1-41o5, is prepared from an appropriate butylene chlorohydrin (W. E. Bissinger et al., J. Amer. chem. Soc., 1947, 69, 2955; Z. M. Raciszewski, E. Y. Spencer and L. W. Trevoy, Canad. J. Technol., I955, 33, 129; W. Reppe et al., Ann., 1955, 596, 8o) or by the action of peracetic acid on butadiene (A. N. Pudovik and B. E. Ivanov, J. gen. Chem. U.S.S.R., 1956, 26, 2771). 3,4-Epoxy-3-methylbut-I-ene, CH~.-C(CH 3) .CH :CH v b.p. 79" 5-80.5 ~ d 2~ ~OJ o'8574, *r i .418o, Call be obtained by treating isoprene with peracetic acid (Pudovik and Ivanov, loc. tit.).
(c) Glycol esters (i) Halides When glycols are allowed to react with halogen acids either one or both hydroxyl groups m a y be esterified (replaced by halogen) with the formation of halogenohydrins* and alkylene dihalides, respectively. Both these classes of compounds have already been described (Vol. IB, pp. 34 et seq. for halogenohydrins and Vol. IA, pp. 488 et seq. for dihalogenoalkanes) and need no further description here.
(ii) Esters of oxy-acids Nitrates are prepared from glycols by esterification with concentrated nitric acid in the presence of sulphuric acid, acetic or trifluoroacetic anhydrides. They are also formed in replacement reactions of dihalogeno compounds with silver or mercuric nitrates, and by electrolysis of salts of mono- and di-carboxylic acids in the presence of nitrate ions.
Ethylene glycol dinitrate, b.p. lO6~ ram., f . p . - - 2 2 ~ d~ 1-496, n~ 1.499, explodes on distillation at atmospheric pressure, and as an explosive is more powerful than nitroglycerine. Ethylene oxide and nitrogen dioxide form ethylene * This term is used also specifically for the halogen esters of glycerol (see Vol. I E, Chap. 18).
3
DERIVATIVES
25
glycol nitrate nitrite, O N O C H , . C H g O N O , (G. Rossmy, ]3er., I955, 88, 1969). The nitrite group is readily hydrolysed (to the alcohol) or oxidised (to the nitrate).
Phosphates and phosphites. 2-Hydroxypropyl mono-phosphate has been isolated from brain, liver, and kidney, and also from eggs of the sea-urchin (0. Lindberg, Art. Kemi. Min. Geol., 1943, x6A, No. I5, I, and later papers). For discussion of the formation and reactions of phosphate esters, see G. M. Kosolapo~, "Organosphosphorus Compounds", Wiley, New York, I95O; "Phosphoric Esters and Related Compounds", Chem. Soc. Special publication No. 8, London, I957 . Glycols form cyclic esters as well as normal esters with oxy-acids of phosphorus. (I) Alkyl phosphorodichloridites, ROPCI,, react with glycots in the presence of a base to give alkyl alkylene phosphites which on hydrolysis give hydroxyalkyl phosphites (A. E. Arbuzov, V. M. Zoroastrova and N. I. Rizpolozhenskii, Bull. Acad. Sci. U.S.S.R., I948, 2o8), thus: I
HOCH 2. CH2OH + C12POCH8
I
-> OCHi. CH~OPOCH 8 HOCH 2. CH, OP(OH)OCH s
(2) Epoxides react with phosphoric acid or its salts to form hydroxyalkyl phosphates (F. R. Atherton, H. T. Openshaw and A. R. Todd, J. chem. Soc., 1945, 382; G. R. Lam#son and H. A. Lardy, J. biol. Chem., 1949, I8x, 693, 697 ), e.g. : CH 8. CH. CH 2 + K3HPO 4 ~OJ
) CHsCH(OH)CHiOPO(OH)s
Sulphates and sulphites. (i) Glycols react with sulphuric acid or oleum under controlled conditions to give mono- and bis-hydrogen sulphates, e.g. HOCHi.CH~OSOsH and (CH~OSO3H)z (J. and R. Lichtenberger, Bull. Soc. ckim. Fr., 1948, lOO2). Mono- and di-esters are .also formed with chlorosulphonic and alkane- and arene-sulphonic acids, e.g. "Myleran", (. CH~. CH~OSOaCH3) ~. (2) Cyclic (neutral) esters are also known; thus ethylene glycol gives the t
I
I
I
sulphite, OCH~.CH20SO, on treatment with thionyl chloride and the sulphate, OCH~.CH~OSO~, with sulphuryl chloride. The properties of the glycol sulphuric acids are analogous to those of ethyl sulphuric acid (C. M. Suter, "The Organic Chemistry of Sulphur", Wiley, I944, P' 40). Borates. 1,2-Diols react with boric acid to form complexes of the type:
26
GLYCOLS
12
L io o
----C---O"
~0
!
O~
0
These are frequently formed in aqueous solution and cause an increase in conductivity and a decrease in pH as well as in rotatory exaltation if the glycol is optically active. Boric acid derivatives of the glycols have been well investigated (for reviews and references see M. F. Lappert, Chem. Reviews, 1956, 56, 959" W. Gerrard, "The Organic Chemistry of Boron", Academic Press, New York, 1961 , p. 16). The use of borate complexes in the separation of diastereoisomers of 1,2- and 1,3-diols has been described (J. Dale, J. chem. Soc., 1961, 91o). Similar esters containing silicon, arsenic and osmium have also been isolated. Esters containing B, V, As, Mo, Ti are said to inhibit oxidation and corrosion in lubricating oils in which they are used as additives (J. R. Thomas et al., U.S.P., 2,795,548-553/1954).
(iii) Esters of carboxylic acids Esters of glycols with carboxylic acids are of wide technical interest, e.g. as solvents, plasticizers, fibres and resins (see G. O. Curme and F. Johnston, ot). cir. Formation. (I) From dihalides, halogenohydrins or their esters by substitution reactions. The mechanism and stereochemistry of this class of substitution reactions have been investigated by S. Winstein and R. E. Buckles (J. Amer. chem. Soc., 1942 , 64, 2780, 2787), thus: CHs Br~
--H
CH3 AgOAc
H~ ~Br CHs DL-2,3-Dibromobutane
AcO~ - - H
CHs AcOrn[- H
AgOAc O HsO
___>
H-- mBr (~mole)
HOm[--H
CHs
CHs
threo-
erytkroCHs AcO~ ~ H Hm
~0Ac CHs
DL o
CHs AcO~
mH
AcO~
mH
CHs ~8S0-
3
DERIVATIVES
27
Cyclic intermediates have been postulated which account well for the high stereochemical purity ( > 95%) of the various products. (2) B y reaction of glycols with acids, acid chlorides or acid anhydrides, under conditions similar to those employed in the esterification of monohydric alcohols. (3) B o t h mono- a n d di-esters can be obtained b y the action of acids or acid anhydrides on epoxides; CH~mCH~ +CH 39CO,H -+ HOCH 2. CHzOCO. CH 8
AcOH HtSO~----~-
CHaCO,CH *. CH2OCO. CH8
(4) Mono-esters are obtainable b y the action of per-acids on olefins, the i n t e r m e d i a t e epoxide being unstable u n d e r sufficiently acidic conditions (cf. p. 2I). (5) B y ester interchange; e.g. ethylene glycol with isopropenyl acetate in the presence of sulphuric acid gives ethylene glycol diacetate and acetone (D. C. Hull a n d A. H. Agett, U.S.P., 2,422,o16/1947).
Ethylene glycol mono/ormate, HOCH~.CH,OCHO, b.p. 179-18o~ mm., d~s 1"1915, n~)s 1-413o" di/ormate, b.p. I74 ~ d o 1"193" monoacetate, b.p. 187I89~ mm., d~~ I. lO9O, n~)~ i -4209" diacetate, b.p. 19o. 5~ ram., d~o~ i . lO63" n~~ 1"4159. For other esters of the glycols with monocarboxylic acids, see under the various carboxylic acids: Beilstein, " H a n d b u c h der Organischen Chemie", 3rd supplement, I96O, Vol. II. Esters of dicarboxylic acids. The cyclic esters of carbonic acid have i m p o r t a n t industrial applications, for example, as solvents, a n d in the formation of polyesters. I
I
Ethylene carbonate, 1,3-dioxolan-2-one, OCH~-CH,OCO, m.p. 38-5-39 ~ b.p. 238~ can be prepared (I) from glycol and either phosgene or ethyl chloroformate in the presence of pyridine (C. F. AUpress and W. Maw, J. chem. Soc., 1924, 125, 2259); (2) by heating ethylene oxide and carbon dioxide under pressure in the presence of tetraethylammonium bromide (J. G. N. Deewite and J. Lincoln, U.S.P., 2,773,o7o/1957 ). When heated with formic acid it gives ethylene glycol diformate, while with mono-esters of dicarboxylic acids it forms polyesters (M. Lichtenwalter and J. F. Cooper, U.S.P., 2,8o2,8o7/1956 ). Glycols and dibasic acids of the type HO,C(CH~)nCO,H form lilxear polyesters many of which can be drawn into fibres; e.g. poly(ethylene glycol terephthalate) is now of great importance in the synthetic fibre field as the basis of Terylene, Dacron, etc. (W. H. Carothers and J. W. Hill, J. Amer. chem. Soc., 1932, 54, 15591. When these products are heated under reduced pressure in the presence of a catalyst such as stannous chloride, depolymerization occurs with the formation of macrocyclic lactones (W. H. Carothers et al., ibid., 1933, 55, 5o31,
28
GLYCOLS
12
5039; 1935, 57, 925, 929. For more details see thisVol., Chapter 26; Rowland Hill, "Fibres from Synthetic Polymers", 1953, Elsevier, Amsterdam; R. W. Moncrie~, "Man-made Fibres", 4th Edn., 1963, Heywood, London). 4. Polyethylene glycols
Diethylene glycol, 2,2"-dihydroxydiethyl ether, HO(CH~)90(CH2)9.OH , m.p. - - I O . 5 ~ b.p. 245~ ram., 1330/14 mm. d~~ 1.1184, n~~ 1.4472, is formed together with ethylene glycol and triethylene glycol by the action of water on ethylene oxide (C. Matignon, H. Moureu and M. Dodd, Bull. Soc. chim. Fr., 1934, Iv], z, 13o8). It is also produced by the reaction of glycol with ethylene oxide or ethylene halogenohydrins. It is a stable, slightly viscous, colourless, odourless liquid, with sweetish burning taste. It is completely miscible with water, the lower alcohols, and acetone. It is a solvent for a wide variety of dyes, resins, oils and other organic compounds, and has a number of other important uses. Diethylene glycol chlorohydrin, 2-(2'-chloroethoxy)-ethanol, CI(CHz)3" O. (CHI) aOH, b.p. 18o-185~ mm., is prepared from ethylene oxide and ethylene chlorohydrilx at 14~ in the presence of acidic catalysts; it is very soluble in water. Diethylene glycol fluorohydrin, b.p. I72-I740 , d~o~ 1.115 o, n~~ I .413 o, on treatment with thionyl chloride gives 2-chloro-2'-fluorodiethyl ether. Diethylene glycol bromohydrin, b.p. 1420/12 mm. Diethylene glycol monvethyl ether, Carbitol, C~H~O(CH~) ~O(CH2) 2OH, b.p. 2Ol .9~ mm., is obtained as a secondary product in the manufacture of glycol monoethyl ether from ethylene oxide and ethanol (see above). It, and other alkyl ethers are excellent solvents for cellulose esters; they are widely used as mutual solvents and in hydraulic fluids. Monomethyl ether, b.p. 194-2~ mm.; monobutyl ether, b.p. 23o.4~ mm. Dimethyl ether, b.p. I6O-I6I~ mm.; diethyl ether b.p. 188.9~ mm.; dibutyl ether, b.p. 254.6~ mm.; butyl ethyl ether, b.p. 218--2190. Dinitrate, m . p . - - i 1 - 2 ~ b.p. I6I~ mm., d~ I "391, is manufactured by the direct nitration of diethylene glycol. It is colourless, odourless, and slightly hydroscopic. It is less sensitive to shock than nitroglycerine, but a mixture with the .latter has a higher velocity of detonation than that of nitroglycerine alone. Diacetate, b.p. I20--I220/I2 mm. Monobenzoate, b.p. I53-4~ mm. Dibenzoate, b.p. 247~ mm. For other aromatic esters see H. C. Helm and C. F. Poe (J. org. Chem., 1944, 9, 299). Bisphenylurethane, m.p. 116-118 ~ Many esters of diethylene glycol are used industrially as plasticizers, and solvents and in the formation of synthetic resins. Triethylene glycol, triglycol, HO(CH,),O(CH,)~O(CH2),OH , b.p. 287.4~ 76o mm., i620/io mm., m.p. - - 9 . 4 ~ d~o~ 1"1254, n~~ I "4559, is obtained in the reaction of ethylene oxide with water, together with ethylene glycol and diethylerie glycol (see above). It has also been obtained, with other polyglycols, by heating ethylene glycol at 19o o with a trace of iodine (S. Z. Perry and H. Hibbert, Canad. J. Res., 1936, 14B, 77).
5
SULPHUR A N A L O G U E S
29
Triethylene glycol dimethyl ether, b.p. 216~ mm., d ~* 0"974, n~)~ 1"4233. Higher polymers. A number of pure polyethylene glycols have been described (H. Hibbert et al., ibid., 1936, I4 B, 77; J- Amer. chem. Soc., 1939, 6x, 19o5, 191o). Commercially available polyethylene glycols, made from the reaction of water, ethylene glycol, or diethylene glycol with ethylene oxide at 12o-1350 under pressure, are mixtures; e.g. "polyethylene glycol 4oo '' consists mainly of HOCH2(CH,OCI-I,)nCH,OH where n = 7 or 8 giving an average molecular weight of 40o. They are colourless, non-volatile, oils or waxy solids, and with their esters and ethers are widely used as lubricants, ointment bases, emulsifiers, demulsifiers, solvents, hydraulic fluids, etc. They are employed as intermediates in the production of rubbers and resins, e.g. polyurethanes. For a discussion of the technical applications of polyethylene glycols and their derivatives, see G. O. Curme and F. Johnston, in "Glycols", Reinhold, New-York, 1952, Chap. 7. 5. Sulphur analogues of the glycols
(i) Preparation
(a) Thiols and thio-ethers
(I) F r o m halogenohydrins or dihalides by substitution reactions; thiols are obtained with alkali metal hydrosulphides or alkali metal disulphides, thio-ethers with metal alkylthiolates" Br(CH2).Br + HS |
-
CICHa. CH, OH + CHsS| ~
_
>
HS(CHa)nSH Alkane cr CH3SCH~. CHgOH 2-methylthioethanol
Thiols can also be obtained by hydrolysis of dithiocarbamates (J. yon Braun, Ber., I9O 9, 42, 4568) and isothiuronium salts (Org. Synth., I95o, 3o, 35) obtained by the action of a m m o n i u m dithiocarbamate and thiourea respectively on dihalides. (2) Thiols can be obtained from epoxides or episulphides: CHa--CH 2 + H2S ~
HSCHaCHaSH
CHg--CH~ q- H2S ~
HOCH,CH2SH
Alternatively the epoxide ring can be opened with a thio-S-acid and the mixture of esters thus obtained subjected to hydrolysis (W. Davies and W. E. Savige, J. chem. Soc., 195o, 317):
3~
GLYCOLS
CH3CH_CH 2 CHnCOSH.-->
12
{
CH39CH(OzCCH3) 9CHgSH ---~ CH3. CHOH. CHISH
CH3. CHOH. CH2SCOCH3 J (3) 1,2-Dithiols are formed in good yield b y the reduction of x a n t h a t e s a n d trithiocarbonates, for example, with lithium aluminium hydride (C. Djerassi et al., J. Amer. chem. Soc., 1955, 77, 568; S. M. Iqbal and L. N. Owen, J. chem. Soc., 196o, lO3O): I
S. CH(CH3).
J
CH(CHs).
SCS ~--> CH 3. CH(SH).
CH(SH).
CH 3
(4) Acetates of dithiols are obtained b y the addition of thiolacetic acid to acetylenes (H. Bader et al., J. chem. Soc., 1949, 619; Owen and M. U. S. Sultanbawa, ibid., 1949, 31o9): R C ~ C H + CH3COSH: -~ RCH---CHSCOCH 3 CHsCOSH
> RCH(SCOCH3). CH~SCOCH3 ---+ RCHSH- CHgSH
(ii) Properties The properties of thiols and their derivatives in this series resemble in the main those of simple thiols (see Vol. IB, p. 73 et seq.)" there is however a t e n d e n c y to form cyclic products, thus: HSCH. CHzOCOCH a
OH |
--~ CHzmCHz "~S j
(For the p r e p a r a t i o n and properties of alkylene sulphides, see Rodd, C.C.C., Ist Edn., 1957, IVa, II). 2-Mercaptoethan-I-ol, HOCHz-CH~SH, b.p. 1570/748 mm., 53.5~ mm., d~5 1 9I 196, is soluble ill alcohol, slightly soluble in water. With lead tetra-acetate the disulphide, 2,2'-dithioethanol (HOCHz.CH~S)~, is formed (L. Field and J. E. Lawson, J. Amer. chem. Soc., 1958, 8o, 838); cleavage products are not obtained (cf. 1,2-diols). 2-Methoxyethanethiol, CHsOCH2-CHzSH , b.p. lO9-11o ~ 2-Methylthioethanol, CH3SCH~.CH~OH, b.p. 74-75~ mm. Ethane- I, 2-dithiol, HSCHz-CHgSH, b.p. I46~ mm., d~~ 1.1243, n~)~ I "5590, is insoluble in water and soluble in organic solvents. The disodium salt with dihalogenoalkanes forms dithiacyclanes (N. B. Tucker and E. E. Reid, ibid., 1933, 55, 775; Org. Synth., 1959, 39, 23). 2-Methylthioethanethiol, CH3SCHz-CHzSH , b.p. 57-61~ mm. 1,2-Bis(methylthio)ethane, CH3SCHi-CH2SCH3, b.p. 8o~ mm., n~)~ 1.5292, is prepared by the addition of methanethiol to methyl vinyl sulphide. 2-Mercaptopropanol, CH3.CHSH-CH2OH , b.p. 51~ ram., d ~-~ 1.o483,
5
SULPHUR
ANALOGUES
31
n~~ 1.4862; bisphenylurethane, m.p. 14o-5 ~ I-Methylthiopropan-2-ol, b.p. 67o/ 20 mm., d~o i "039, n~~ 1-4869. Propane-I,2-dithiol, b.p. 49-5o~ mm., d~~ I .o61. 3-Memaptopropan-I-ol, b.p. 81-82~ mm., d "~ I .o656, n~~ I "4952" 3,5-dinitrobenzoate, m.p. 139-14 o~ Propane-I,3-dithiol, b.p. 173~ ram., 57~ ram., d~~ 1-0783, n~~ I. 5406. Butane-I,4-dithiol, b.p. 196~ mm. Pentane-I,5-dithiol, b.p. 217~ mm. Hexane-I,6-dithiol, b.p. 237~ mm. 2-Acetylthioethanol, I-IOCHz-CH2SCOCH s, b.p. 95-96o/8 ram., n~~ I "4963, is prepared from ethylene oxide and thiolacetic acid in ethanol. On heating an aqueous solution 2-mercc~ptoahyl acetate, CH3CO~.CHz-CH2SH, is obtained, b.p. 52-53~ mm., n~~ 1.461o. 2-Acaylthioethyl acetate, b.p. IO4~ mm., is prepared from 2-mercaptoethanol and acetic anhydride in the presence of a trace of sulphuric acid. For an investigation of the alkaline hydrolysis of the acetates of 1,2-hydroxythiols, see J. S. Harding and L. N. Owen, J. chem. Soc., 1954, I528,. Thiodiglycol, 2,2"-dihydroxydiethyl sulphide, (HOCH~.CH~)zS, f.p. m i 6 ~ b.p. 165~ mm., 121.8~ mm., d~5 I. 1793, n~~ 1"52o3, is prepared" as follows. (I) By heating 2-mercaptoethanol with ethylene carbonate (W. W. Carlson, U.S.P., 2,448,76711948 ) or ethylene chlorhydrin and alkali (F. N. Woodward, J. chem. Soc., 1948, 1892). (2) From ethylene chlorhydrin and sodium sulphide (Org. Synth., Coll.Vol. II, 1943, P. 576) 9 (3) By the action of hydrogen sulphide on ethylene oxide in the presence of a base (C. D. Nenitzescu and N. Scdrldtescu, Ber., 1935, 68, 587). Thiodiglycol is miscible with water and alcohol. An intermediate in the preparation of mustard gas, it and its esters now have a number of technical applications, e.g. as plasticizers, lubricating oil additives, etc. Its mono-acaate, b.p. 137-138~ mm., n~~ I-4879, is obtained by the addition of 2-hydroxyethanethiol to freshly distilled vinyl acetate (W. H. C. Rueggebe~'get aI., J. Amaer. chem. Soc., 1948, 7o, 2292). Diacetate, b.p. I I 8 - I I 8 . 5 ~ mm., n~5 1.4675. Dibenzoate, m.p. 65 ~ By the action of hydrogen chloride at 6O-lOO~ thiodiglycol is converted into 2,2'-dichlorodiethyl sulphide, mustard gas, a powerful vesicant (see Vol. IB, p. 80).
(b) Sulphoxides and sulphones The sulphones of this series are p r e p a r e d b y m e t h o d s exactly analogous to those employed for the monosulphones (see Vol. IB, p. 88 and C. M. Surer, op. tit., p. 734). 1,2-Disulphones undergo a characteristic substitution reaction with alkali (E. Stuffer, Ber., 189o, 23, 14o8, 3226; R. Otto and H. Damk6hler, J. pr. Chem., 1884, 3o, 171, 321): (CH~SO2R)~ + NaOH---+ RSO~CHg. CH2OH + RSO~Na Analogous substitutions occur with amines.
1,2-Bis(methylsulphonyl)ethane, CHsSO2CH~.CHzSO2CH 3, m.p. 19o~ 1,2-Bis(ahylsulphonyl)ahane, m.p. 136.5 ~ Oxidation of thiodiglycol (see above) gives
32
GLYCOLS
12
first 2,2"-dihydroxydiethyl sulphoxide, m.p. 112 ~ then the sulphone, m.p. 57-58~ which on heating cyclizes to form 1,4-oxathian-4,4-dioxide, m.p. I3 ~ (see Rodd, C.C.C., Ist Edn., I96O, Vol. IVc, p. 153o); divinyl sulphone is also obtained (D. L. Schoene, U.S.P., 2,474,8o8/1949 ).
(c) Sulphonic acids 2-Hydroxyethanesulphonic acid, isethionic acid, HOCH,.CH2SO3H, isomeric with ethylsulphuric acid and formed with it (in small m o u n t ) in the addition of sulphuric acid to ethylene (see A. Michael and N. Weiner, J. Amer. chem. Soc., 1936, 58, 294), is made by the following methods. (I) By the action of sulphur trioxide on ethanol, diethyl ether, or diethyl sulphate (G. Magnus, Ann., 1833, 6, 163; R. Hiibner, ibid., 1884, 223, 198 ). (2) From ethylene and sulphur trioxide or chlorosulphonic acid; carbyl sulphate (Vol. IB, p. 24) is formed first and this, on hydrolysis, gives isethionic acid (Michael and Weiner, loc. cit.). (3) From ethylene oxide, or ethylene chlorohydrin, with sodium sulphite or bisulphite (M. Lauer and A. Hill, J. Amer. chem. Soc., 1936, 58, 1873). (4) By deamination of taurine with nitrous acid. (5) By oxidation of 2-mercaptoethanol with nitric acid. .
The free acid is a syrup, soluble in water, and forming crystalline salts: ammonium salt, m.p. 13o~ potassium salt, m.p. 19o~ sodium salt, m.p. 192 ~ Ammonium bisulphite reacts with isethionic acid to give taurine; oxidation gives sulphoacetic acid, HOSO~CHiCO~H. With phosphorus pentachloride or hydrogen chloride 2-chloroethanesulphonic acid is formed first followed by the sulphonyl chloride. 2-Hydroxypropane-I-sulphonic acid is formed in poor yield by the oxidation of propylene sulphide with hydrogen peroxide (J. M. Stewart and H. P. Cordts, J. Amer. chem. Soc., 1952, 74, 5880). For further information about the higher hydroxyalkanesulphonic acids see C. W. Surer, op. cir., p. I33. Ethionic acid, CH~(OSO3H).CH,SOsH , is a dark brown, unstable oil; the hydrated salts are stable. Its anhydride is carbyl sulphate, OSO,CH2.CH,OSO, I
_t
(R. Hi, brier, Ann., 1884, 223, 21o). With aqueous sodium hydroxide at 650 ethionic acid forms sodium ethenesulphonate (D. S. Breslow, R. R. Hough and J. T. Fairclough, J. Amer. chem. Soc., 1954, 76, 5361). Ethane-I,2-disulphonic acid, HOsSCH~.CH2SO3H, m.p. 172-1740 (hydrate, m.p. 111-112~ can be obtained by oxidation of the corresponding dithiol or dithiocyanate, or by the reaction of ethylene dibromide and sodium bisulphite (G. C. H. Stone, ibid., 1936, 58, 488). The free acid can be obtained from its salts, e.g. from the barium salt with sulphuric acid (S. M. McElvain et al., ibid., 1945, 67, 1578). The sodium salt decomposes on heating with the formation of acetylene (H. J. Backer and P. Terpstra, Rec. Tray. chim., 1931, 5o, lO78). Diethyl ester, m.p. 78o (McElvain et al., loc. cir.). Ethane-I,2-disulphonyl chloride, C1SO2CH,-
5
SULPHUR ANALOGUES
33
CH~SO~C1, m.p. 98 o is prepared by the standard methods from salts of the acid, or by the action of chlorine on the bisisothiuronium salt (T. B. Johnson and T. M. Sprague, J. Amer. chem. Soc., 1936, 58, I348). On boiling with water it gives ethene sulphonic acid" (CH2SOzC1)2 + H20 ~
CH~:CHSO3H + 2HC1 + SO2
With amines vinyl sulphonamides, CH2.CHSO2NHR ' can be obtained, but substitution products of the type CH2(NTAR) .CH2SOzRrHR are also formed (P. W. Clutterbuck and J. B. Cohen, J. chem. Soc., 1922 , 12, 120). Taurine, 2-arninoethanesulphonic acid, *~H~CH~CH2SO3e, m.p. 3o5-3io 0 (decomp.), crystallizes in monoclinic prisms soluble in water, insoluble in alcohol. It is a very weak acid, pK a 9"2o, but forms salts with bases; the mercuric salt is insoluble in cold water. With nitrous acid it yields isethionic acid (p. 32). Taurine can be prepared from 1,2-dibromoethane by the following route (Org. Synth., Coll. Vol. II, 1943, P. 563)" BrCH2"CH~.Br + Na~SO3----+ BrCHg-CH2SOsNa + NaBr BrCHg"CH2SO3Na + NH8 ~
NH3CH2.CHgSO3 + NaBr
Alternative procedures have been proposed, e.g., the oxidation of 2-mercaptoethylamine hydrochloride with hydrogen peroxide in acetic acid (F. Y. Rachinskii, N. M. Slavachevskaya, and D. V. Yoffe, J. gen. Chem. U.S.S.R., 1958, 28, 2998). Taurine may also be isolated in large amounts from natural sources (C. L. A. Schmidt and T. Watson, J. biol. Chem., 1918, 33, 499). Taurine occurs in animal tissue, e.g. in the muscle of invertebrates (Schmidt and Watson, loc. cir.) and as the amide of cholic acid (taurocholic acid) in ox bile. Sodium taurocholate is a surface-active agent and in aqueous solution emulsifies fats. Synthetic detergents are produced by forming esters or amides of higher fatty acids with isethionic acid and N-substituted taurines, respectively, thus Igepon-T is the sodium salt of N-methyloleyltaurilxe (for a discussion of this type of surface-active agent, see A. M. Schwartz, J. W. Perry and J. Berch, "Surface Active Agenlts and Detergents" Vol. II, Reinhold, New York, 1958). Pantoyltaurine, HOCH,- C(CH3), .CHOH-CO" N H "CH,.. CH,SOsH, and amide (R. O. Roblin et al., Chem. Reviews, 1946, 38, 3IO), see Rodd, C.C.C. ISt Edn., Vol. IB, 1952, p. lO53). .
.
.
.
Anhydrotaurine, SO~CH~CH,N'H, m.p. 88 ~ is formed by the action of ammonia on 2-chloroethanlesulphonyl chloride or on ethane-I,2-disulphonyl chloride (E. P. Kohler, J. Amer. chem. Soc., 1897, 19, 728).
6. Nitrogen analogues of the glycols (a) Nitro-compounds The nitro-analogues of the glycols, in which one or b o t h h y d r o x y l groups are replaced b y nitro, are the nitroalkanols a n d the dinitroparaffins, respec-
34
GLYCOLS
12
tively. These have already been described along with their derivatives in Vol. IB, pp. 37 and lO4 et seq., respectively. Nitroglycols (dihydroxynitroalkanes) are usually obtained by condensing a nitroalkane with two moles of an aldehyde (cf. Vol. IB. p. 37). The following table lists some of these compounds and their simple ethers. Dihydroxynitroalkane
M.p. ~
Ref.
CH 8. C (NO,) (CH~OH) 9
149-150
1
EtC(CH2OH)zNO9
56-57
1
E t C H O H . CHNO 2- C H O H . CH s
94
2
CH2OH.CMeNOz.CHMeOCH 3
b.p. 110/15 mm.
3
PrC(CH~OH)zNO 2
81-81.5
1
MegCH. CNO2(CHgOH) 2
87-88
1
E t C H O H . CHNO 2. C H E t O H
97
2
~e#~'ence$ B. M . Vanderbilt and H . B . Hass, Ind. Eng. Chem., 194 o, 32, 35. s C. A . sprang and E. F. Degering, J. Amer. chem. Soc., I942, 64, 1735. a A . Lambert, C. W. Scai/e and A . E . Wilder-Smith, J. chem. Soc., 1947, 1477.
(b) Mono-amino analogues of the glycols (i) Aminoalkanols or alkanolamines* These are compounds like 2-aminoethanol, HOCH,.CH,NH,, which may be regarded as being derived from glycols by replacement of one hydroxyl group by amino. Many aminoalkanols are of physiological importance, chief among these being choline (p. 37). Included in the class are many pharmaceuticals, for example, the local anaesthetic "novocaine" (or "procaine"), (see Rodd, C.C.C., Ist Edn., Vol. IIIA, 1954, p. 587) and the antihistamine "benadryl" which are respectively the p-aminobenzyl ester and the benzhydryl ether of 2-diethylaminoethanol. The alkanolamines, and in particular the ethanolamines are manufactured in very large quantities and are of very wide technical importance, especially as basic intermediates for detergents and emulsifying agents (see Schwartz, Perry and Berch, op. cir., 1958). Preparation. (I) By reaction of ammonia or an amine with a halogenohydrin. (2) By reaction of ammonia or an amine with an epoxide. * The I.U.P.A.C. systematic name is aminoalkanol, the suffix -el taking precedence over -amine. The commercial name is alkanolamine.
NITROGEN ANALOGUES
35
Ethylene oxide and aqueous ammonia give mono-, di-, and tri-ethanolamines: (CH,),O + NH 3
> HzNCH,CHaOH Ethanolamine; aminoethanol
2(CHz),O + NH 3 - - + HN(CH2CHzOH)z Diethanolamine; 2,2'-iminodiethanol 3(CH2)~O + NH3 ---+ N(CH.CHzOH). Triethanolamine; 2,2", 2~-nitrilotriethanol With a large excess of ammonia the main product is ethanolamine, with equimolecular proportions the product is largely triethanolamine (P. Ferrero et al., Bull. Soc. chim. Belg., 1947, 56, 349). Polymeric materials of the type R2N(CH2CH20)n "CH," CH2OH may be formed if excess of the epoxide is present (A. J. W. Headlee et al., J. Amer. chem. Soc., 1933, 55, IO66). The reactions of z,2-epoxypropane and 2-methyl-2,3-epoxypentane with primary and secondary amines have been studied in detail by T. Colclough, J. I. Cunneen and C. G. Moore (Tetrahedron, 1961, 15, 187); the nitrogen becomes attached to the leastalkylated carbon atom: R2NH + (CH8)2C CHCHzCH a ~O /
> (CH3).C(OH)- C(NR2)CHgCH3
(3) By the reductive amination of a hydroxy-carbonyl or dicarbonyl compound. Thus the catalytic hydrogenation of 5-hydroxyvaleraldehyde in the presence of ammonia or a primary or secondary amine gives 5-aminopentanols: HO(CH~),CHO H, + NH, -- > HO(CH,.)sNH~ (4) By the reduction, especially with lithium aluminium hydride, etc., of a suitable bi-functional compound, e.g., (a) a h y d r o x y - o r benzyloxy-nitrile (P. A. Levene, J. biol. Chem., 1936, xz3, 153); (b) a hydroxy-amide (J. D. d'Ianni and H. Adkins, J. Amer. chem. Soc., 1939, 6i, 1675; cf. Org. Synth., Coll. Vol. III, ~955, p. 5oi); (c) an a-cyanoester (A. Dornow et al., Ber., 195o ,
83, 445): RCH "C(CN)9CO,C2H5 LiAIH, > RCH~. CH(CH2NH.) 9CH.OH (d) the oxime of a hydroxycarbonyl compound (D. E. Sunko and M. Prostenik, J. org. Chem., 1953, z8, 1523) or the monoxime of a dicarbonyl compound (P. Freon and S. Ser, Compt. rend., 1946, 222, 447) ; (e) an amino-
36
GLYCOLS
12
acid or ester (Adkins and A. A. Pavlic, J. Amer. chem. Soc., 1947, 69, 3039; P. Karrer et al., Helv., 1949, 32, lO34, 1156; O. Vogl and M. PGhm, Monatsh. 1953, 84, lO97) ; or (f) a nitro-alcohol (W. C. Gakenheimer and W. H. Hartung, J. org. Chem., 1944, 9, 85). (5) By the reaction of Grignard reagents with tertiary amino-esters or -ketones: (CH3)~NCH 2" CHg" CH 2" CO~C~H5 -
CtH~MgBr
~ (CH3)~NCH ~. CH~. CH~. CO. C2H 6
C,H,MgBr---~. (CHs)gNCH,. CHg" CHg" C(C,Hs)9OH
(6) By the hydrolysis of N-(halogenoalkyl)phthalimides (Gabriel's method, cf. Vol. IB, pp. II4 and I3o). (7) From aldehydes and ketones by way of the Marmich reaction (L. C. Cheney, J. Amer. chem. Soc., I95I, 73, 685; J. Matt and E. P. Gunther, ibid., 1955, 77, 3655) : RCHzCOCH s + H C H O + M % N H
HC1
~ RCH(CHzNM%)COCH a NaBH,
R C H (CHgNMeg.) CH (OH) CH 3
Reactions. Aminoalkanols have the normal properties of aliphatic alcohols and amines. They form salts with acids, and alkoxides with alkali metals. With dicarboxylic acids and with di-isocyanates they yield polymeric products. i-Aminoalkan-2-ols undergo some special reactions, as follows: (I) With phosgene they form oxazolidones, and with carbon disulphide (or thiophosgene) oxazolidine-2-thiones or thiazolidine-2-thiones (see Rodd, C.C.C., 1st Edn., Vol. IVa, I957, pp. 372, 373, 4o8) 9 (2) Dehydration affords ethyleneimines (see ibid., p. 16). (3) Primary and secondary aminoalkanols are cleaved by periodic acid (E. L. Jackson, Org. Reactions, 1944, 2, 341) and by lead tetra-acetate: R C H O H . C H ( N H ~ ) R " : H!~
R C H O + R ' C H O + N H 3 -l- Hg.O
Tertiary aminoalkanols appear not to be attacked by periodic acid but give secondary amines on oxidation with lead tetra-acetate (N. J. Leonard and M. A. Rebenstorf, J. Amer. chem. Soc., I945, 67, 49)(4) With nitrous acid 1,2-aminoalkanols, instead of forming glycols, may undergo pinacolic-deamination (an example of a carbonium-ion rearrangement) : (CH3)~C~C(CHs) 2
1
l
O H NH9
HNO, ~ nH _~ ( C H 3 ) ~ C ~ C ( C H 3 ) 9 ~ - +
I
OH
CH3"CO'C(CH3) a
6
NITROGEN
ANALOGUES
37
Ethanolamine, colamine, 2-aminoethanol, H~NCH~.CH,OH, is a colourless oil, b.p. 171~ d2,7 I .OlII, ~r I "45o8, miscible with water in all proportions. It is the basic constituent of phospholipids of the cephalin type. It is manufactured from ethylene oxide and ammonia (see above), together with iminobis(2-hydroxyethane), 2,2"-iminodiethanol, diethanolaminv, (HOCH~CH~)~NH, m.p. 28 ~ b.p. 27oO/748 mm., d~~ 1.o966, n~~ 1-4776, and nitrilotris(2-hydroxyethane), 2,2t,2 "nitrilotriethanol, triethanolamine, (HOCH~CH,)3N , b.p. 206--207~ mm., d '~ 1.1242, n~~ I .4852. 2-Methylaminoethanol, C H s N H C H 2-CH~OH, b.p. I55-1560/76o mm. ; 2-ethylaminoethanol, b.p. 169-176~ 2-dimethylaminoethanol, (CH3)z!XTCH~.CH~OH , b.p. 135~ 2-diethylaminoethanol, b.p. 161-163 ~ Choline, 2-hydroxyethyltrimethylammonium hydroxide, [HOCHz. CH~N(CH3) 3] ~ OH o, occurs very widely in nature as the basic constituent of phospholipids of the lecithin type. First isolated and named by A. Strecker (Ann., 1862, z23, 353) it has also been named bilineurine and sincalin as a result of isolation from other sources. Choline appears to be an essential dietary factor and is classed with the B~ group of vitamins; it is the source of acetylcholine (see below) and methylates homocysteine to yield methionine. For reviews, see M. Guggenheim, "Die biogenen Amine", S. Karger, Basel, 194o; T. H. Lukes, Ann. Review Biochem., 1947, z6, 193; H. P. Broquist, ibid., 1958, 27, 285. The most convenient natural source of choline is the lecithin of egg yolk, from which it is obtained, after hydrolysis, as its mercuric chloride complex, CsHz4ONC1.6HgCI~, m.p. 2520. The reaction of trimethylamine and ethylene chlorhydrin or ethylene oxide affords choline chloride, m.p. 247 ~ which m a y be converted to choline by t r e a t m e n t with silver hydroxide. Choline derivatives m a y also be prepared by this method (Org. Synth., I95O, 3o, io), or by quaternization of the appropriate dimethylaminoalkanol (R. T. Major and H. T. Bonnett, J. Amer. chem. Soc., 1936, 58, 22/, or by reduction of the corresponding ketone (Major and J. K. Clive, ibid., 1932, 54, 242): [CH3. CO. CHiN (CHa)a] * C1e ---> [CH 8. CHOH. CHg.N(CH3)8]$ C1e Acetylcholine, [CH3CO2CHz.CI-IzN(CHs)3] * OH e, is of great physiological importance as the neuro-hormone of the parasympathetic nervous system. Physiologically it is m a n y thousand times more active t h a n choline. It produces a lowering of the blood pressure, but is, however, rapidly destroyed by the choline esterases. Acetylcholine was first isolated (from ergot) by A. J. Ewins (Biochem. J., 1914, 8, 44). Acetylcholine chloride, m.p. 151~ m a y be conveniently synthesized from dimethylaminoethanol (L. W. Jones and Major, J. Amer. chem. Soc., 193o, 52, 307). Numerous other acylcholines have been prepared. Neurine, trimethylvinylammonium hydroxide, [CH~:CHlq'(CH3)~]eOHe, is produced from choline on putrefaction. It occurs among the ptomaines (produced by breakdown of protein) particularly in dead animal tissue. Its physiological activity is similar to t h a t of choline but it is extremely toxic. The bromide m.p. I94 ~ m a y be prepared as follows:
38
GLYCOLS
BrCH~.CH~Br + (CH3)3N~
I2
[BrCH2.CH~N(CHs)3~~ Br | KOH E ~ -~ [CH~'CHN(CH3)31~ Br |
Neurine can be obtained by treatment of the bromide with silver hydroxide. Alternatively neurine is produced directly when acetylene ~nd aqueous trimethylamine are heated under pressure (C. Gardner et al., J. chem. Soc., 1949, 789). I-Aminopropan-2-ol, CH3-CHOH.CH2NH~., b.p. 16o-161 ~ is prepared by the action of ammonia on propylene oxide; the racemic product has been resolved (R. L. Clark et al., J. Amer. chem. Soc., 1954, 76, 3995) yielding D(~)- and L(+)I-aminopropan-2-ol, [x]~5 ~ 3 i .5o and +35 ~ (as the hydrochlorides). 1-Aminopropan-3-ol, b.p. 187-188 ~ 2-Aminopropan-I-Ol, alaninol, b.p. I75-I76~ is formed on reduction of alanine. I-Aminobutan-2-ol, C~Hs.CHOH.CH2NH~, b.p. 172~ N,N-diethyl deriv., b.p. 74-75~ mm.; 2-aminobutan-I-ol, b.p. 172-174~ Iq, N-diethyl deriv., b.p. 85~ 13 mm.; 3-aminobutan-I-ol, b.p. 82-85~ mm.; I-aminobutan-4-ol, b.p. 2o5~ 2-aminobutan-3-ol, DL-threo-, b.p. 69-7oO]2o mm., n~5 I "4445, DL-erythro-, m.p. 43-44.8 ~ b.p. 75-75.5~ mm., D(~)-threo-, b.p. 71~ mm., [~]~5 ~ i 7 . o 5 o, L(+)-threo-, [x]~5 + I 6 . 9 i o , L(+)-erythro-, m.p. 49-2-49.3 ~ [~]~5 +o.85 o (F. H. Dickey, W. Fickett and H. J. Lucas, ibid., 1952, 74, 944); i-amino-2methylpropan-2-ol, b.p. 15o-151~ N,N-diethyl deriv., b.p. 164-165 ~ I-Aminopentan-5-ol, m.p. 36~ b.p. 27o-271~ Iq-methyl deriv., b.p. 94-97 ~ 3 mm.; N,N-dimethyl deriv., b.p. II3-II4-5~ mm. D(~)-2-Amino-octadecan-I-ol, sphingine, CH 3 9(CH~)15. CH(NH~ ) .CH~OH, m.p. 84-89 ~ [a]~2 ~ 5 " 5 ~ is a degradation product of the phosphatide sphingomyelin (H. E. Carter and C. G. Humiston, J. biol. Chem., 1951, I9X, 727); it and its L(+)-enantiomorph have been synthesized (D. E. Sunko and M. Prostenik, J. org. Chem., 1953, I8, 1523).
(ii) Aminoalkanethiols and derivatives Preparation. Aminoalkanethiols can be prepared by the standard methods for thiols, for example, by" (I) the reaction of halogenoalkylamines with a hydrosulphide (H. Gilman et al., J. Amer. chem. Soc., 1935, 67, 1845) or with thiourea followed by hydrolysis of the isothiuronium salt (J. Harley-Mason, J. chem. Soc., 1947, 320); (2) the reaction of amines with ethylene sulphide, and of hydrogen sulphide or thiols with ethyleneimine (H. R. Snyder, J. M. Stewart and J. B. Ziegler, J. Amer. chem. Soc., 1947, 69, 2672; H. Bestian et al., Ann., I95O, 566, 21o; F. Y. Rachinskii a n d N . M. Slavachevskaya, C.A., 196o, 54, 24368g) : RNHo + CH2~CH9 - - + RNHCHg. CHgSH ~S / RSH + C H ~ C H z ~ RSCH~. CHtNH~ ~ N H ~/
N I T R O G E N ANALOGUES
6
39
(3) the hydrolysis of N-mercaptoalkylphthalimides (S. Gabriel and J. Colman, Ber., 1912, 45, 1643). Properties. Aminothiols have the expected bi-functional properties, e.g. oxidation forms disulphides; with aldehydes and ketones 2-aminoalkanethiols form thiazolines (see Rodd, C.C.C., Ist Edn., 1957, Vol. IVA, p. 407). 2-Aminoethanethiol, cysteamine, H2NCHz.CH2SH, m.p. IOO~ b.p. 13 o~ m a y
be prepared by the methods given above, or by acid hydrolysis of thiazolidine2-thione (see p. 36). It is of some physiological interest and has been tested as a protective agent against exposure to ionizing radiations. 2-Diethylaminoethanethiol, b.p. 62-65~ ram. ; bis(2-mercaptoethyl)ethylamine, b.p. lO8-1o9~ mm.; tris(2-mercaptoethyl)amine, b.p. 145-147~ mm. 2-Methylthioethylamine, CH3SCHs.CH,NH v b.p. 147~ 2-ethylthioethylamine, b.p. 163 ~ 2,2"-Diaminodiethylsulphide, (H,NCH~-CH~)~S, b.p. 232~ can be obtained from hydrogen sulphide and ethyleneimine; 2,2"-diaminodiethyl disulphide, cystamine, (H,NCH,.CHzS),, m.p. I35-I36~ is prepared by aerial oxidation of a methanolic solution of 2-aminoethanethiol (R. Kuhn and F. Drawert, Ann., 1954, 590, 55)-
(c) Aliphatic diamines T h e s e compounds contain two amino groups each of which may be primary, secondary or tertiary. Of diamines of natural occurrence the ptomaines, putrescine, (tetramethylenediamine) and cadaverine, (pentamethylenediamine) are best known. These substances are produced in the putrefaction of proteins by a wide variety of agents and occur in cheese and in brewer's yeast. Putrescine is derived from arginine via ornithine, cadaverine from lysine" H2NC (:NH). (CHz)3. CH(NH~). COgH ~ arginine H2N. (CH~)4- CH(NH.). CO.H ~ lysine
HgN(CH.)4NH 2 putrescine
H~N(CH~)sNH. cadaverine
Diamines are extensively used in the synthesis of medicinal chemicals such as anti-malarials and ganglionic blocking agents. Certain of the polymethylenediamines, e.g. hexamethylenediamine, are made on a large scale for conversion to polymers (e.g. nylon).
(i) Preparation Diamines may be prepared by methods analogous to those used for simple amines (Vol. IB, pp. 112 et seq.).
4~
GLYCOLS
12
(I) By the reaction of ammonia or an amine with a halogenoalkylamine (Org. Synth., Coll. Vol. h i , 1955, p. 254). Diamines can be prepared from ammonia or an amine and a dihalogenoalkane but the method is not normally satisfactory as further alkylation occurs, e.g. with the formation of cyclic dimers such as piperazine derivatives. Gabriel's method may be applied to the synthesis of diamines in which one or both amino groups are primary (H. E. French et al., J. Amer. chem. Soc., 1945, 57, 882; J. C. Sheehan and W. A. Bolhofer, ibid., 195o, 72, 2786; Org. Synth., Coll. Vol. III, 1955, p. 256) :
.~. co\
<~CO/NK+ Br(CH2,aBr
~.
co\ ~/CO2H
R'NH"+ "~/'C0" ( I'~/CO~N(CH~)nNR~ - > HgN(CH')nNR' + ~'~'C09H (2) By the reduction of a bifunctional compound. (a) Dinitriles may be converted to diamines with a variety of reducing agents, thus decane-I,IOdiamine can be obtained from sebaconitrile with hydrogen and Raney nickel in liquid ammonia (Org. Synth., Co11. Vol. nI, 1955, p. 229) or with lithium aluminium hydride (A. E. Finholt, A. C. Bond and H. I. Schlesinger, J. Amer. chem. Soc., 1947, 69, 1199). Aminonitriles are also convenient starting materials and may be reduced by controlled hydrogenation (E. Strack and H. Schwaneberg, Bet., 1932, 65, 71o; 1933, 66, I33O), by sodium ill ether over potassium bicarbonate (W. McMeeking and T. S. Stevens, J. chem. Soc., 1933, 347) or, in the case of tertiary aminoacetonitriles, sodium and alcohol (M. S. Bloom et al., J. Amer. chem. Soc., 1945, 67, 539); lithium aluminium hydride may also be employed (H. E. Zaugg and B. W. Horrom, ibid., 1953, 75, 292). For further information on the preparation of diamines from aminonitriles, see F. C. Whitmore et al., ibid., 1944, 66, 725; W. Huber et al., ibid., 1945, 67, 1618; A. A. Goldberg and W. Kelly, J. chem. Soc., I947, 1360. (b) By reduction of nitroamines (R. L. Heath and J. D. Rose, ibid., 1947, 1486). (c) By reduction of dioximes (E. Strack and H. Schwaneberg, Bet., 1934, 67, lOO6) or the oximes of aminoketones (D. S. Breslow et al., J. Amer. chem. Soc., 1944, 66, 1921). (d) By catalytic reductive amination of glycols or aminoalcohols (R. C. Schryer, U.S.P., 2,754,33o/I956 ), or aminoketones. A number of ~oo-diamines have been prepared by reductive amination of bis(cyanoalkoxy)alkanes (A. Hrubesch, G.P., 823,295/1951): (CH i-CH~OCHg. CH2CN)~
Ht +Ni NH.
>
HO(CH2)4OH
+ H2N(CH2)3NH9
6
NITROGEN
41
ANALOGUES
and of alkyl lactims (Bad. Anilin u. Soda Fabrik, B.P., 824,419/1957): I
CHz(CHg)nC(OR)'I~
Hs+ NiNH. -> H~.N(CHg.) n + 9.NH~
(3) From the amides of dicarboxylic acids by the Hofmann reaction (Vol. IB, p. ~7)(4) From the azides of dicarboxylic acids by the Curtius reaction (Vol. IB, p. IIS). (5) N-Substituted ethylenediamines can be obtained from ethyleneimine and primary or secondary amines, under anhydrous conditions in the presence of aluminium chloride (G. H. Coleman and J. E. Callen, J. Amer. chem. Soc., 1946, 58, 2oo6).
(ii) Properties The aliphatic diainines are liquids or low-melting solids, which fume slightly in air, absorb carbon dioxide, and form stable hydrates. They have a peculiar odour, which resembles ammonia and recalls piperidine. (iii) Reactions The reactions of diamines are similar to those of aliphatic mono-amines. They form salts; those members with primary and secondary amino groups react with acid chlorides and anhydrides to form acyl derivatives, and with isocyanides to give ureas. The typical reactions of aliphatic amines with nitrous acid are observed, except that 1,2-diprimary amines tend to form epoxides. The diamines and their derivatives are starting materials for the preparation of a number of heterocyclic systems. 1,2- and 1,3-Diamine hydrochlorides may be converted into pyrrolidines and piperidines, respectively (cf. Rodd, C.C.C., Ist Edn., Vol. IVa, 1957, p. 32). Among other systems I
I
which can be obtained are 1,3-diazacycloalkenes, HN(CH~)nN:CR (ibid., pp. 302, 304, 312, 1295, I594), 2,3-dihydro-I,4-diazepins (ibid., p. I595), and higher polyazacyclanes (ibid., p. 1629; H. Sletter and E. E. Roos, Ber., 1954, 87, 566). Diamines readily form linear polymers in reactions with bifunctional compounds. Thus with dibasic acids they give polyamides, with di-isocyanates polyureas, and with dihalogenoalkanes polyamines. Diamines readily co-ordinate with metallic salts to form complex ions related to those formed by ammonia. Thus ethylenediamine gives salts of the type, [Co.(HgNCH~CHgNH~)3]
$e$
3 x|
and [Cu.(HzNCH~CH~NH2)~]
ee 2X e
42
GLYCOLS
12
F o r further information on the stability a n d stereochemistry of such coordination compounds, see A. E. Martell and M. Calvin, " C h e m i s t r y of the Metal Chelate Compounds", Prentice Hall, New York, 1952; " T h e Chemistry of the Co-ordination C o m p o u n d s " (Ed. J. C. Bailar, jr.), Reinhold, New York, 1956.
(iv) Individual atiphatic diamines Methylenediamine, CH,(NH2)~, is, like its oxygen analogue, very unstable. Its salts are obtained on acid hydrolysis of methylenediformamide (P. Knudsen, Ber., 1914, 47, 2698). Tetra-alkylmethylenediamines, t~2NCH,~tZ,, can be obtained by the reaction of a dialkylamine with formaldehyde, a methylene dihalide, or chloromethyl sulphate (J. Houben and H. R. Arnold, ibid., 19o8, 4 I, 1565; R. Damiens, Ann. chim., 1951, 6, 835 ) . N,N,N',N'-Tetramethylmethylene diamine, b.p. 82-84o/76o mm., gives With hydrogen chloride in N,N-dimethylformamide (chloromethyl)dimethylamine; other tetra-alkyl derivatives react similarly (H. Bohme, W. Lehners and G. Kreitzer, Ber., 1958, 91, 340). Ethane-I,2-diamine, ethylenediamine, H2N(CH2) ,NH,, m.p. 8.5 ~ b.p. 116.5 ~ forms a hydrate, m.p. I o ~ b.p. I 18 ~ Anhydrous ethylenediamine may be obtained by heating the complex [Zn.(H,NCH2),]**C20, e e, obtained from the hydrate and zinc oxalate, at 2oo ~ in vacuo (J. C. Bailar, J. Amer. chem. Soc., 1934, 56, 955)- It is strongly alkaline and has an ammoniacal odour. Acetyl-, m.p. 5 I~ b.p. 128~ mm.; diacetyl-, m.p. 173~ propionyl-, b.p. 13o~ ram.; dipropionyl-, m.p. 189~ dibutyryl-ethylenediamine, m.p. 191 ~ N-Methyl-, b.p. 115-116~ N,N-dimethyl-, b.p. lO7~ N,N'-dimethyl-, b.p. 119~ N,N,N'-trimethyl-, b.p. 14o~ N,N,N',N'-tetramethyl-, b.p. 121~ N-ethyl-, b.p. 129131~ N,N-diethyl, b.p. 144-145~ N-octyl-, m.p. 29-31~ N-decyl, m.p. 36-37o; N-dodecyl-, m.p. 36-38o; N-tetradecyl-, m.p. 42-43~ ~-hexadecyl-, m.p. 55-57~ •-octadecyl-ethylenediamine, m.p. 64-65 ~ Propane-I,2-diamine, propylenediamine, C H s . C H ( N H , ) . C H ~ N H , , b.p. 119I2O ~ has been resolved into its optical enantiomorphs, [a]D +34 .8o (F. P. Dwyer, F. L. Garvan and A. Shulman, ibid., 1959, 81, 29o). Butane-I,2-diamine, butylenediamine, CH 3 -CH,. CH(NH,) 9C H , N H , , b.p. I3514 o~ Butane-2,3-diamine, CHs.CH(NH,).CH(NH2).CH3, DL-isomer, b.p. 5758016o rnm., n~5 1"44o8, l.(+)-isomer, b.p. 58-59~ mm., n~5 1-4462, [0e]~5 + 29-48, meso-isomer, b.p. 59-6o~ ram., n~5 1-442o (F. H. Dichey, W. Fickett and H. J. Lucas, ibid., 1952, 74, 944). Butane-l,3-diamine, CH3-CH(NH~). CH~.CH~NH 2, b.p. 141~
occo-Potymethy lened ia mines Propane-I,3-diamine, trimethylenediamine, H2N(CH,.)sNH ,, b.p. 136-137~ 76o mm., diacetyl deriv., m.p. IOI ~ hydrochloride, m.p. 246-247 ~ Butane-I,4-diamine, tetramethylenediamine, putrescine, H , N ( C H i ) i N H ,, m.p. 27 ~ b.p. 158-159 ~ occurs in many products of bacterial decomposition. It is found in urine and faeces of patients suffering from cystinuria. The tetramethyl deriva-
6
I~ITROGEN ANALOGUES
43
tire, (H3C),N(CH2)4N(CH~)2, occurs in henbane (Hyoscyamus). N,N'-bis(3-aminopropyl)butane-I,4-diamine, spermine, HzN(CH2)3NH(CH,)4NH(CH2)3NH,, m.p. 66 ~ b.p. 15 o~ is present in fresh human semen (P. Schreiner, Ann., 1878, 194, 68) and was possibly first isolated by Van Leeuwenhoek in 1678. It may by synthesized from putrescine (H. P. Schultz, J. Amer. chem. Soc., 1948, 7o, 2666), and forms crystalline salts, the phosphate being characteristic. A second polyamine, 3-aminopropylbutane-I,4-diamine, spermidine, H,N(CH,) 3NH(CH2)4NH ,, accompanies spermine in many tissue extracts (0. Rosenheim et al., Biochem. J., 1927, 21, 97). Pentane-I,5-diamine, cadaverine, H~N(CH2)sNHz, b.p. I78-I8O ~ occurs frequently with putrescine and like it has a foul smell. The tetramethyl deriv., b.p. I9O-I9 I~ is obtained from the bis-methiodide, pentamethonium iodide, (CH3)sN.(CH2)s.N(CH3)s-2Ie, m.p. 3o2 ~ The latter and the hexamethylene analogue (see below) are ganglionic blocking agents, used for treating hypertension and for decreasing bleeding during surgical operations. Hexane-I,6-diamine, hexamethylenediamine, m.p. 42~ b.p. 196~ is manufactured on a large scale mostly for conversion to polyamide fibres(e.g, nylon 66). It is prepared by reduction of adiponitrile although other methods have been proposed (see refs. to patent literature pp. 4o-41). N,N,~',2q'-Tetramethylhexane1,6-diamine, b.p. 2o9-21o~ hexamethylene bis(trimethylammonium chloride), hexamethonium chloride, m.p. 289-291 ~ and the corresponding bromide, iodide, and tartrate are ganglionic blocking agents (see above). Heptane-I,7-diamine, m.p. 28-29 ~ b.p. 223-225~ octane-I,8-diamine, m.p. 52~ b.p. 225-226~ nonane-I,9-diamine, m.p. 37-5 ~ b.p. 258-259~ decane-I,io-diamine, m.p. 61.5 ~ b.p. I4O~ mm.; undecane-I,II-diamine, m.p. 58~ b.p. 14oI5O~ mm.; dodecane-I,I2-diamine, m.p. 66-67 ~ b.p. 187~ mm.; tridecaneI,I3-diamine, m.p. 51~ octadecane-I,I8-diamine, m.p. 93 ~
Dihydric Alcohols or Glycols and their Derivatives E. S. WAIGHT
This chapter is concerned with the glycols, those compounds in which two hydroxyl groups are attached to different carbon atoms, and their derivatives in which one oi both of the hydroxyl groups are alkylated to form ethers, esterified with organic or inorganic acids, or replaced by thiol or amino groups. The hydroxyl groups in the glycols may be primary, secondary, or tertiary and can undergo reactions analogous to those of primary, secondary, and tertiary alcohols. Thus on oxidation those members with primary groups form first aldehydes and then carboxylic acids, while those with secondary groups yield ketones, in this way several classes of compounds containing two functional groups, other than two hydroxyl groups, can be obtained, namely, hydroxy-aldehydes and -ketones, dialdehydes, diketones, aldehydocarboxylic acids, ketocarboxylic acids, and dicarbox3~lic acids. These classes will be dealt with in the following chapters. 1. Saturated aliphatic glycols; alkanediols,
Cni-I2n+202
The first dihydric alcohol, HOCH~-CH,OH, was discovered by A. Wurtz (Compt. rend., 1856, 43, 199) who named it ethylene glycol as it was intermediate between the monohydric ethyl alcohol on one hand and the trihydric glycerol on the other. Subsequently, other glycols became known having hydroxyl groups attached to adjacent (1,2-) or other (I,3-, 1,4-, 1,5-, etc.) carbon atoms. Compounds with two hydroxyl groups attached to the same carbon atom are unstable and readily lose water with the formation of aldehydes and ketones (see Vol. IC, p. I). The systematic names of glycols are derived by adding the suffix diol to the name of the parent hydrocarbon, so that ethylene glycol is correctly named ethane-I,2-diol. As indicated above either or both hydroxyl groups of a glycol may be
2
GLYCOLS
I2
converted to some other functional group so that, in the case of ethylene glycol, the following can be obtained: CHg.0H
CH~0CgH 5
I
[
CHg.0COCH3
I
CHgOH
CHzOH
CHz0H
Glycol
Glycol mono-ethyl ether
Glycol mono-acetate
Such compounds behave as monohydric alcohols. On the other hand, the following behave as simple ethers and esters" CHg0COCH 3
CH,0C2H 5
I
[
CH~.OCzH5
CH 20COCH s
Glycol diethyl ether
Glycol diacetate
Replacement of the hydroxyl groups by halogen, thiol and amino groups produces the corresponding halides, thiols and amines, thus: CH2C1
CH2C1
CH,NH~
I
I
I
CH2NH ~
I
CHg.0H
CHg.C1
CHg.OH
CHzNH 2
Ethylene chlorohydrin
Ethylene dichloride
2-Aminoethanol ethanolamine
Ethylenediamine
CH2SH
CHgSH
;
i
CHg0H
CH~SH
2-Mercaptoethanol
Ethane-I,2dithiol
Ethylene chlorohydrin and ethylene dichloride have already been discussed in Vol. IB, p. 36 and Vol. IA, p. 497, respectively. Glycols form characteristic cyclic derivatives, for example, cyclic ethers such as: CH2- ~
I
o
CH~ "/
Ethylene oxide
CH~--O--CH 2
;
[
CH~--O--CHg.
Dioxan (diethylene oxide)
Ethylene oxide and its homologues are discussed in this chapter, although they are cyclic compounds, because of their importance in the chemistry of glycols, but trimethylene oxide, dioxan and the sulphur and nitrogen analogues of all these systems are discussed in Vol. IV.
ALKANEDIOLS
I
3
Stereoisomerism may be observed in glycols containing secondary or tertiary hydroxyl groups, and in several cases racemic mixtures have been resolved to give pure optical isomers. Apart from this any glycol more complex than ethylene glycol has structural isomers (e.g. propane-I,2-diol, CHs.CHOH.CH~OH , and propane-I,3-diol, HOCH2.CH2.CH,OH ) the number of which becomes very large in the case of a high molecular weight glycol ( c . f . H . R . Henze and C. M. Blair, J. Amer. chem. Soc., 1934, 56, 157). (i) Methods of formation Glycols m a y be obtained by applying to bifunctional compounds m e t h o d s used for forming monohydric alcohols. (I) Dihalogenoalkanes give glycols directly on hydrolysis under mild conditions. Although prolonged t r e a t m e n t with water under pressure is satisfactory, less direct methods are more convenient; that of A. Wurtz (1859) is frequently employed. This consists in converting the dihalide to the diacetate, by warming either with a solution of silver or lead acetate in acetic acid or with a methanolic solution of an alkali metal acetate, followed by hydrolysis of the diester. With methanolic sodium formate the dihalide is converted in one operation into the glycol, the intermediate diformate being very easily hydrolysed. Conditions must be chosen to avoid side reactions such as elimination of hydrogen halide or formation of carbonyl compounds. Thus hydrolysis of 1,2-dibromo-2-methylpropane may give isobutanal (A. Elteko~, Bet., 1878, x x, 989; C. M. Surer and H. D. Zook, J. Amer. chem. Soc., 1944, 66, 738), while t r e a t m e n t with sodium acetate in acetic acid leads to the formation of 2-methylallyl acetate (K. Krassuski and F. Schenderowitsch, Chem. Ztbl., 1926, II, 183). The mechanism of replacement of bromine by acetate in 1,2-dibromoalkanes has been investigated by S. Winstein and R. E. Buckles (J. Amer. chem. Soc., 1942, 64, 2787). (2) Halogenohydrins, or their mono-esters, give glycols on hydrolysis
(H. D. Cowan, C. L. McCabe and J. C. Warner, J. Amer. chem. Soc., 195o, 72, 1194). 1,2-Halogenohydrins react considerably more slowly under neutral conditions than the analogous alkyl halides, but in the presence of strong bases form the epoxide [see s(b) below]. Tetramethylene chlorohydrin reacts rapidly with water to give tetrahydrofuran (H. W. Heine et al., ibid., 1953, 75, 4778), but this may be avoided by protecting the hydroxyl group, for example, by formation of a 2-pyranyl ether, before carrying out the hydrolysis (C. Croisan, Ann. chim., I956, [I 3 ], 1,436). Carbonyl compounds may be formed; thus 2-chloro-2-methylpropanol gives isobutanal with aqueous sodium hydroxide, and pinacolone is formed from 3-iodo-2,3-dimethylbutan-2-ol (M. T i ~ e ~ a u and J. Ldvy, Bull. Soc. chim. Fr., I93I, [iv], 49, I8O6):
4
GLYCOLS
12
heat
(CHs),C(OH) 9C(CH~),I ~ or AgOH ~- CHa. CO. C(CHa)a While the above two methods are applicable to the formation of any dihydric alcohol, they are particularly useful for 1,2-glycols as the relevant dihalide or halogenohydrin is readily available from the olefin. (3) 1,2-Glycols, specifically, m a y be obtained by the oxidation of olefins. For a review see F. D. Gunstone, "Advances in Org. Chem." Methods and Results", Vol. I, Interscience, New York, 196o, p. lO3. (a) Alkaline or neutral permanganate, alkaline manganate (W. Rigby, J. chem. Soc., 1956, 2452), or permanganate and magnesium sulphate (C. J. Maan, Rec. Tray. chim., 1929, 48, 332) give diols by cis-addition, although yields are often poor. Osmium tetroxide adds to olefins giving stable osmate esters, which on hydrolysis in the presence of sodium sulphite or chlorate give the vicinal diols. (b) Alkenes are readily converted by peracids to epoxides (see p. x9) which, can be hydrolysed by dilute acid to the 1,2-diols (D. Swern, Chem. Reviews, 1949, 45, 16). Peracetic and performic acids give glycol mono-esters which are readily converted by hydrolysis to the diols in excellent yield. Peroxytrifluoroacetic acid in the presence of trifluoroacetate ions (W. D. Emmons, A. S. Pagano and J. P. Freeman, J. Amer. chem. Soc., I954, 75, 3472) is more reactive than performic acid. The glycol monotrifluoroacetate may be converted to the glycol by treatment with methanolic hydrogen chloride. (c) Hydrogen peroxide hydroxylates double bonds in the presence of metallic oxide catalysts (M. Mugdan and D. P. Young, J. chem. Soc., I949, 2988), water, dioxan, or tert-butanol being employed as a solvent. Osmium tetroxide leads to cis-addition, but pertungstic acid, permolybdic acid, and selenium dioxide, which are rather less efficient catalysts, give trans-addition. (d) Iodine-silver benzoate complex, C6HsCO,Ag.CeHsCOI, (C. Prdvost, Compt. rend., 1933, I96, II29; I97, 1661; for a review see C. V. Wilson, Org. Reactions, 1957, 9, 332), gives with olefins dibenzoates by trans-addition; but iodine-silver acetate in wet acetic acid gives diacetates by cis-addition (R. B. Woodward and F. V. Brutcher, J. Amer. chem. Soc., 1958, 80, 209, but see C..4. Bunton and M. D. Cart, J. chem. Soc., 1963, 77o). The diesters are readily hydrolysed to 1,2-diols. (4) Diamines or amino-alcohols give diols on t r e a t m e n t with nitrous acid. Pinacolic deamination (see p. 36) m a y be observed with 1,2-diamines or amino-alcohols in which one amino group is tertiary (F. Feist and H. Arnstein, Ber., 1895, 28, 3169; F. R. Japp and J. Moir, J. chem. Soc., 19oo, 77, 642; A. McKenzie and W. S. Dennler, ibid., 1924, I25, 21o5; J. Kenyon et al., ibid., 193o, 421).. Choline is decomposed to glycol by heating: o
CH~OH.CH~N(CHa)3OHe
> (CH~OH)~ + H,O + (CHa)aN
I
ALKANEDIOLS
5
(5) Paraffin glycols can be obtained by hydrogenation of ethylenic and acetylenic glycols (W. Reppe et al., Ann., I955, 596, 38). (6) Reduction of carboxylic acids and their derivatives m a y give diols. (a) Diesters may be reduced with sodium and an alcohol under vigorous conditions. The method is best suited to the higher homologues (G. M. Bennett and A. N. Mosses, J. chem. Soc., 1931, 1697; Org. Synth., Coll. Vol. II, 1943, p. 154). Diesters can be hydrogenated over copper chromite catalysts at high temperature and pressure (see Org. Synth., Coll. Vol. II, 1943, P. 325; H. Adkins, "Reactions of Hydrogen", University of Wisconsin Press, Madison, Wisconsin, 1946, p. lO3 et seq.; A. Guyer, A. Bider and M. Sommaruga, Helv., 1955, 38, 976). Dicarboxylic acids, particularly the higher members, may be reduced under rather similar conditions (Guyer et al., loc. cit.). (b) Diamides are reduced by sodium and alcohol (R. Scheuble and E. Loebl, Monatsh., 19o4, 25, 341) or sodium in liquid ammonia a t - - 5 o~ (E. Chablay, Ann. chim., 1917, 8, 216) to diprimary glycols. (7) Diols m a y be prepared b y the hydrogenation of dialdehydes, diketones, aldols, and ketols. Sodium and alcohol or wet ether may be used. The selective reduction of carbonyl groups with aluminium isopropoxide (T. Bersin, "Newer Methods of Prep. Org. Chem.", Interscience, l~ew York, 1948, p. 125) allows diols to be obtained from substituted ketones and ketols. Carbonyl compounds, especially those unstable to alkali, such as 1,2- and 1,3-dicarbonyl compounds, may be hydrogenated catalytically (c.f.G.F. Hennion and E. J. Watson, J. org. Chem., 1958, 23, 656, 658), a method used to prepare very high members of the 1,2-glycol series (V. L. Hansley, J. Amer. chem. Soc., 1935, 57, 23o3; U.S.P., 2,o79,4o3/ 1937; F. Bouquet and C. Paquot, Bull. Soc. chim. Ft., 1948, 15, II65), or reduced with sodium borohydride (J. Dale, J. chem. Soc., 1961, 91o). Lithium aluminium hydride may be employed to obtain diols from a wide variety of bifunctional compounds, for example, diketones, keto-esters, aldols, ketols, and lactones (N. G. Gaylord, "Reduction with Complex Metal Hydrides", Interscience, New York, I956), as well as dicarboxylic acids and their esters. (8) Reduction of epoxy-alcohols can give diols. The reaction is of wide scope. Alcohols containing 1,2- (A. K6tz and F. Richter, J. pr. Chem., 1925, xxx, 373), 1,4- (R. Adams et al., J. Amer. chem. Soc., 1923, 45, 3o29; 1925, 47, lO98; R. Connor and H. Adkins, ibid., 1932, 54, 4678) and 1,5-oxide rings (R. Paul, Bull. Soc. chim. Fr., 1934, Iv], x, 978) have all been reduced to the corresponding diols. Thus 2,3-epoxypropan-i-ol is catalytically hydrogenated over palladium to propane-i,2-diol (K6tz and Richter, loc. cit.): CHz--CH. CHgOH --H-L+ CH3- CHOH. CH~OH Furyl alcohol and its derivatives yield mainly pentane-I,2-diol together with a little of the 1,5-dioI (jr. Pierce and R. Adams, J. Amer. chem. Soc., 1925, 47, lO98).
6
GLYCOLS
12
(9) 1,2-Glycols (including pinacols, see p. 13) are formed by bimolecular reduction of carbonyl compounds" 2 RCHO + 2H:
.~CHR(OH).CH(OH)R
2 RCOR' + 2H---~ CRR'(OH).C(0H)RR" A pinacol
Unsymmetrical glycols of this latter type may be obtained if a mixture of ketones is used (G. Lande and J. Wiemann, Bull. Soc. chim. Fr., 1946, 256). Suitable reducing agents are: sodium or sodium amalgam, preferably in acetic acid (J. B~eseken and G. H. van Senden, Rec. Tray. chim., 1913, 32, 26); sodium in moist ether (J. Bredt and W. H. Perkin, J. chem. Soc., 1913, xo3, 2213); magnesium amalgam (Org. Synth., Coll. Vol. I, 1941, p. 459); magnesium in aqueous acetic acid (M. Kolobielski, Ann. Chim., 1955, xo, 271); a mixture of magnesium and magnesium iodide (R. C. Fuson et al., J. Amer. chem. Soc., 1942, 64, 3o) ; chromous chloride or vanadous sulphate (J. B. Conant and H. B. Cutter, ibid., 1926, 48, lO16); the zinc-copper couple, which is particularly good for the bimolecular reduction of unsaturated carbonyl compounds (J. Wiemann, Ann. Chim., 1936, 5, 287)- Pinacols are produced in the electrolytic reduction of ketones but the method is not satisfactory for the preparation of aliphatic pinacols (M. J. Allen, "Organic Electrode Processes", Chapman and Hall Ltd., London, 1958, p. 61). For a discussion of the mechanism of pinacol formation see A. J. Birch, Quart. Reviews, 195o, 4, 79. The following offer general methods of carbon chain extension with the formation of glycols of all types. (IO) Syntheses with Grignard reagents. (a) Dialdehydes and diketones yield disecondary and ditertiary glycols respectively" HCO. (CH~)n.CHO + 2RMgX----+ CHR(OH). (CH~)n.CH(OH)R RC0. (CHg)n.COR' + 2 R ' M g X ~
CRR'(0H). (CH,)n.C(OH)R'R*
The method is of very wide application (see M . S . Kharasch and 0. Reinmuth, "Grignard Reactions of Nonmetallic Substances", Prentice Hall Inc., New York, 1954). Diesters, keto-esters, hydroxy-esters, lactones, aldols, ketols, and glycides may also be employed. Lithium alkyls have some advantages over Grignard reagents (W. J. Hickinbottom, A. A. Hyatt and M. B. S~arke, J. chem. Soc., 1954, 2533). (b) The Grignard reagents from dihalides react with carbonyl compounds to form glycols" thus formaldehyde gives diprimary products (J. yon Braun and W. Sobecki, Bet., 1911 , 44, 1918):
I
ALKANEDIOLS
7
XMg(CH~)nMgX + 2CH~O---+ HO.(CH2)n+9. OH Other aldehydes and ketones give secondary and tertiary glycols. AlkoxyGrignard reagents give mono-ethers of glycols (M. H. Palomaa and A. A. Erikowski, ibid., 1938, 7I, 574). The reaction of alkoxy-Grignard reagents with ethylene oxide can be used to extend the carbon chain by two units (Palomaa and R. Jansson, ibid., 1931, 54, 16o6) thus: /O.~ ROCHz. CH2MgC1 + CH2mCHl ~ ROCHI. CHg.CHg. CH~OH (c) Dimagnesium compounds with aft-unsaturated aldehydes give diallylic glycols. Acrolein reacts as follows (J. Cologne and R. Davis, Compt. rend., 1958, 247, 88I): BrMg.(CH2)n-MgBr + 2CHB:CH-CHO~
>
CH~ CH. CHOH. (CHg)n-CHOH. CH CHs PBr, .
.
_
r
BrCH~. CH: CH. (CH2)n"CH: CH. CH,Br Conversion of the above dibromide to the diacetate followed by hydrogenation and hydrolysis leads to diprimary glycols, HO. (CH2) 2n+6-OH. (II) Dialkyl ethers of glycols are also prepared by subjecting alkoxyalkyl halides to a Wurtz reaction. This method is useful for the higher diprimary glycols (J. Hamonet, ibid., 19o3, I36, 96; 19o4, 138, 975): 2R0. (CH,).. I
Na
> [R0. (CHz)n] ,
> H 0 . (CH,)... O H
(12) 1,3-Glycols may be obtained from olefins by hydrolysis of 1,3-dioxan derivatives produced in the Prins reaction (see Houben-Weyl, "Methoden der org. Chemie", 1955, 4/2, 45)" /CHz~ CH~--CH CH2 CH$ 9CH: CH~ + 2CH20
H,SO4-->
[
I
--+ CH 3- C H O H . CH z. CHaOH
o o ~CH~ / (13) The hydroboronation of dienes can lead to diols. The reaction a t - - I O ~ of diborane with conjugated or unconjugated dienes gives organoboranes which are decomposed by alkaline hydrogen peroxide
8
GLYCOLS
12
affording diols; the method in effect involves "anti-Markownikoff" hydration of the carbon-carbon double bonds. Thus butane-I,4-diol is obtained from butax,3-diene, and hexalxe-I,6-diol from hexa-I,5-diene (H. C. Brown and G. Zweifel, J. Amer. chem. Soc., 1959, 8I, 5832; K. A. Saegebarth, ibid., 196o, 82, 2o81). Isomerization of the organoborane may occur on heating. (14) 1,2-Glycols are formed, a m o n g other products, when m o n o h y d r i c alcohols are exposed to ionizing radiations (E. Collinson a n d A. J. Swallow, Chem. Reviews, 1956, 56, 471). Ethylene glycol can be prepared by neutron-irradiation of a suspension of methanol and uranium dioxide (Hercules Powder Co., B.P., 77o,594/I955).
(if) Industrial manufacture and uses of the glycols The huge demand for glycols is met by four main methods (see G. Machell. Mfg. Chemist., I96O, 3 x, 2o, I i I). (I) The hydrolysis of epoxides and of halogenohydrins, obtained from olefins. (2) The fermentation of molasses (giving butane-2,3-diol). (3) The hydrogenation of sucrose and glucose (giving propane-I,2-diol). (4) The reduction of aldols and ketols. An efficient process for ethylene glycol, now little used, involves the reaction of water gas with formaldehyde at 20o o under 7oo at. pressure. The glycollic acid thus formed is esterified and the ester hydrogenated at 2oo o using a copper chromite catalyst. The glycols have a variety of uses. Ethylene glycol has major outlets in automobile "anti-freeze" solutions, in the manufacture of polyester fibres, resins, and elastomers, and in the industries based on cellulose. Propylene glycol, less toxic than ethylene glycol, is extensively used as a humectant in foodstuffs, in hydraulic fluids, and in the production of polyester and polyurethane resins. Many other important glycol derivatives are obtained from ethylene oxide (see p. 21). Di- and poly-ethylene glycols, their esters and ethers, are used as solvents, rubber lubricants, hydraulic fluids, and in the cosmetics and pharmaceuticals industries. The butanediols are declining in importance as sources of butadiene, but butane-I,4-diol provides a useful route to tetrahydrofuran and is also used as a cross-linking agent for polyurethane rubbers.
(iii) Biochemical significance of the glycols The most important natural sources of glycols are fermentation liquors in which they occur along with ethanol. Glycols arise by anaerobic transformations of pyruvic acid to acetoin or other acyloins, which are reduced enzymatically to diols. The action of Acetobacter aerogenes on sugars yields a mixture of mesoand (+)-butane-2,3-diols. Fermentation of starches by Bacillus polymyxa yields the (--)-isomer (G. E. Ward et al., J. Amer. chem. Soc., 1944, 66, 541; A. C. Neish, Canad. J. Research, 1945, 23B, io). By enzymatic reduction glycolaldehyde may be converted to ethylene glycol (C. Neuberg and E. Schwenk, Biochem. Z.,
I
ALKANEDIOLS
9
19x5, 7x, IX4). For the metabolism of ethylene glycol, see C. J. Cart and J . C. Krantz, Adv. carbohydrate Chem., 1945, x, I76; G. Reif, Pharmazie, 195 o, 5, 276-
(iv) General properties and reactions The lower paraffin glycols are thick, neutral, high boiling liquids, having a sweetish taste. They show extensive hydrogen bonding (see G. C. Pimental and A. L. McClellan, "The Hydrogen Bond", W. H. Freeman & Co., San Francisco and London, I96O), are easily soluble in water but only slightly soluble in ether. The higher homologues may be obtained as crystalline solids and are often appreciably soluble in ether. Diols form the normal functional derivatives like ethers and esters by the usual methods applied to monohydric alcohols. Some polyesters with dibasic acids are of great commercial importance, e.g. poly(ethylene glycol terephthalate). Diols readily form acetals and ketals with aldehydes and ketones, which with 1,2- (and sometimes 1,3- ) diols are cyclic and thus provide means of protecting carbonyl groups during reactions involving other functional groups in the molecule. With 1,2-diols and acetone cyclic isopropylidene ethers are obtained, which are readily reconverted into the original starting materials on hydrolysis" CHgOH
CH,--O. ~- OC(CH3) 2 ----~ [ )C(CH3) 2 CH9OH CH~--O" Glycol isopropylidene ether
I
Glycols also undergo the following more specific reactions. (I) Action of alkali metals. At ordinary temperatures sodium forms with ethylene glycol a mono-sodium glycoxide from which the di-sodium salt can be obtained by heating with sodium at z 9o~ Solutions of sodium, potassium, and lithium in liquid ammonia give mono-metallic salts (E. Chablay, Compt. rend., I912, I54, I5o7). The di-metallic salts of pinacols may be obtained by treating ketones with alkali metals in ether or liquid ammonia (W. E. Bawl,mann, J. Amer. chem. Soc., I933, 55, II79; C. B. Wooster, ibid., I934, 56, 2436). (2) Action of dehydrating agents. Dehydration, with acid catalysts or by heating, of each class of glycol is summarized below. 1,2-Glycols. Ethylene glycol gives acetaldehyde" CH,OH. CH,OH -----> CHsCHO
Other 1,2-glycols give mixtures of carbonyl compounds" CHROH. CHR'OH
~ RCOCH~R' ~- CHgRCOR'
IO
GLYCOLS
12
(L. Bouveault and R. Locquin, Bull. Soc. chim. Fr., 19o6, [iii], 35, 643, 646). Tertiary 1,2-glycols undergo the pinacol-~inacolone rearrangement. The dehydration of pinacol, obtained by reduction of acetone, to tert-butyl methyl ketone by dilute acid was first observed by R. Fittig in 1859. The mechanism of the rearrangement has been extensively investigated, and involves formation of a carbonium ion from the conjugate acid as the rate-determining step, followed by migration of an alkyl group: (CHs)sC----C(CHs)s ,.
i
I
OH OH
(CHs)sC----C(CHs)s
I
I
*0H s OH
- - + (CHs)tG--C(OH) (CHs)s ---+ (CHs)sC--C(OH) .CHs # (CHs)sC.CO. CHs A number of closely related rearrangements are known; all proceed by similar mechanisms (see C. K. Ingold, "Structure and Mechanism in Organic Chemistry', Bell, London, 1953).
1,3-Gtycols. Butane-I,3-diol is dehydrated to butadiene at 200-24 ~ over a phosphate catalyst. With a zinc oxide catalyst at 4000 a mixture of methyl vinyl ketone and crotonaldehyde is obtained (E. Arundale and H. O. Mottern, U.S.P., 2,62o,357/1952). Saturated carbonyl compounds are also obtained (F. X. Schmalzhofer, Monatsh., 19oo, 21, 680" T. Hackhofer, ibid., 19Ol, 22, 95):
CHROH. CHR'. CHsOH ---+ CHsR. CHR'. CHO In 2,2-dialkyl-I,3-diols rearrangements similar to the pinacolic change m a y be observed, or oxide rings m a y be formed (M. A. Perry and R. E. de Busk, U.S.]~., 2,87o,214/1959): (CHs)sCH. CHOH. C(CH3)s. CHsOH i
l
(CHs)sCH. CHs. C(CHs)s. CHO + (CHs)sC.CH,. C(CHs)s. CH,O Rearrangements m a y also be observed in neopentyl systems (A. Fischer and
B. Winter, Monatsh., 19oo, 21, 3oi), thus: (CHs)sC(CHzOH)s ---+ (CHs)sC:CH. CHsOH ---+ (CH3)sCH. CHs. CHO Cleavage of ditertiary 1,3-glycols has been observed under acid conditions
(J. English and F. V. Brutcher, J. Amer. chem. Soc., 1952, 74, 4279), for example, 2,4-dimethylpentane-2,4-diol on treatment with sulphuric acid at room temperature forms acetone. 1,4-, 1,5-, z,6-etc. Glycols. The reactions of 1,4-diols have been investigated by T. A. Favorskaya and co-workers (J. gen. Chem. U.S.S.R.,
I
ALKANEDIOLS
II
1955, 25, 1459; 1956, 26, 447; 1957, 27, lO18). Tetrahydrofuran derivatives are formed through the intermediacy of unsaturated alcohols, which m a y themselves be isolated under favourable conditions. 2-Methylpentane-2,5-diol with dilute sulphuric acid yields a mixture of 2methylpent-2-en-5-ol and 2,2-dimethyltetrahydrofuran, whereas only the latter is obtained using a trace of acid as catalyst. Higher homologues, however, form derivatives of tetrahydrofuran and tetrahydropyran with 5o % sulphuric acid (A. Franke et al., Monatsh., 1929, 53-54, 577; Ber., 1932, 6o, lO6; 1936, 69, I67), but give alkenols on heating to 15o-3oo o with traces of acid (E. Ebel and H. Friederich, G.P., 8o3,354/I948). (3) Hydrogenation and dehydrogenation. Vigorous catalytic hydrogenation m a y result in carbon-carbon bond fission. Thus ethylene glycol gives ethanol or methanol, depending on the catalyst used (J. Mizuguchi and M. Ohashi, J. chem. Soc. Japan, Ind. Chem. Sec., I95O, 53, 93), and 2-methylpentane-2,4-diol gives isopropanol (H. Adkins et al., J. Amer. chem. Soc., 1932, 54, 4678, and later papers). Dehydrogenation of 1,4-diols has been studied extensively by W. Reppe (Ann., 1955, 596, 158). The most important products are ?-lactones, but diketones, ketols, and other compounds are also obtained. (4) Oxidation. Vigorous oxidation of diprimary glycols gives dibasic acids. Alkaline permanganate m a y cause carbon-carbon bond fission particularly in highly substituted glycols (Franke and M. Kohn, Monatsh., T9o7, 28, lO14). Cleavage of 1,2-diols to carbonyl compounds: CRR'(0H). C(0H)R'R" ---+ R R ' C 0 + R ' R " C 0
is conveniently brought about using lead tetra-acetate (R. Criegee et al., Ber., 1931, 64, 26o; I94 o, 73, 563; Ann., 1933, 5o7, I59), periodic acid (L. Malaprade, Bull. Soc. chim. Ft., 1928, [iv], 43, 683; Compt. rend., 1931, x86, 382), or sodium bismuthate (W. Rigby, J. chem. Soc., I95O, 19o7). Acyloins and x-dicarbonyl compounds are also cleaved by these reagents. Periodic acid is particularly valuable in quantitative analysis (see I. M. Koltho~ et al., "Volumetric Analysis", Vol. III, Interscience, New York, 1957, P. 475).
(a) 1,2-Glycols Ethylene glycol, ethane-I,2-diol, glycol, CH2OH.CHzOH, m.p. m I 3 ~ b.p. I97"2 ~ d~~ 1-1155, n~~ I "4316, is miscible with water and alcohol, and sparingly soluble in ether. It is best purified by distillation under reduced pressure (B. T. Brooks and I. Humphrey, Ind. Eng. Chem., 1917, 9, 75o). It is prepared industrially
GLYCOLS
12
12
from ethylene oxide and by other methods mentioned on p. 8 and in the laboratory by any of the relevant methods described on pp. 3-8. It dissolves inorganic compounds such as lq'aC1, ZnC1v K2CO 3, KOH and Ca(OH)~. Isopropylidene ether, b.p. 92-6~ ram.; bisphenylurethane, m.p. 157.5 ~ For physical constants of this and other common glycols, see G. O. Curme (Ed.), "Glycols", Reinhold, New York, 1952; (for patent literature, see H. Bahr and H. Zieler, Angew. Chem., I93 o, 43, 286; Ann. Report appl. Chem., 1932 and onwards; P. P. McClellan, Ind. Eng. Chem., I95 o, 42, 24o2). Oxidation. The stepwise oxidation of glycol may be represented as follows: CH~OH
[
CH~OH
~l
CHO
--+l
CHgOH Glycolaldehyde
C02H I
CHO
C09H
---~i
CHO CHO Glyoxal Glyoxylic acid
//
CO~H
---+J
C09H Oxalic acid
HCO~H
~ +
COs
CHz0H Glycoliic acid Under mild oxidizing conditions glycolaldehyde (see p. 45) is formed. Glyoxal may be obtained in good yield by vapour phase oxidation. Vigorous oxidation gives oxalic and formic acids and carbon dioxide. Biochemical oxidation leads to glycollic and oxalic acids (P. Mayer, Z. physiol. Chem., 19o 3, 38, 144; A. J. Brown, J. chem. Soc., 1887, 5 I, 638; A. Harden and D. Norris, Proc. roy. Soc., 1911, B84, 492; 1912, B85, 73)(+)-Propane-I,2-diol, propylene glycol, C H s . C H O H . C H z O H , b.p. 188.2 ~ d22o ~ I. o381, n~)~ i- 4326; bisphenylurethane, m.p. 152" 5-153" 5 ~ is miscible with water and sparingly soluble in ether. Its properties and methods of preparation are similar to those of ethylene glycol. It has been detected in fermentation liquors (A. J. Kluyver and C. Schellen, Enzymologia, 1937, 4, 7). Optical isomers. Both D- and L-forms, [x]~o + i5 o, are known. Resolution of the strychnine salt of the (+)-diol is possible (A. Gri~n, Bet., 1919, 52, 26o). L(+)-Propylene glycol is formed by the asymmetric reduction of acetol with yeast reductase (Org. Synth., Coll.Vol. II, I943, p. 545) and from D( +)-isopropylideneglycerol (E. Baer and H. O. L. Fischer, J. Amer. chem. Soc., 1948, 70, 6o9). Butans-I,2-diol, CzHs.CHOH. CHzOH , b.p. 191 ~ ( + )-Isomer, b.p. 91~ mm., [x]~2 + 12.40. (--)-isomer, b.p. 94~ ram., [x]~2 w 7 . 4 0 (P.A. Levene and H. L. Hallsr, J. biol. Chem., 1927, 74, 343). Butane-2,3-diol, C H s - C H O H . C H O H . C H 3 , is a product of the fermentation industry. (+)-Form, b.p. 177 ~ m.p. 7.6~ bisphenylurethane, m.p. 2Ol-2O2~ meso-]orm, b.p. 182 ~ m.p. 34.4 ~ bisphenylurethane, m.p. 175~ D(m)-buta~ce-
I
ALKANEDIOLS
13
2,3-diol, b.p. 178~ m.p. 18 ~ [x]~ --13.20 (H. J. Lucas and H. 14. Garner, J. Amer. chem. Soc., 1948, 7 O, 990)" L( + )-isomer, [x]~~ + 14"60 (J. B6esehen and R. Cohen, Rec. Tray. chim., 1928, 47, 839; cf. L. J. Rubin, H. A. Lardy and H. O. L. Fischer, J. Amer. chem. Soc., 1952, 74, 424) 9 When passed over a hot copper catalyst, butane-2,3-diol is dehydrogenated to 3-hydroxybutan-2-one, or, if oxygen is present, to diacetyl. 2-Methylpropane-I,2-diol, b.p. I97 ~ can be obtained from isobutene by hydroxylation or by hydrolysis of isobutylene oxide. Pentane-I,2-diol, b.p. 2o9 ~ is formed in the hydrogenation of furfuryl alcohol. Pentane-2,3-diol, b.p. 187 ~ 3-Methylbutane-I,2-diol, b.p. lO3~ mm. 2-Methylbutane-I,2-diol, b.p. 188 ~ 2-Methylbutane-2,B-diol, b.p. 178~ Pinacol, 2,3-dimethylbutane-2,3-diol, tetramahylethylene glycol, (CH3),C(OH) 9 C(OH)(CH3),, m.p. 4 I~ b.p. I72-8 ~ hexai~ydrate, m.p. 46-47 ~ (Org. Synth. Coll. Vol. I, 1941, p. 459). tert-Butyl methyl ketone is the chief product under many conditions of dehydration (see p. IO) but with hydrobromic acid or by passing pinacol vapour over alumina, 2,3-dimethylbuta-I,3-diene can be obtained.
(b) 1,3-Clycols Propane-l,3-diol, trimethylene, glycol, C H , O H . C H , . C H , O H , b.p. 2 I O - - 2 I I 0, "O554 " bisphenylurethane, m.p. 137.5 ~ is produced in the fermentation of glycerol (A. J. Rayner, J. Soc. Chem. Ind., I926, 45, 265, 287; C. H. Werkman et al., J. Bact., 1932, 23, I67; I94 o, 39, 7o9) 9 I t can also be obtained from acrolein by hydration followed by hydrogenation (L. F. Hatch and T. W. Evans, U.S.P., 2,434,IIO/I948 ) and is present in the products of the vigorous catalytic reduction of sucrose (T. Tanno, Bull. chem. Soc. Japan, I936, xz, 204). Butane-I,3-diol, CH 3 .CHOH .CH,. CH2OH, b.p. 2o7.5 ~ d~~ 1.oo59, is prepared by the reduction of aldol. Enzymatic reduction of acetoacetaldehyde or of I-hydroxybutan-3-one yields the (m)-isomer, [a]~5 - - 1 8 . 8 ~ (P. A. Levene and A. Walti, J. biol. Chem., 1931, 94, 361). The (+)-isomer, [~]~* 7.5 ~ has been obtained by reduction of D-methyl 3-hydroxybutyrate and by deamination of D-I-aminobutan-3-ol (Levene and H. L. Haller, ibid., 1926, 69, 165, 569). Pentane-2,4-diol, C H 3 . C H O H . C H , . C H O H . C H 3, b.p. I99 ~ m.p. 45 ~ is prepared by reduction of acetylacetone (H. Adkins et al., J. Amer. chem. Soc., I934, 56, 2669; 1939, 61, 33o3), or of the corresponding ketol (J. E. Dubois, Compt. rend., 1947, z24, 1234). Dehydration affords piperylene. 2-Mahylbutane2,4-diol, b.p. 2o3 ~ yields isoprene on dehydration. 2-Methylpentane-2,4-diol, hexylene glycol, b.p. 197.1 ~ d**o ~ o'9234, is manufactured by the hydrogenation of diacetone alcohol. Dehydration gives 2-methylpenta-I,3-diene together with some 4-methylpenta-I,3-diene (L. P. Kyriakides, J. Amer. chem. Soc., 1914, 36, 980; G. B. Bachman and C. G. Goebel, ibid., 1942, 64, 787). I t reacts specifically with aldehydes at pH 3 to give derivatives of 1,3-dioxan ill high yields (F. R. Fischer and C. W. Smith, J. org. Chem., 1963, z8, 594). 2,4-Dimethylpentane-2,4-diol, (CHs),C(OH) .CH,.C(OH)(CHs) ,, b.p. 98~
d~ ~ I
14
GLYCOLS
12
13 mm., is prepared by the action of methylmagnesium halides on diacetone alcohol; it loses water on distillation at ordinary pressure to give 2,4-dimethylpentI-en-4-ol, b.p. I28~ ram. 2,3,3,4-Tetramethylpentane-2,4-diol, (CHb)~C(OH) -C(CHb) 2"C(CHb)~OH, b.p. 2340/76o mm., m.p. 76 ~ is prepared by the reaction of methylmagnesium iodide and dimethylmalonic ester. 2-Ethylhexane-I,3-diol, CH 8 -CH 2 .CHi .CHOH. CH(C,Hs). CH ~OH, b.p. 244.2~ mm., d=2o ~ 0"9422, is manufactured by the reduction of butyraldol. It is one of the most effective insect repellents known.
2,2-Dimethylpropane-I,3-diol,
2,2-dimethyltrimethylene
glycol, pentaglycol,
(CHs) ,C(CH ~OH) ~, m.p. 129 ~ b.p. 2o6 ~ This and its homologues, RR'C(CH2OH ) 2, are prepared by reduction of the appropriate aldol or substituted malonic ester (H. L. Yale et al., ibid., 195o, 72, 3716). 2-Methyl-2-propylpropane-I,3-diol, m.p. 62-63 ~ is the parent of the important tranquilizing drug "Meprobamate". 2,2-Dimethylbutane-I,3-diol, CHzOH'C(CHs)~.CHOH.CH 8, m.p. IO~ b.p. 2o70/760 mm. 2,2-Dimethylpentane-I,3-diol, CH2OH'C(CHs) z'CHOH'C2Hs, m.p. 6o-63 ~ b.p. 213~ mm. 2,2,4-Trimethylpentane-I,3-diol , m.p. 52~ b.p. 223o/76o ram.
(c) 1,4-Glycols Butane-I,4-diol, tetramethylene glycol, HO(CH2)4OH, m.p. 16 ~ b.p. 23o0/ 76o mm., d~~ 1-020; bisphenylurethane, m.p. I8O ~ is prepared by the hydrogenation of but-2-yne-I,4-diol (Reppe et al., Ann., 1955, 596, 38). Dehydration may be controlled to give either butadiene or tetrahydrofuran, while dehydrogenation gives ~-butyrolactone (Reppe et al., ibid., p. 8o, 158 ). Pyrrolidine is formed by passing the diol and ammonia over alumina at 40o~ with hydrogen sulphide under similar conditions, tetrahydrothiophen is obtained (Y. K. Yur'ev and N. G. Medovshchikov, J. gen. Chem. U.S.S.R., 1939, 9, 628). A series of 2-alkylbutane-I,4-diols have been prepared by reducing diethyl 2-alkylsuccinates with lithium aluminium hydride (C. G. Overberger and C. W. Roberts, J. Amer. chem. Soc., 1949, 7I, 3618). Pentane-I,4-diol, CHb'CHOH'(CH~)3.OH, b.p. I23-I26~ ram., 2220/76o mm., with partial dehydration to the oxide (see R. M. Hill and H. Adkins, ibid., 1938, 6o, lO33 ). An optically active form is known (P. A. Levene et al., J. biol. Chem., 1927, 72, 591). 2-Methylpentane-2,5-diol, (CHb)zC(OH).(CH2)s.OH , b.p. IO7~ ram., 2220/ 76o mm. (L. Henry, Compt. rend., 19o6, x43, 1221; A. Franke and M. Kokn, Monatsh., I9O7, 28, IOO6). 3-Methylpentane-2,5-diol, CHs'CHOH-CH(CHb).CH2.CH~OH, b.p. I34~/ 2o mm. (C. D. Nenitzescu, Bet., 1937, 70, 277). Hexane-I,4-diol, b.p. i280/i3 mm. (C. Glacet, Compt. rend., 1944, 2z8, 283). Hexane-2,5-diol, b.p. 22o-8~ ram.; a solid form, m.p. 43 ~ is also known (G. Dupont, Ann. Chim., 1913, 30, 526; Y. S. Zal'kindandA. I. Nogaideli, J. gen. Chem., U.S.S.R., 1938, 8, 1816).
2
UNSATURATED
GLYCOLS
15
(d) 1,5-Glycols Pentane-x,5-diol, pentamethylene glycol, b.p. 239.40/760 mm., d22o ~ 0"994" bisphe~cylurethane,, m.p. I74 ~ is obtained by hydrogenation of 2-hydroxytetrahydrolyyran or of tetrahydrofurfuryl alcohol at high temperature and pressure (Org. Synth., 1946, 26, 83). Hexane-I,5-diol, b.p. 14o-141~ mm., may be prepared by reduction of x-hydroxyhexan-5-one, or of ethyl 5-oxohexanoate (R. M. Hill and H. Adkins, J. Amer. chem. Soc., 1938, 69, lO33). (e) 1,6-, 1,7-, 1,8-Glycols, etc. The higher diprimary glycols may be obtained by reduction of the dicarboxylic acids or their esters (Org. Synth., Coll. Vol. II, p. I54" R. F. Nystrom and W. G. Brown, J. Amer. chem. Soc., 1947, 69, 2548). Hexane-I,6-diol is also prepared by reduction of hexa-2,4-diyne-I,6-diol (Reppe et al., Ann., 1955, 596, 38). Certain of the higher glycols, in particular hexane-I,6-diol, decane-I,Io-diol, and octadecane-I, I2-diol (prepared from ricinoleic acid or castor oil, W. A. Lazier, U.S.P., 2,o94,6II/I937), are of some technical interest. The physical constants of some higher diprimary glycols are listed below. Hexane-I,6-diol, m.p. 42. 80, b.p. 243~ mm. Heptane-I,7-diol, m.p. 20.2 ~ b.p. 151~ mm. Octane-I,8diol, m.p. 62 ~ b.p. 154-156~ mm. Nonane-I,9-diot, m.p. 43 ~ b.p. I73~ mm. Decane-I,Io-diol, m.p. 72~ b.p. I79~ mm. Undecane-I,Ii-diol, m.p. 63 ~ Dodecane-I,I2-diol, m.p. 81 ~ Tridecane-I,I3-diol , m.p. 75-77 ~ Tetradecane-i,i 4diol, m.p. 85 ~ Octadecane-I,I8-diol, m.p. 97-98~
2. Unsaturated glycols (a) Olefinic glycols The simplest representatives, e.g. ethene-I,2-diol, H O C H : C H O H , are, like vinyl alcohol, not stable substances although derivatives such as esters and ethers are known. Preparation" Ethylenic diols are conveniently obtained from: (I) dienes by methods similar to those given on pp. 4 and 7. (2) acetylenic diols by partial hydrogenation (A. W. Johnson, "The Acetylenic Alcohols", Arnold & Co., London, 1946; cf. Re~bpe et al., loc. cit., p. 38) ; (3) unsaturated carbonyl compounds by bimolecular reduction or by reaction with the Grignard reagents from dihalogen compounds. Properties and reactions. The physical properties of olefinic glycols are similar to those of the analogous paraffinic glycols, and their chemical properties combine those of glycols and olefins. Thus they form crystalline dibromides which are converted to mono- and di-epoxides by the action
16
GLYCOLS
12
of potassium hydroxide. On hydrogenation they form saturated glycols and on hydroxylation saturated tetraols. Butene-3,4-diol, e~,ythrol, CH~:CH.CHOH-CH~OH, b.p. 196.5 ~ 91-92~ 12 mm., d 2~ 1-o47o3, **~o 1.4614 (C. Prdvost, Axln. Chim., 1928, 1o, 113, 356" A. Valette, ibid., 1948, 3, 644); bisphenylurethane, m.p. 125-126~ dibromide, m.p. 88-89 ~ But-2-ene-I,4-diol, CH,(OH).CH:CH.CHzOH. The cis-isomer b.p. I34-I35~ 15 mm., n~5 1.4716, is formed by hydrogenation of but-2-yne-I,4-diol (,4. W. Johnson, J. chem. Soc., 1946, lO14); dibenzoate, m.p. 69-70~ bis(3,5-dinitrobenzoate), m.p. 171-172~ The trans-isomer produced by the action of caustic soda on 1,4-dichloro- or 1,4-dibromo-but-2-ene , has m.p. 25.5~ b.p. i3i-5~ 12 mm." d~~ 1-o698" n~~ 1.4772; dibenzoate, m.p. IOI ~ (Prdvost, Compt. rend., 1926, I83, 1291; Valette, loc. cir.).
(b) Diolefinic glycols Hexa-I,5-diene-3,4-diol, CHz:CH.CHOH-CHOH.CH:CH~, b.p. 197-198~ 97~ mm., d~s 1.oo7, prepared by bimolecular reduction of acrolein, exists in meso-, m.p. 18 o and racemic-, m.p. 14 ~ forms (J. Wiemann, Ann. (;him., 1936, 5, 287; W. G. Young et al., J. Amer. chem. Soc., 1943, 65, 1245). The diols can be purified via the tetmbromides, m.p. 1740 and m.p. 90 ~ The (+)-isomer (3R, 4R) [x]~7 +82.60, is formed by treating the tetra-toluene-p-sulphonyl derivative of D-mannitol with sodium iodide ill acetone (P. Karrer and P. C. Davis, Helv., 1948, 31, 1611; R. Criegee et al., Ann., 1956, 599, 81). Dehydration by boiling with dilute sulphuric acid gives vinylcrotonaldehyde (M. Ti~eneau and P. Weill, Compt. rend., 1937, 2o4, 590).
(c) Acetylenic glycols The most important members of this class are the acetylenic-I,4-glycols , R R ' C ( O H ) . C i C . C ( O H ) R R ' , which are readily prepared by the reaction of acetylene and two equivalents of a carbonyl compound (Reppe et al., Ann., 1955, 596, I; see also A. W. Johnson, op. cir.; R. A. Raphael, "Acetylenic compounds in Organic Synthesis", Butterworths, London, 1955). Unsymmetrically substituted analogues m a y be obtained by reaction of ethynyl carbinols with carbonyl compounds. But-2-yne-I,4-diol CHeOH.CZC.CH2OH, m.p. 64 ~ b.p. I45~ ram., is prepared by the reaction of acetylene and formaldehyde in the presence of a copper acetylide catalyst containing bismuth to inhibit the formation of cuprene (Reppe et al., loc. dr.). It was prepared on a very large scale in Germany during the 1939-1945 war for conversion to buta-I,3-diene and synthetic rubbers. Its reactions have been discussed by A. W. Johnson (J. chem. Soc., 1946, lOO9
2
UNSATURATED GLYCOLS
17
lO14). It forms normal esters and ethers. On hydrogenation it yields successively but-2-ene-I,4-diol (p. 16) and butane-I,4-diol (p. 14). With bromine 2,3-dibromobut-2-ene-I,4-diol, m.p. 116-1170, is formed. With thionyl chloride and pyridine 1,4-dichlorobut-2-yne, b.p. 68-69~ mm., is obtained, which on treatment with IO% aqueous caustic soda gives diacetylene (Vol. IA, p. 467). Hex-3-yne-2,5-diol, CHs-CHOH.CiC.CHOH.CH s, exists in two forms, one of which has m.p. 7o~ The mixture has b.p. 122~ mm., n~3 I "4733, d~3 I-o23. 2,5-Dimethylhex-3-yne-2,5-diol, (CH3)2C(OH).CiC.C(OH)(CH3) 2, m.p. 95 ~ b.p. 2o5-2o6, is obtained from acetone and acetylene, via the dimagnesium derivative, or in the presence of caustic potash (e.g.C. Weizmann, B.P., 573,527/1941, 58o,921-2/I941). Dehydration gives dimethyldivinylacetylene, [CH,: C(CH 3) i C] 3; this reaction is typical of ditertiary acetylenic glycols. Hydrogenation yields successively either the ethylenic and saturated glycols, or tetramethyl-di- and -tetra-hydrofurans. Hydration in acid solution in the presence of mercuric salts gives a cyclic product:
C--C(0H) (CI-I,), C---C(OH) (CHs),
Hi0
CHa-C(CH,), CO--C(CH,)z
The diols are readily converted to the dihalides which undergo rearrangement to diene dihalides (W. Krestinsky, Ber., I926 , 59, 193 O) e.g.: (CH,) ~CBr. C i C. CBr(CH,) t
~ (CH,),C: CBr. CBr: C(CH,) ~
(d) Glycols of greater unsaturation A number of more complex acetylenic glycols occur in nature, e. g. octa2,6-dien-4-yne-I,8-diol, HOCH2CH" CH. C ! C- C H ' C H . CH~OH, trans-nona2-ene-4,6-diyne-I,9-diol, HOCH,. C H ' C H . (C" C)z" CH2" CH2OH, and deca-8ene-2,4,6-triyne-I,IO-diol, HOCH~-(CiC)a.CH:CH-CH~OH, are mould metabolites, and heptadeca-2,8,Io-triene-4,6-diyne-I,I4-diol , HOCH~. CH: CH(C i C) ~" (CH: CH) 3" (CHz) ~. CHOH. CHz" CH,. CH3, and octadeca-8,IO,I2triene-4,6-diyne-I,I5-diol, HO(CH2)3-(CiC),. (CH:CH)s.CH~-CHOH.CH~. CH2" CHs, are responsible for the toxicity of Umbelliferae (see E. R. H. Jones, Proc. chem. Soc., 196o, 199; R. C. Cambie et al., J. chem. Soc., 1963, 412o). Hexa-2,4-diyne-I,6-diol, CH2OH-(CiC),.CH,OH, m.p. I i i - I I 2 ~ is obtained by the oxidation of propargyl alcohol in the presence of cuprous chloride and ammonium chloride (Reppe et al., Ann., 1955, 596, 38). Hydrogenation gives hexane-I,6-diol. Octa-3,5-diyne-2,7-diol, CH3.CHOH. (C iC) ,-CHOH .CH v is similarly obtained from but-3-yn-2-ol. It occurs in meso- and DL-/orms, m.p. 67" 5-680 and lO8-1o9 ~ respectively. Hydrogenation gives octane-2,7-diol. A number of more complex unsaturated glycols are involved as intermediates in syntheses of members of the carotenoid group and will be discussed in Vol. II.
18
GLYCOLS
12
3. Derivatives of glycols
(a) O-Alkyl derivatives; alkoxyalkanols and bisalkoxyalkanes (i) Preparation The mono-alkyl ethers of the glycols i.e. the alkoxyalkanols, are prepared as follows. (I) By reacting a monometallic glycoxide with an alkylating agent: HOCH3. CH2ONa + C,HsI ~
NaI + HOCH2. CH2OCzH6
or from a halogenohydrin (or its ester) and an alkoxide. (2) By the action of alcohols or alkoxides on epoxides, frequently under increased pressure and temperature in the presence of a catalyst"
CHI. CHz + CzHsOH~ ~O j
HOCH~.CHzOC,H5
(L. H. Cretcher and W. H. Pittenger, J. Amer. chem. Soc., 1924, 46, 15o3; C. O. Young, U.S.P., 1,696,874/1928 ). The catalysts used include: nickel sulphate (W. Gibson and J. B. Payman, U.S.P., 1,774,o89/I93O), hydrosilicates (I.G., G.P., 558,6461193o), boron trifluoride (A. A. Parov, J. gen. Chem. U.S.S.R., 194o, IO, 98I), mineral acids (S. S. Al'tman and V. V. Kedrinskii, C.A., 1937, 3x, 6196; D. Swern, G. N. Billen and H. B. Knight, J. Amer. chem. Soc., 1949, 71, 1152" S. Searles and C. F. Butler, ibid., 1954, 76, 56), bases (H. M. Stanley and J. E. Youdl, B.P., 467,228/I935; Swern, Billen and Knight, loc. cir.). (3) By reduction of esters of the type ROCH,- CH,. CO~R' with sodium and alcohol. (4) From the reaction of alkoxy-derivatives of aldehydes, ketones, or esters with Grignard reagents. (5) By addition of a glycol to an olefin in the presence of sulphuric acid, e.g. ethylene glycol with isobutene forms mono- and di-tert-butyl ethers (T. W. Evans and K. R. Edlund, Ind. Eng. Chem., 1936, 28, 1186). The dialkyl ethers of the glycols i.e. bisalkoxyalkanes, are prepared as follows. (I) By the action of alkoxides on dihalogenoalkanes or on monohalogenoalkyl ethers. (2) From halogenoalkyl ethers by a Wurtz reaction or through a Grignard derivative (R. Dionneau, Ann. Chim., 1915, 3, 194; Compt. rend., 19o7, I45, 127; Bull. Soc. chim. Fr., 191o, [iv], 7, 327):
C~HsO(CH2)eMgI + ICH~OC2Hs----~CgHsO(CH2)~OC2H5
3
DERIVATIVES
19
(3) By alkylation of glycol monoalkyl ethers, e.g. with dialkyl sulphates.
(ii) Properties Glycol monoethers (alkoxyalkanols) undergo the normal reactions of monohydric alcohols, e.g. esterification, oxidation, dehydrogenation, dehydration, etc. They are typical ethers in forming peroxides on standing with air. Monoethers of 1,2-glycols in which the hydroxyl group is tertiary, on dehydration give aldehydes and ketones" R'R'C(OH). C H ( 0 R ) R "
~ R'R'CHCOR"
Diethers are relatively inert substances. Hydrobromic acid in the cold converts them to the bromides of glycol monoethers, (a, co-alkoxybromoalkanes) RO(CH,)nBr (J. Hamonet, Chem. Ztbl., 19o 4, I, 14oo). Raney nickel and hydrogen at 15o-2oo at. produces the glycol monoethers" thus ethylene glycol benzyl ethyl ether gives toluene, methylcyclohexane, and ethylene glycol monoethyl ether. The latter and the monomethyl ether are stable to hydrogen and Raney nickel at 200 o (E. M. Van Duzee and H. Adkins, J. Amer. chem. Soc., I935, 57, 147)-
Glycol monoethyl ether, 2-ethoxyethanol, Cellosolve, b.p. 135" I~ ram., d22~ o'9311, n~~ 1.4o76, is manufactured by the action of ethanol on ethylene oxide under pressure (see above). It is a colourless, almost odourless, mobile liquid, completely miscible with water and with many organic solvents. It is widely used as a solvent, e.g. for cellulose nitrate and acetate, resins, lacquers and enamels, leather dyestuffs and printing inks, and has a variety of other uses. Glycol monomethyl ether, Methylcellosolve, b.p. I24-5~ mm., d~o~ 0"9663, n~~ 1.4o21" monoisopropyl ether, b.p. I44 ~ dX~ o'9139, n~6 1"4o8o; monobutyl ether, b.p. I71.2 ~ d~ o-9o19, n~~ 1.4193. For urethane derivatives of the eellosolves see J. F. Manning and J. P. Mason, ibid., I94 o, 62, 3136. Ethylene glycol dimethyl ether, 1,2-dimethoxyethane, b.p. 85.2 ~ d~~ o.8692" diethyl ether, b.p. I2I-4~ d~O o.8417, n~~ 1.3922- dibutyl ether, b.p. 2o3.3~ d~~ o'8374, n~)~ 1.4131 (B. O. Field and C. J. Hardy, Chem. and Ind., 1962, 212). Ethylene glycol bis-2-chloroethyl ether, C1. (CH,) 2" O. (CH2) 0. O. (CH2) ~.C1, b.p. 23 o~ d~~ 1"197 (G. F. Zellhoeffer, Ind. Eng. Chem., 1937, 29, 548). The ethylene glycol diethers are useful as inert reaction media, e.g. in reactions involving lithium aluminium hydride. Ethers of higher glycols are useful industrial solvents, e.g. the monobutyl ether of butane-I,4-diol, 4-butoxybutan-i-ol, is a solvent for polyvinyl chloride.
(b) 1,2-Cyclic ethers. Alkylene oxides. Epoxides The cyclic ethers of 1,2-glycols, i.e. ethylene oxide and its homologues, are discussed here; for trimethylene oxide, dioxan, etc., see Vol. IV.
20
GLYCOLS
12
(i) Preparation The ethylene oxide (oxirane) ring is formed by the following methods. (I) By the action of alkali or a base on a halogenohydrin or the derived halogeno-ester, or on a glycol monotoluene-p-sulphonate. The method, first employed by A. Wurtz (Ann., 1859, 1io, I25), is still used in the manufacture of ethylene oxide and especially of propylene oxide: HOCH 2. CHIC1
Ca(0H)t
-+ C H 2 - - C H ~ + CaCI 2 + H 2 0
(2) The direct oxidation of olefins can give epoxides. In the presence of a silver catalyst at 25o-3000 ethylene vapour reacts with air to give ethylene oxide, together with carbon dioxide and water, the products of further oxidation. The process was discovered by T. E. Le]ort (F.P., 729,952] 1931 ) and is presently the basis of the most important industrial method for ethylene oxide. :Numerous descriptions of the analogous oxidation of propylene exist in the patent literature, but propylene oxide is not currently prepared by such a method. (3) Per-acids react with olefins to give epoxides directly:
I I --C=C--+
I RCOsH
->--C
; C---+ R C O ~ H
Perbenzoic, monoperphthalic, and peracetic acids (D. Swern, Org. Reactions, 1953, 7, 378; J. A. John and P. ]. Weymouth, Chem. and Ind., 1962, 62) have been employed. Peroxytrifluoroacetic acid in the presence of sodium carbonate is especially useful for the epoxidation of carbon-carbon double bonds deactivated by electron-withdrawing substituents such as C--O, C~-I~ (W. D. Emmons and A. S. Pagano, J. Amer. chem. Soc., 1955, 77, 89). In sufficiently acid conditions the oxide ring may be opened to give the glycol monoester. (4) The action of diazomethane on an aldehyde or ketone may give an epoxide (see B. Eistert, "Newer methods of Preparative Organic Chemistry", Interscience, 1948, pp. 521,527): RCOR"
+ CHgN 2
-> R R ' C
CH 2
(5) The Hofmann degration of alkylcholines produces epoxy compounds
(E. SJ)~th et al., Ber., 1933, 66, 591; 1941, 74, 599; C. E. Wilson and H. W. Lucas, J. Amer. chem. Soc., 1936, 58, 2396):
3
DERIVATIVES [CH s. (CH~) 5 9C H O H .
C H i N (CHa)a]eOH | ~
21 C H a. (CH~)5. C H - - C H
s
(ii) Properties and reactions Isomerization. In the vapour phase or in solution in the presence of mineral or Lewis acids, epoxides isomerize to aldehydes or ketones (V. Ipatiev and K. Leontovitsch, Ber., 19o 3, 36, 2o16; R. Lagrave, Ann. Chim., 1927, 8, 363; G. H. Twigg, Trans. F a r a d a y Soc., 1946, 42, 284, 657; E. L. Eliel and D. W. Delmonte, J. Amer. chem. Soc., 1958, 8o, 1744): RzC----CR i ~
RCO.
CR3
"~o/
Addition reactions. Alkylene oxides undergo ring-opening reactions with a wide variety of substances. Asymmetric oxides can form two products" R- C H ~ C H
2 + HA
> R.
CHOH. CHIA +
R. CH(A)-
CH2OH
~OJ Under basic or neutral conditions and when R is an electron-donating group, e.g. alkyl, the main product is that formed by attack at the least substituted carbon atom, namely R-CHOH.CHtA. Under acid conditions mixtures are likely to be produced: R.CH CHI ~OHeJ
slow
* Ae > R. CHCH2OH fast > R-CH(A).CHIOH
R. CHOH. CHI*
A|
fast
"-> R. CHOH. CHIA
There is evidence that A e attacks before the CmO bond is completely broken; thus cis-2,3-epoxybutane on acid hydrolysis gives the DL-glyco1, whereas the trans-isomer forms the meso-glycol (see p. 23). For a discussion of the mechanism of epoxide reactions, see R. E. Parker and N. S. Isaacs, Chem. Reviews, 1959, 59, 737. (I) With water epoxides give glycols or polyglycols (see pp. 3, 4, 28). (2) Alcohols and phenols give hydroxyethers; thiols react similarly to give hydroxy-thioethers. (3) Hydrogen halides and certain metallic halides, e.g. magnesium chloride, form halogenohydr ins. (4) Ammonia gives mono-, di-, and tri-alkanolamines; primary and secondary amines react similarly. (5) Hydrogen cyanide and metallic cyanides yield cyanohydrins. Thus
22
GLYCOLS
12
ethylene oxide gives 2-hydroxyacetonitrile which is readily dehydrated to give acrylonitrile. (6) Carboxylic acids and anhydrides react to give glycol mono- and diesters, respectively; thioacids react similarly. (7) With aldehydes and ketones, cyclic acetals and ketals (i.e. 1,3-dioxolane derivatives) may be isolated. Polymeric products are also formed. (8) Grignard reagents give alcohols: R C H ~ C H 2 + R'MgX
~ RCHOH-CHgR'
Two equivalents of the oxide must be employed to avoid formation of the halogenohydrin, R C H O H . C H , X ; the latter is always the main product when tert-alkylmagnesium halides are employed (N. G. Gaylord and E. I. Becker, ibid., 1951, 49, 413) 9 (9) Sodio-derivatives of malonic ester and acetoacetic ester react normally to give 2-hydroxyalkyl derivatives which may be converted to lactones. (IO) Sodium acetylides give acetylenic alcohols. (II) Sodium bisulphite forms hydroxy-sulphonic acids, RCHOH. CH,S03 H. (12) Thiourea and a variety of other thioamides react with epoxides to produce alkylene sulphides (cf. Rodd, C.C.C., Ist Edn., 1957, Vol. IVa, p. ~2). The products of many of these additions reactions are themselves capable of reacting with epoxides, thus polymeric materials may also be obtained in amounts depending on the reaction conditions employed. Reduction. Hydrogenation with nickel or platinum catalysts leads to an alcohol with the hydroxyl group attached to the least substituted carbon atom. The isomeric product is obtained by the use of lithium aluminium hydride. Olefins are obtained by heating epoxides with triethyl phosphite at 15o-1750 (C. B. Scott, J. org. Chem., 1957, 22, 1118).
Ethylene oxide, 1,2-epoxyethane, oxirane, CH,PCH 2, b.p. IO.7~
mm., crit.
temp. 195" 8~ d22~o'8711 (for physical constants, see G. O. Curme and F. Johnston, "Glycols", i~ew York, 1952, p. 88), is manufactured by the direct oxidation of ethylene, and also from ethylene chlorohydrin (R. P. Van Oosten, J. Inst. Petroleum, 196o, 46, 347)- It is miscible with water, alcohol, and ether, and forms a hexahydrate, m.p. 12 ~ It gives a positive iodoform reaction and precipitates silver from Tollen's reagent. Ethylene oxide is manufactured on a very large scale, for conversion into ethylene glycol and its ethers, non-ionic detergents, ethanolamines, polyethylene glycols and ethers, and acrylic polymers. It is also employed as a fumigant, being capable of destroying insects, moulds and bacteria. Structure. The bond lengths and angles in ethylene oxide have been computed
3
DERIVATIVES
23
from the microwave s p e c t r u m and confirmed b y electron diffraction (G. L.
Cunningham et al., J. chem. Phys., 1949, x7, 211; I95I, x9, 676; T. E. Turner and J. A. Howe, ibid., I956, 24, 924; M. Igarashi, Bull. chem. Soc. Japan, 1953, 26, 330). The r e p r e s e n t a t i o n of ethylene oxide as a ~-complex (A. D. Walsh, Nature, I947, x59, 165, 712" Trans. F a r a d a y Soc., 1949, 45, 179)" C H , ~ C H s , O has some advantages in explaining its properties (see Parker and Isaacs, loc. cir.) Propylene oxide, 1,2-epoxypropane, C H 3 . C H - - C H t, DL-/Orf~, b.p. 33"9~ 76o mm., d~~ o.83o 4, n~~ 1-3657" L(+)-/orm, [x]~x +150 (C. C. Price and M. Osgan, J. Amer. chem. Soc., 1956, 78, 4787) . D(--)-/orm, [~]~8 __8.260 (E. Abderhalden and E. Eichwald, Ber., 1918, 5z, 1312). Propylene oxide, manufactured from propylene chlorhydrin, is converted mainly to propane-I,2-diol and propanolamines. I t is also useful as a low boiling solvent and as a fumigant. 2,3-Epoxybutane, C H s ' C H ' C H - C H s, trans-(DL)-isomer, b.p. 53.5~ mm., -,O / d~5 o . 8 o l o , n~5 1.37o5 . D( + )-isomer, b.p. 53-5-53.7~ ram., [~]~5 + 5 9 . o 5 0 . cis-(meso)-isomer, b.p. 59.7~ ram., d~5 0.8226, n~s 1.38o2 (F. H. Dickey, et al., J. Amer. chem. Soc., 1952, 74, 944). The stereochemical relationships between the but-2-enes and their diols, chlorohydrins, and oxides are indicated in the schemes given below (cf. Dickey et al., loc. cir., and references therein): CH a
CH a
H 0 - - --H
Ac0-- --H
H
CH a
I ActO
pyridine
H-- ~ 0 H
HC1
HO---
H-- --0Ac
C1--- H
D(+)-
Ac0-- - - H
Act0
HCI o
Meso-
I H--C II H--C
HO-- --H
CH~
CH s
CI-Is
Cis-
CH 3
KOH O _+
-I'b
H__ --C1
Threo-
0___>.
CHs
CH s
H-- - - O H
H,O ~ 0
-.>.
H0-- --H
I
Cis-
CH s
D L-Threo-
CH 3 HOC1
D( +)-Trans
H-- --C1
CH s
CH s
CH s
I
CH a
HO-- --H
Ac0-- ~ H
Meso-
H--I/
CH s
pyridine H0-- --H
HC1
L( +)-ErythroCH s
CH s
<-'-O
CH a
CH s
CH s
H0-- --H
KOH0_> CHs--]%]
O
>
D(--)-
H
CI-Is
Cis-
CHa
Threo-
24
GLYCOLS CH 3
H--C
'
I2
CH8
HOC1 HO-- - - H
CHs--C
1
CH 8
KOH
H--
1
CHs-- J
I H
Trans-
CH 8
Erythro-
H
Trans-
CH 3 HtO ~
H0--
~H
H0--
~H
_._.D__..~
CH3
Meso-
(-Q--+ signifies inversion)
3,4-Epoxybut-I-ene, butadiene monoxide, CH~-CH.CH :CH v b.p. 66-66.5 ~ d "~ o.872o, n~~ 1-41o5, is prepared from an appropriate butylene chlorohydrin (W. E. Bissinger et al., J. Amer. chem. Soc., 1947, 69, 2955; Z. M. Raciszewski, E. Y. Spencer and L. W. Trevoy, Canad. J. Technol., I955, 33, 129; W. Reppe et al., Ann., 1955, 596, 8o) or by the action of peracetic acid on butadiene (A. N. Pudovik and B. E. Ivanov, J. gen. Chem. U.S.S.R., 1956, 26, 2771). 3,4-Epoxy-3-methylbut-I-ene, CH~.-C(CH 3) .CH :CH v b.p. 79" 5-80.5 ~ d 2~ ~OJ o'8574, *r i .418o, Call be obtained by treating isoprene with peracetic acid (Pudovik and Ivanov, loc. tit.).
(c) Glycol esters (i) Halides When glycols are allowed to react with halogen acids either one or both hydroxyl groups m a y be esterified (replaced by halogen) with the formation of halogenohydrins* and alkylene dihalides, respectively. Both these classes of compounds have already been described (Vol. IB, pp. 34 et seq. for halogenohydrins and Vol. IA, pp. 488 et seq. for dihalogenoalkanes) and need no further description here.
(ii) Esters of oxy-acids Nitrates are prepared from glycols by esterification with concentrated nitric acid in the presence of sulphuric acid, acetic or trifluoroacetic anhydrides. They are also formed in replacement reactions of dihalogeno compounds with silver or mercuric nitrates, and by electrolysis of salts of mono- and di-carboxylic acids in the presence of nitrate ions.
Ethylene glycol dinitrate, b.p. lO6~ ram., f . p . - - 2 2 ~ d~ 1-496, n~ 1.499, explodes on distillation at atmospheric pressure, and as an explosive is more powerful than nitroglycerine. Ethylene oxide and nitrogen dioxide form ethylene * This term is used also specifically for the halogen esters of glycerol (see Vol. I E, Chap. 18).
3
DERIVATIVES
25
glycol nitrate nitrite, O N O C H , . C H g O N O , (G. Rossmy, ]3er., I955, 88, 1969). The nitrite group is readily hydrolysed (to the alcohol) or oxidised (to the nitrate).
Phosphates and phosphites. 2-Hydroxypropyl mono-phosphate has been isolated from brain, liver, and kidney, and also from eggs of the sea-urchin (0. Lindberg, Art. Kemi. Min. Geol., 1943, x6A, No. I5, I, and later papers). For discussion of the formation and reactions of phosphate esters, see G. M. Kosolapo~, "Organosphosphorus Compounds", Wiley, New York, I95O; "Phosphoric Esters and Related Compounds", Chem. Soc. Special publication No. 8, London, I957 . Glycols form cyclic esters as well as normal esters with oxy-acids of phosphorus. (I) Alkyl phosphorodichloridites, ROPCI,, react with glycots in the presence of a base to give alkyl alkylene phosphites which on hydrolysis give hydroxyalkyl phosphites (A. E. Arbuzov, V. M. Zoroastrova and N. I. Rizpolozhenskii, Bull. Acad. Sci. U.S.S.R., I948, 2o8), thus: I
HOCH 2. CH2OH + C12POCH8
I
-> OCHi. CH~OPOCH 8 HOCH 2. CH, OP(OH)OCH s
(2) Epoxides react with phosphoric acid or its salts to form hydroxyalkyl phosphates (F. R. Atherton, H. T. Openshaw and A. R. Todd, J. chem. Soc., 1945, 382; G. R. Lam#son and H. A. Lardy, J. biol. Chem., 1949, I8x, 693, 697 ), e.g. : CH 8. CH. CH 2 + K3HPO 4 ~OJ
) CHsCH(OH)CHiOPO(OH)s
Sulphates and sulphites. (i) Glycols react with sulphuric acid or oleum under controlled conditions to give mono- and bis-hydrogen sulphates, e.g. HOCHi.CH~OSOsH and (CH~OSO3H)z (J. and R. Lichtenberger, Bull. Soc. ckim. Fr., 1948, lOO2). Mono- and di-esters are .also formed with chlorosulphonic and alkane- and arene-sulphonic acids, e.g. "Myleran", (. CH~. CH~OSOaCH3) ~. (2) Cyclic (neutral) esters are also known; thus ethylene glycol gives the t
I
I
I
sulphite, OCH~.CH20SO, on treatment with thionyl chloride and the sulphate, OCH~.CH~OSO~, with sulphuryl chloride. The properties of the glycol sulphuric acids are analogous to those of ethyl sulphuric acid (C. M. Suter, "The Organic Chemistry of Sulphur", Wiley, I944, P' 40). Borates. 1,2-Diols react with boric acid to form complexes of the type:
26
GLYCOLS
12
L io o
----C---O"
~0
!
O~
0
These are frequently formed in aqueous solution and cause an increase in conductivity and a decrease in pH as well as in rotatory exaltation if the glycol is optically active. Boric acid derivatives of the glycols have been well investigated (for reviews and references see M. F. Lappert, Chem. Reviews, 1956, 56, 959" W. Gerrard, "The Organic Chemistry of Boron", Academic Press, New York, 1961 , p. 16). The use of borate complexes in the separation of diastereoisomers of 1,2- and 1,3-diols has been described (J. Dale, J. chem. Soc., 1961, 91o). Similar esters containing silicon, arsenic and osmium have also been isolated. Esters containing B, V, As, Mo, Ti are said to inhibit oxidation and corrosion in lubricating oils in which they are used as additives (J. R. Thomas et al., U.S.P., 2,795,548-553/1954).
(iii) Esters of carboxylic acids Esters of glycols with carboxylic acids are of wide technical interest, e.g. as solvents, plasticizers, fibres and resins (see G. O. Curme and F. Johnston, ot). cir. Formation. (I) From dihalides, halogenohydrins or their esters by substitution reactions. The mechanism and stereochemistry of this class of substitution reactions have been investigated by S. Winstein and R. E. Buckles (J. Amer. chem. Soc., 1942 , 64, 2780, 2787), thus: CHs Br~
--H
CH3 AgOAc
H~ ~Br CHs DL-2,3-Dibromobutane
AcO~ - - H
CHs AcOrn[- H
AgOAc O HsO
___>
H-- mBr (~mole)
HOm[--H
CHs
CHs
threo-
erytkroCHs AcO~ ~ H Hm
~0Ac CHs
DL o
CHs AcO~
mH
AcO~
mH
CHs ~8S0-
3
DERIVATIVES
27
Cyclic intermediates have been postulated which account well for the high stereochemical purity ( > 95%) of the various products. (2) B y reaction of glycols with acids, acid chlorides or acid anhydrides, under conditions similar to those employed in the esterification of monohydric alcohols. (3) B o t h mono- a n d di-esters can be obtained b y the action of acids or acid anhydrides on epoxides; CH~mCH~ +CH 39CO,H -+ HOCH 2. CHzOCO. CH 8
AcOH HtSO~----~-
CHaCO,CH *. CH2OCO. CH8
(4) Mono-esters are obtainable b y the action of per-acids on olefins, the i n t e r m e d i a t e epoxide being unstable u n d e r sufficiently acidic conditions (cf. p. 2I). (5) B y ester interchange; e.g. ethylene glycol with isopropenyl acetate in the presence of sulphuric acid gives ethylene glycol diacetate and acetone (D. C. Hull a n d A. H. Agett, U.S.P., 2,422,o16/1947).
Ethylene glycol mono/ormate, HOCH~.CH,OCHO, b.p. 179-18o~ mm., d~s 1"1915, n~)s 1-413o" di/ormate, b.p. I74 ~ d o 1"193" monoacetate, b.p. 187I89~ mm., d~~ I. lO9O, n~)~ i -4209" diacetate, b.p. 19o. 5~ ram., d~o~ i . lO63" n~~ 1"4159. For other esters of the glycols with monocarboxylic acids, see under the various carboxylic acids: Beilstein, " H a n d b u c h der Organischen Chemie", 3rd supplement, I96O, Vol. II. Esters of dicarboxylic acids. The cyclic esters of carbonic acid have i m p o r t a n t industrial applications, for example, as solvents, a n d in the formation of polyesters. I
I
Ethylene carbonate, 1,3-dioxolan-2-one, OCH~-CH,OCO, m.p. 38-5-39 ~ b.p. 238~ can be prepared (I) from glycol and either phosgene or ethyl chloroformate in the presence of pyridine (C. F. AUpress and W. Maw, J. chem. Soc., 1924, 125, 2259); (2) by heating ethylene oxide and carbon dioxide under pressure in the presence of tetraethylammonium bromide (J. G. N. Deewite and J. Lincoln, U.S.P., 2,773,o7o/1957 ). When heated with formic acid it gives ethylene glycol diformate, while with mono-esters of dicarboxylic acids it forms polyesters (M. Lichtenwalter and J. F. Cooper, U.S.P., 2,8o2,8o7/1956 ). Glycols and dibasic acids of the type HO,C(CH~)nCO,H form lilxear polyesters many of which can be drawn into fibres; e.g. poly(ethylene glycol terephthalate) is now of great importance in the synthetic fibre field as the basis of Terylene, Dacron, etc. (W. H. Carothers and J. W. Hill, J. Amer. chem. Soc., 1932, 54, 15591. When these products are heated under reduced pressure in the presence of a catalyst such as stannous chloride, depolymerization occurs with the formation of macrocyclic lactones (W. H. Carothers et al., ibid., 1933, 55, 5o31,
28
GLYCOLS
12
5039; 1935, 57, 925, 929. For more details see thisVol., Chapter 26; Rowland Hill, "Fibres from Synthetic Polymers", 1953, Elsevier, Amsterdam; R. W. Moncrie~, "Man-made Fibres", 4th Edn., 1963, Heywood, London). 4. Polyethylene glycols
Diethylene glycol, 2,2"-dihydroxydiethyl ether, HO(CH~)90(CH2)9.OH , m.p. - - I O . 5 ~ b.p. 245~ ram., 1330/14 mm. d~~ 1.1184, n~~ 1.4472, is formed together with ethylene glycol and triethylene glycol by the action of water on ethylene oxide (C. Matignon, H. Moureu and M. Dodd, Bull. Soc. chim. Fr., 1934, Iv], z, 13o8). It is also produced by the reaction of glycol with ethylene oxide or ethylene halogenohydrins. It is a stable, slightly viscous, colourless, odourless liquid, with sweetish burning taste. It is completely miscible with water, the lower alcohols, and acetone. It is a solvent for a wide variety of dyes, resins, oils and other organic compounds, and has a number of other important uses. Diethylene glycol chlorohydrin, 2-(2'-chloroethoxy)-ethanol, CI(CHz)3" O. (CHI) aOH, b.p. 18o-185~ mm., is prepared from ethylene oxide and ethylene chlorohydrilx at 14~ in the presence of acidic catalysts; it is very soluble in water. Diethylene glycol fluorohydrin, b.p. I72-I740 , d~o~ 1.115 o, n~~ I .413 o, on treatment with thionyl chloride gives 2-chloro-2'-fluorodiethyl ether. Diethylene glycol bromohydrin, b.p. 1420/12 mm. Diethylene glycol monvethyl ether, Carbitol, C~H~O(CH~) ~O(CH2) 2OH, b.p. 2Ol .9~ mm., is obtained as a secondary product in the manufacture of glycol monoethyl ether from ethylene oxide and ethanol (see above). It, and other alkyl ethers are excellent solvents for cellulose esters; they are widely used as mutual solvents and in hydraulic fluids. Monomethyl ether, b.p. 194-2~ mm.; monobutyl ether, b.p. 23o.4~ mm. Dimethyl ether, b.p. I6O-I6I~ mm.; diethyl ether b.p. 188.9~ mm.; dibutyl ether, b.p. 254.6~ mm.; butyl ethyl ether, b.p. 218--2190. Dinitrate, m . p . - - i 1 - 2 ~ b.p. I6I~ mm., d~ I "391, is manufactured by the direct nitration of diethylene glycol. It is colourless, odourless, and slightly hydroscopic. It is less sensitive to shock than nitroglycerine, but a mixture with the .latter has a higher velocity of detonation than that of nitroglycerine alone. Diacetate, b.p. I20--I220/I2 mm. Monobenzoate, b.p. I53-4~ mm. Dibenzoate, b.p. 247~ mm. For other aromatic esters see H. C. Helm and C. F. Poe (J. org. Chem., 1944, 9, 299). Bisphenylurethane, m.p. 116-118 ~ Many esters of diethylene glycol are used industrially as plasticizers, and solvents and in the formation of synthetic resins. Triethylene glycol, triglycol, HO(CH,),O(CH,)~O(CH2),OH , b.p. 287.4~ 76o mm., i620/io mm., m.p. - - 9 . 4 ~ d~o~ 1"1254, n~~ I "4559, is obtained in the reaction of ethylene oxide with water, together with ethylene glycol and diethylerie glycol (see above). It has also been obtained, with other polyglycols, by heating ethylene glycol at 19o o with a trace of iodine (S. Z. Perry and H. Hibbert, Canad. J. Res., 1936, 14B, 77).
5
SULPHUR A N A L O G U E S
29
Triethylene glycol dimethyl ether, b.p. 216~ mm., d ~* 0"974, n~)~ 1"4233. Higher polymers. A number of pure polyethylene glycols have been described (H. Hibbert et al., ibid., 1936, I4 B, 77; J- Amer. chem. Soc., 1939, 6x, 19o5, 191o). Commercially available polyethylene glycols, made from the reaction of water, ethylene glycol, or diethylene glycol with ethylene oxide at 12o-1350 under pressure, are mixtures; e.g. "polyethylene glycol 4oo '' consists mainly of HOCH2(CH,OCI-I,)nCH,OH where n = 7 or 8 giving an average molecular weight of 40o. They are colourless, non-volatile, oils or waxy solids, and with their esters and ethers are widely used as lubricants, ointment bases, emulsifiers, demulsifiers, solvents, hydraulic fluids, etc. They are employed as intermediates in the production of rubbers and resins, e.g. polyurethanes. For a discussion of the technical applications of polyethylene glycols and their derivatives, see G. O. Curme and F. Johnston, in "Glycols", Reinhold, New-York, 1952, Chap. 7. 5. Sulphur analogues of the glycols
(i) Preparation
(a) Thiols and thio-ethers
(I) F r o m halogenohydrins or dihalides by substitution reactions; thiols are obtained with alkali metal hydrosulphides or alkali metal disulphides, thio-ethers with metal alkylthiolates" Br(CH2).Br + HS |
-
CICHa. CH, OH + CHsS| ~
_
>
HS(CHa)nSH Alkane cr CH3SCH~. CHgOH 2-methylthioethanol
Thiols can also be obtained by hydrolysis of dithiocarbamates (J. yon Braun, Ber., I9O 9, 42, 4568) and isothiuronium salts (Org. Synth., I95o, 3o, 35) obtained by the action of a m m o n i u m dithiocarbamate and thiourea respectively on dihalides. (2) Thiols can be obtained from epoxides or episulphides: CHa--CH 2 + H2S ~
HSCHaCHaSH
CHg--CH~ q- H2S ~
HOCH,CH2SH
Alternatively the epoxide ring can be opened with a thio-S-acid and the mixture of esters thus obtained subjected to hydrolysis (W. Davies and W. E. Savige, J. chem. Soc., 195o, 317):
3~
GLYCOLS
CH3CH_CH 2 CHnCOSH.-->
12
{
CH39CH(OzCCH3) 9CHgSH ---~ CH3. CHOH. CHISH
CH3. CHOH. CH2SCOCH3 J (3) 1,2-Dithiols are formed in good yield b y the reduction of x a n t h a t e s a n d trithiocarbonates, for example, with lithium aluminium hydride (C. Djerassi et al., J. Amer. chem. Soc., 1955, 77, 568; S. M. Iqbal and L. N. Owen, J. chem. Soc., 196o, lO3O): I
S. CH(CH3).
J
CH(CHs).
SCS ~--> CH 3. CH(SH).
CH(SH).
CH 3
(4) Acetates of dithiols are obtained b y the addition of thiolacetic acid to acetylenes (H. Bader et al., J. chem. Soc., 1949, 619; Owen and M. U. S. Sultanbawa, ibid., 1949, 31o9): R C ~ C H + CH3COSH: -~ RCH---CHSCOCH 3 CHsCOSH
> RCH(SCOCH3). CH~SCOCH3 ---+ RCHSH- CHgSH
(ii) Properties The properties of thiols and their derivatives in this series resemble in the main those of simple thiols (see Vol. IB, p. 73 et seq.)" there is however a t e n d e n c y to form cyclic products, thus: HSCH. CHzOCOCH a
OH |
--~ CHzmCHz "~S j
(For the p r e p a r a t i o n and properties of alkylene sulphides, see Rodd, C.C.C., Ist Edn., 1957, IVa, II). 2-Mercaptoethan-I-ol, HOCHz-CH~SH, b.p. 1570/748 mm., 53.5~ mm., d~5 1 9I 196, is soluble ill alcohol, slightly soluble in water. With lead tetra-acetate the disulphide, 2,2'-dithioethanol (HOCHz.CH~S)~, is formed (L. Field and J. E. Lawson, J. Amer. chem. Soc., 1958, 8o, 838); cleavage products are not obtained (cf. 1,2-diols). 2-Methoxyethanethiol, CHsOCH2-CHzSH , b.p. lO9-11o ~ 2-Methylthioethanol, CH3SCH~.CH~OH, b.p. 74-75~ mm. Ethane- I, 2-dithiol, HSCHz-CHgSH, b.p. I46~ mm., d~~ 1.1243, n~)~ I "5590, is insoluble in water and soluble in organic solvents. The disodium salt with dihalogenoalkanes forms dithiacyclanes (N. B. Tucker and E. E. Reid, ibid., 1933, 55, 775; Org. Synth., 1959, 39, 23). 2-Methylthioethanethiol, CH3SCHz-CHzSH , b.p. 57-61~ mm. 1,2-Bis(methylthio)ethane, CH3SCHi-CH2SCH3, b.p. 8o~ mm., n~)~ 1.5292, is prepared by the addition of methanethiol to methyl vinyl sulphide. 2-Mercaptopropanol, CH3.CHSH-CH2OH , b.p. 51~ ram., d ~-~ 1.o483,
5
SULPHUR
ANALOGUES
31
n~~ 1.4862; bisphenylurethane, m.p. 14o-5 ~ I-Methylthiopropan-2-ol, b.p. 67o/ 20 mm., d~o i "039, n~~ 1-4869. Propane-I,2-dithiol, b.p. 49-5o~ mm., d~~ I .o61. 3-Memaptopropan-I-ol, b.p. 81-82~ mm., d "~ I .o656, n~~ I "4952" 3,5-dinitrobenzoate, m.p. 139-14 o~ Propane-I,3-dithiol, b.p. 173~ ram., 57~ ram., d~~ 1-0783, n~~ I. 5406. Butane-I,4-dithiol, b.p. 196~ mm. Pentane-I,5-dithiol, b.p. 217~ mm. Hexane-I,6-dithiol, b.p. 237~ mm. 2-Acetylthioethanol, I-IOCHz-CH2SCOCH s, b.p. 95-96o/8 ram., n~~ I "4963, is prepared from ethylene oxide and thiolacetic acid in ethanol. On heating an aqueous solution 2-mercc~ptoahyl acetate, CH3CO~.CHz-CH2SH, is obtained, b.p. 52-53~ mm., n~~ 1.461o. 2-Acaylthioethyl acetate, b.p. IO4~ mm., is prepared from 2-mercaptoethanol and acetic anhydride in the presence of a trace of sulphuric acid. For an investigation of the alkaline hydrolysis of the acetates of 1,2-hydroxythiols, see J. S. Harding and L. N. Owen, J. chem. Soc., 1954, I528,. Thiodiglycol, 2,2"-dihydroxydiethyl sulphide, (HOCH~.CH~)zS, f.p. m i 6 ~ b.p. 165~ mm., 121.8~ mm., d~5 I. 1793, n~~ 1"52o3, is prepared" as follows. (I) By heating 2-mercaptoethanol with ethylene carbonate (W. W. Carlson, U.S.P., 2,448,76711948 ) or ethylene chlorhydrin and alkali (F. N. Woodward, J. chem. Soc., 1948, 1892). (2) From ethylene chlorhydrin and sodium sulphide (Org. Synth., Coll.Vol. II, 1943, P. 576) 9 (3) By the action of hydrogen sulphide on ethylene oxide in the presence of a base (C. D. Nenitzescu and N. Scdrldtescu, Ber., 1935, 68, 587). Thiodiglycol is miscible with water and alcohol. An intermediate in the preparation of mustard gas, it and its esters now have a number of technical applications, e.g. as plasticizers, lubricating oil additives, etc. Its mono-acaate, b.p. 137-138~ mm., n~~ I-4879, is obtained by the addition of 2-hydroxyethanethiol to freshly distilled vinyl acetate (W. H. C. Rueggebe~'get aI., J. Amaer. chem. Soc., 1948, 7o, 2292). Diacetate, b.p. I I 8 - I I 8 . 5 ~ mm., n~5 1.4675. Dibenzoate, m.p. 65 ~ By the action of hydrogen chloride at 6O-lOO~ thiodiglycol is converted into 2,2'-dichlorodiethyl sulphide, mustard gas, a powerful vesicant (see Vol. IB, p. 80).
(b) Sulphoxides and sulphones The sulphones of this series are p r e p a r e d b y m e t h o d s exactly analogous to those employed for the monosulphones (see Vol. IB, p. 88 and C. M. Surer, op. tit., p. 734). 1,2-Disulphones undergo a characteristic substitution reaction with alkali (E. Stuffer, Ber., 189o, 23, 14o8, 3226; R. Otto and H. Damk6hler, J. pr. Chem., 1884, 3o, 171, 321): (CH~SO2R)~ + NaOH---+ RSO~CHg. CH2OH + RSO~Na Analogous substitutions occur with amines.
1,2-Bis(methylsulphonyl)ethane, CHsSO2CH~.CHzSO2CH 3, m.p. 19o~ 1,2-Bis(ahylsulphonyl)ahane, m.p. 136.5 ~ Oxidation of thiodiglycol (see above) gives
32
GLYCOLS
12
first 2,2"-dihydroxydiethyl sulphoxide, m.p. 112 ~ then the sulphone, m.p. 57-58~ which on heating cyclizes to form 1,4-oxathian-4,4-dioxide, m.p. I3 ~ (see Rodd, C.C.C., Ist Edn., I96O, Vol. IVc, p. 153o); divinyl sulphone is also obtained (D. L. Schoene, U.S.P., 2,474,8o8/1949 ).
(c) Sulphonic acids 2-Hydroxyethanesulphonic acid, isethionic acid, HOCH,.CH2SO3H, isomeric with ethylsulphuric acid and formed with it (in small m o u n t ) in the addition of sulphuric acid to ethylene (see A. Michael and N. Weiner, J. Amer. chem. Soc., 1936, 58, 294), is made by the following methods. (I) By the action of sulphur trioxide on ethanol, diethyl ether, or diethyl sulphate (G. Magnus, Ann., 1833, 6, 163; R. Hiibner, ibid., 1884, 223, 198 ). (2) From ethylene and sulphur trioxide or chlorosulphonic acid; carbyl sulphate (Vol. IB, p. 24) is formed first and this, on hydrolysis, gives isethionic acid (Michael and Weiner, loc. cit.). (3) From ethylene oxide, or ethylene chlorohydrin, with sodium sulphite or bisulphite (M. Lauer and A. Hill, J. Amer. chem. Soc., 1936, 58, 1873). (4) By deamination of taurine with nitrous acid. (5) By oxidation of 2-mercaptoethanol with nitric acid. .
The free acid is a syrup, soluble in water, and forming crystalline salts: ammonium salt, m.p. 13o~ potassium salt, m.p. 19o~ sodium salt, m.p. 192 ~ Ammonium bisulphite reacts with isethionic acid to give taurine; oxidation gives sulphoacetic acid, HOSO~CHiCO~H. With phosphorus pentachloride or hydrogen chloride 2-chloroethanesulphonic acid is formed first followed by the sulphonyl chloride. 2-Hydroxypropane-I-sulphonic acid is formed in poor yield by the oxidation of propylene sulphide with hydrogen peroxide (J. M. Stewart and H. P. Cordts, J. Amer. chem. Soc., 1952, 74, 5880). For further information about the higher hydroxyalkanesulphonic acids see C. W. Surer, op. cir., p. I33. Ethionic acid, CH~(OSO3H).CH,SOsH , is a dark brown, unstable oil; the hydrated salts are stable. Its anhydride is carbyl sulphate, OSO,CH2.CH,OSO, I
_t
(R. Hi, brier, Ann., 1884, 223, 21o). With aqueous sodium hydroxide at 650 ethionic acid forms sodium ethenesulphonate (D. S. Breslow, R. R. Hough and J. T. Fairclough, J. Amer. chem. Soc., 1954, 76, 5361). Ethane-I,2-disulphonic acid, HOsSCH~.CH2SO3H, m.p. 172-1740 (hydrate, m.p. 111-112~ can be obtained by oxidation of the corresponding dithiol or dithiocyanate, or by the reaction of ethylene dibromide and sodium bisulphite (G. C. H. Stone, ibid., 1936, 58, 488). The free acid can be obtained from its salts, e.g. from the barium salt with sulphuric acid (S. M. McElvain et al., ibid., 1945, 67, 1578). The sodium salt decomposes on heating with the formation of acetylene (H. J. Backer and P. Terpstra, Rec. Tray. chim., 1931, 5o, lO78). Diethyl ester, m.p. 78o (McElvain et al., loc. cir.). Ethane-I,2-disulphonyl chloride, C1SO2CH,-
5
SULPHUR ANALOGUES
33
CH~SO~C1, m.p. 98 o is prepared by the standard methods from salts of the acid, or by the action of chlorine on the bisisothiuronium salt (T. B. Johnson and T. M. Sprague, J. Amer. chem. Soc., 1936, 58, I348). On boiling with water it gives ethene sulphonic acid" (CH2SOzC1)2 + H20 ~
CH~:CHSO3H + 2HC1 + SO2
With amines vinyl sulphonamides, CH2.CHSO2NHR ' can be obtained, but substitution products of the type CH2(NTAR) .CH2SOzRrHR are also formed (P. W. Clutterbuck and J. B. Cohen, J. chem. Soc., 1922 , 12, 120). Taurine, 2-arninoethanesulphonic acid, *~H~CH~CH2SO3e, m.p. 3o5-3io 0 (decomp.), crystallizes in monoclinic prisms soluble in water, insoluble in alcohol. It is a very weak acid, pK a 9"2o, but forms salts with bases; the mercuric salt is insoluble in cold water. With nitrous acid it yields isethionic acid (p. 32). Taurine can be prepared from 1,2-dibromoethane by the following route (Org. Synth., Coll. Vol. II, 1943, P. 563)" BrCH2"CH~.Br + Na~SO3----+ BrCHg-CH2SOsNa + NaBr BrCHg"CH2SO3Na + NH8 ~
NH3CH2.CHgSO3 + NaBr
Alternative procedures have been proposed, e.g., the oxidation of 2-mercaptoethylamine hydrochloride with hydrogen peroxide in acetic acid (F. Y. Rachinskii, N. M. Slavachevskaya, and D. V. Yoffe, J. gen. Chem. U.S.S.R., 1958, 28, 2998). Taurine may also be isolated in large amounts from natural sources (C. L. A. Schmidt and T. Watson, J. biol. Chem., 1918, 33, 499). Taurine occurs in animal tissue, e.g. in the muscle of invertebrates (Schmidt and Watson, loc. cir.) and as the amide of cholic acid (taurocholic acid) in ox bile. Sodium taurocholate is a surface-active agent and in aqueous solution emulsifies fats. Synthetic detergents are produced by forming esters or amides of higher fatty acids with isethionic acid and N-substituted taurines, respectively, thus Igepon-T is the sodium salt of N-methyloleyltaurilxe (for a discussion of this type of surface-active agent, see A. M. Schwartz, J. W. Perry and J. Berch, "Surface Active Agenlts and Detergents" Vol. II, Reinhold, New York, 1958). Pantoyltaurine, HOCH,- C(CH3), .CHOH-CO" N H "CH,.. CH,SOsH, and amide (R. O. Roblin et al., Chem. Reviews, 1946, 38, 3IO), see Rodd, C.C.C. ISt Edn., Vol. IB, 1952, p. lO53). .
.
.
.
Anhydrotaurine, SO~CH~CH,N'H, m.p. 88 ~ is formed by the action of ammonia on 2-chloroethanlesulphonyl chloride or on ethane-I,2-disulphonyl chloride (E. P. Kohler, J. Amer. chem. Soc., 1897, 19, 728).
6. Nitrogen analogues of the glycols (a) Nitro-compounds The nitro-analogues of the glycols, in which one or b o t h h y d r o x y l groups are replaced b y nitro, are the nitroalkanols a n d the dinitroparaffins, respec-
34
GLYCOLS
12
tively. These have already been described along with their derivatives in Vol. IB, pp. 37 and lO4 et seq., respectively. Nitroglycols (dihydroxynitroalkanes) are usually obtained by condensing a nitroalkane with two moles of an aldehyde (cf. Vol. IB. p. 37). The following table lists some of these compounds and their simple ethers. Dihydroxynitroalkane
M.p. ~
Ref.
CH 8. C (NO,) (CH~OH) 9
149-150
1
EtC(CH2OH)zNO9
56-57
1
E t C H O H . CHNO 2- C H O H . CH s
94
2
CH2OH.CMeNOz.CHMeOCH 3
b.p. 110/15 mm.
3
PrC(CH~OH)zNO 2
81-81.5
1
MegCH. CNO2(CHgOH) 2
87-88
1
E t C H O H . CHNO 2. C H E t O H
97
2
~e#~'ence$ B. M . Vanderbilt and H . B . Hass, Ind. Eng. Chem., 194 o, 32, 35. s C. A . sprang and E. F. Degering, J. Amer. chem. Soc., I942, 64, 1735. a A . Lambert, C. W. Scai/e and A . E . Wilder-Smith, J. chem. Soc., 1947, 1477.
(b) Mono-amino analogues of the glycols (i) Aminoalkanols or alkanolamines* These are compounds like 2-aminoethanol, HOCH,.CH,NH,, which may be regarded as being derived from glycols by replacement of one hydroxyl group by amino. Many aminoalkanols are of physiological importance, chief among these being choline (p. 37). Included in the class are many pharmaceuticals, for example, the local anaesthetic "novocaine" (or "procaine"), (see Rodd, C.C.C., Ist Edn., Vol. IIIA, 1954, p. 587) and the antihistamine "benadryl" which are respectively the p-aminobenzyl ester and the benzhydryl ether of 2-diethylaminoethanol. The alkanolamines, and in particular the ethanolamines are manufactured in very large quantities and are of very wide technical importance, especially as basic intermediates for detergents and emulsifying agents (see Schwartz, Perry and Berch, op. cir., 1958). Preparation. (I) By reaction of ammonia or an amine with a halogenohydrin. (2) By reaction of ammonia or an amine with an epoxide. * The I.U.P.A.C. systematic name is aminoalkanol, the suffix -el taking precedence over -amine. The commercial name is alkanolamine.
NITROGEN ANALOGUES
35
Ethylene oxide and aqueous ammonia give mono-, di-, and tri-ethanolamines: (CH,),O + NH 3
> HzNCH,CHaOH Ethanolamine; aminoethanol
2(CHz),O + NH 3 - - + HN(CH2CHzOH)z Diethanolamine; 2,2'-iminodiethanol 3(CH2)~O + NH3 ---+ N(CH.CHzOH). Triethanolamine; 2,2", 2~-nitrilotriethanol With a large excess of ammonia the main product is ethanolamine, with equimolecular proportions the product is largely triethanolamine (P. Ferrero et al., Bull. Soc. chim. Belg., 1947, 56, 349). Polymeric materials of the type R2N(CH2CH20)n "CH," CH2OH may be formed if excess of the epoxide is present (A. J. W. Headlee et al., J. Amer. chem. Soc., 1933, 55, IO66). The reactions of z,2-epoxypropane and 2-methyl-2,3-epoxypentane with primary and secondary amines have been studied in detail by T. Colclough, J. I. Cunneen and C. G. Moore (Tetrahedron, 1961, 15, 187); the nitrogen becomes attached to the leastalkylated carbon atom: R2NH + (CH8)2C CHCHzCH a ~O /
> (CH3).C(OH)- C(NR2)CHgCH3
(3) By the reductive amination of a hydroxy-carbonyl or dicarbonyl compound. Thus the catalytic hydrogenation of 5-hydroxyvaleraldehyde in the presence of ammonia or a primary or secondary amine gives 5-aminopentanols: HO(CH~),CHO H, + NH, -- > HO(CH,.)sNH~ (4) By the reduction, especially with lithium aluminium hydride, etc., of a suitable bi-functional compound, e.g., (a) a h y d r o x y - o r benzyloxy-nitrile (P. A. Levene, J. biol. Chem., 1936, xz3, 153); (b) a hydroxy-amide (J. D. d'Ianni and H. Adkins, J. Amer. chem. Soc., 1939, 6i, 1675; cf. Org. Synth., Coll. Vol. III, ~955, p. 5oi); (c) an a-cyanoester (A. Dornow et al., Ber., 195o ,
83, 445): RCH "C(CN)9CO,C2H5 LiAIH, > RCH~. CH(CH2NH.) 9CH.OH (d) the oxime of a hydroxycarbonyl compound (D. E. Sunko and M. Prostenik, J. org. Chem., 1953, z8, 1523) or the monoxime of a dicarbonyl compound (P. Freon and S. Ser, Compt. rend., 1946, 222, 447) ; (e) an amino-
36
GLYCOLS
12
acid or ester (Adkins and A. A. Pavlic, J. Amer. chem. Soc., 1947, 69, 3039; P. Karrer et al., Helv., 1949, 32, lO34, 1156; O. Vogl and M. PGhm, Monatsh. 1953, 84, lO97) ; or (f) a nitro-alcohol (W. C. Gakenheimer and W. H. Hartung, J. org. Chem., 1944, 9, 85). (5) By the reaction of Grignard reagents with tertiary amino-esters or -ketones: (CH3)~NCH 2" CHg" CH 2" CO~C~H5 -
CtH~MgBr
~ (CH3)~NCH ~. CH~. CH~. CO. C2H 6
C,H,MgBr---~. (CHs)gNCH,. CHg" CHg" C(C,Hs)9OH
(6) By the hydrolysis of N-(halogenoalkyl)phthalimides (Gabriel's method, cf. Vol. IB, pp. II4 and I3o). (7) From aldehydes and ketones by way of the Marmich reaction (L. C. Cheney, J. Amer. chem. Soc., I95I, 73, 685; J. Matt and E. P. Gunther, ibid., 1955, 77, 3655) : RCHzCOCH s + H C H O + M % N H
HC1
~ RCH(CHzNM%)COCH a NaBH,
R C H (CHgNMeg.) CH (OH) CH 3
Reactions. Aminoalkanols have the normal properties of aliphatic alcohols and amines. They form salts with acids, and alkoxides with alkali metals. With dicarboxylic acids and with di-isocyanates they yield polymeric products. i-Aminoalkan-2-ols undergo some special reactions, as follows: (I) With phosgene they form oxazolidones, and with carbon disulphide (or thiophosgene) oxazolidine-2-thiones or thiazolidine-2-thiones (see Rodd, C.C.C., 1st Edn., Vol. IVa, I957, pp. 372, 373, 4o8) 9 (2) Dehydration affords ethyleneimines (see ibid., p. 16). (3) Primary and secondary aminoalkanols are cleaved by periodic acid (E. L. Jackson, Org. Reactions, 1944, 2, 341) and by lead tetra-acetate: R C H O H . C H ( N H ~ ) R " : H!~
R C H O + R ' C H O + N H 3 -l- Hg.O
Tertiary aminoalkanols appear not to be attacked by periodic acid but give secondary amines on oxidation with lead tetra-acetate (N. J. Leonard and M. A. Rebenstorf, J. Amer. chem. Soc., I945, 67, 49)(4) With nitrous acid 1,2-aminoalkanols, instead of forming glycols, may undergo pinacolic-deamination (an example of a carbonium-ion rearrangement) : (CH3)~C~C(CHs) 2
1
l
O H NH9
HNO, ~ nH _~ ( C H 3 ) ~ C ~ C ( C H 3 ) 9 ~ - +
I
OH
CH3"CO'C(CH3) a
6
NITROGEN
ANALOGUES
37
Ethanolamine, colamine, 2-aminoethanol, H~NCH~.CH,OH, is a colourless oil, b.p. 171~ d2,7 I .OlII, ~r I "45o8, miscible with water in all proportions. It is the basic constituent of phospholipids of the cephalin type. It is manufactured from ethylene oxide and ammonia (see above), together with iminobis(2-hydroxyethane), 2,2"-iminodiethanol, diethanolaminv, (HOCH~CH~)~NH, m.p. 28 ~ b.p. 27oO/748 mm., d~~ 1.o966, n~~ 1-4776, and nitrilotris(2-hydroxyethane), 2,2t,2 "nitrilotriethanol, triethanolamine, (HOCH~CH,)3N , b.p. 206--207~ mm., d '~ 1.1242, n~~ I .4852. 2-Methylaminoethanol, C H s N H C H 2-CH~OH, b.p. I55-1560/76o mm. ; 2-ethylaminoethanol, b.p. 169-176~ 2-dimethylaminoethanol, (CH3)z!XTCH~.CH~OH , b.p. 135~ 2-diethylaminoethanol, b.p. 161-163 ~ Choline, 2-hydroxyethyltrimethylammonium hydroxide, [HOCHz. CH~N(CH3) 3] ~ OH o, occurs very widely in nature as the basic constituent of phospholipids of the lecithin type. First isolated and named by A. Strecker (Ann., 1862, z23, 353) it has also been named bilineurine and sincalin as a result of isolation from other sources. Choline appears to be an essential dietary factor and is classed with the B~ group of vitamins; it is the source of acetylcholine (see below) and methylates homocysteine to yield methionine. For reviews, see M. Guggenheim, "Die biogenen Amine", S. Karger, Basel, 194o; T. H. Lukes, Ann. Review Biochem., 1947, z6, 193; H. P. Broquist, ibid., 1958, 27, 285. The most convenient natural source of choline is the lecithin of egg yolk, from which it is obtained, after hydrolysis, as its mercuric chloride complex, CsHz4ONC1.6HgCI~, m.p. 2520. The reaction of trimethylamine and ethylene chlorhydrin or ethylene oxide affords choline chloride, m.p. 247 ~ which m a y be converted to choline by t r e a t m e n t with silver hydroxide. Choline derivatives m a y also be prepared by this method (Org. Synth., I95O, 3o, io), or by quaternization of the appropriate dimethylaminoalkanol (R. T. Major and H. T. Bonnett, J. Amer. chem. Soc., 1936, 58, 22/, or by reduction of the corresponding ketone (Major and J. K. Clive, ibid., 1932, 54, 242): [CH3. CO. CHiN (CHa)a] * C1e ---> [CH 8. CHOH. CHg.N(CH3)8]$ C1e Acetylcholine, [CH3CO2CHz.CI-IzN(CHs)3] * OH e, is of great physiological importance as the neuro-hormone of the parasympathetic nervous system. Physiologically it is m a n y thousand times more active t h a n choline. It produces a lowering of the blood pressure, but is, however, rapidly destroyed by the choline esterases. Acetylcholine was first isolated (from ergot) by A. J. Ewins (Biochem. J., 1914, 8, 44). Acetylcholine chloride, m.p. 151~ m a y be conveniently synthesized from dimethylaminoethanol (L. W. Jones and Major, J. Amer. chem. Soc., 193o, 52, 307). Numerous other acylcholines have been prepared. Neurine, trimethylvinylammonium hydroxide, [CH~:CHlq'(CH3)~]eOHe, is produced from choline on putrefaction. It occurs among the ptomaines (produced by breakdown of protein) particularly in dead animal tissue. Its physiological activity is similar to t h a t of choline but it is extremely toxic. The bromide m.p. I94 ~ m a y be prepared as follows:
38
GLYCOLS
BrCH~.CH~Br + (CH3)3N~
I2
[BrCH2.CH~N(CHs)3~~ Br | KOH E ~ -~ [CH~'CHN(CH3)31~ Br |
Neurine can be obtained by treatment of the bromide with silver hydroxide. Alternatively neurine is produced directly when acetylene ~nd aqueous trimethylamine are heated under pressure (C. Gardner et al., J. chem. Soc., 1949, 789). I-Aminopropan-2-ol, CH3-CHOH.CH2NH~., b.p. 16o-161 ~ is prepared by the action of ammonia on propylene oxide; the racemic product has been resolved (R. L. Clark et al., J. Amer. chem. Soc., 1954, 76, 3995) yielding D(~)- and L(+)I-aminopropan-2-ol, [x]~5 ~ 3 i .5o and +35 ~ (as the hydrochlorides). 1-Aminopropan-3-ol, b.p. 187-188 ~ 2-Aminopropan-I-Ol, alaninol, b.p. I75-I76~ is formed on reduction of alanine. I-Aminobutan-2-ol, C~Hs.CHOH.CH2NH~, b.p. 172~ N,N-diethyl deriv., b.p. 74-75~ mm.; 2-aminobutan-I-ol, b.p. 172-174~ Iq, N-diethyl deriv., b.p. 85~ 13 mm.; 3-aminobutan-I-ol, b.p. 82-85~ mm.; I-aminobutan-4-ol, b.p. 2o5~ 2-aminobutan-3-ol, DL-threo-, b.p. 69-7oO]2o mm., n~5 I "4445, DL-erythro-, m.p. 43-44.8 ~ b.p. 75-75.5~ mm., D(~)-threo-, b.p. 71~ mm., [~]~5 ~ i 7 . o 5 o, L(+)-threo-, [x]~5 + I 6 . 9 i o , L(+)-erythro-, m.p. 49-2-49.3 ~ [~]~5 +o.85 o (F. H. Dickey, W. Fickett and H. J. Lucas, ibid., 1952, 74, 944); i-amino-2methylpropan-2-ol, b.p. 15o-151~ N,N-diethyl deriv., b.p. 164-165 ~ I-Aminopentan-5-ol, m.p. 36~ b.p. 27o-271~ Iq-methyl deriv., b.p. 94-97 ~ 3 mm.; N,N-dimethyl deriv., b.p. II3-II4-5~ mm. D(~)-2-Amino-octadecan-I-ol, sphingine, CH 3 9(CH~)15. CH(NH~ ) .CH~OH, m.p. 84-89 ~ [a]~2 ~ 5 " 5 ~ is a degradation product of the phosphatide sphingomyelin (H. E. Carter and C. G. Humiston, J. biol. Chem., 1951, I9X, 727); it and its L(+)-enantiomorph have been synthesized (D. E. Sunko and M. Prostenik, J. org. Chem., 1953, I8, 1523).
(ii) Aminoalkanethiols and derivatives Preparation. Aminoalkanethiols can be prepared by the standard methods for thiols, for example, by" (I) the reaction of halogenoalkylamines with a hydrosulphide (H. Gilman et al., J. Amer. chem. Soc., 1935, 67, 1845) or with thiourea followed by hydrolysis of the isothiuronium salt (J. Harley-Mason, J. chem. Soc., 1947, 320); (2) the reaction of amines with ethylene sulphide, and of hydrogen sulphide or thiols with ethyleneimine (H. R. Snyder, J. M. Stewart and J. B. Ziegler, J. Amer. chem. Soc., 1947, 69, 2672; H. Bestian et al., Ann., I95O, 566, 21o; F. Y. Rachinskii a n d N . M. Slavachevskaya, C.A., 196o, 54, 24368g) : RNHo + CH2~CH9 - - + RNHCHg. CHgSH ~S / RSH + C H ~ C H z ~ RSCH~. CHtNH~ ~ N H ~/
N I T R O G E N ANALOGUES
6
39
(3) the hydrolysis of N-mercaptoalkylphthalimides (S. Gabriel and J. Colman, Ber., 1912, 45, 1643). Properties. Aminothiols have the expected bi-functional properties, e.g. oxidation forms disulphides; with aldehydes and ketones 2-aminoalkanethiols form thiazolines (see Rodd, C.C.C., Ist Edn., 1957, Vol. IVA, p. 407). 2-Aminoethanethiol, cysteamine, H2NCHz.CH2SH, m.p. IOO~ b.p. 13 o~ m a y
be prepared by the methods given above, or by acid hydrolysis of thiazolidine2-thione (see p. 36). It is of some physiological interest and has been tested as a protective agent against exposure to ionizing radiations. 2-Diethylaminoethanethiol, b.p. 62-65~ ram. ; bis(2-mercaptoethyl)ethylamine, b.p. lO8-1o9~ mm.; tris(2-mercaptoethyl)amine, b.p. 145-147~ mm. 2-Methylthioethylamine, CH3SCHs.CH,NH v b.p. 147~ 2-ethylthioethylamine, b.p. 163 ~ 2,2"-Diaminodiethylsulphide, (H,NCH~-CH~)~S, b.p. 232~ can be obtained from hydrogen sulphide and ethyleneimine; 2,2"-diaminodiethyl disulphide, cystamine, (H,NCH,.CHzS),, m.p. I35-I36~ is prepared by aerial oxidation of a methanolic solution of 2-aminoethanethiol (R. Kuhn and F. Drawert, Ann., 1954, 590, 55)-
(c) Aliphatic diamines T h e s e compounds contain two amino groups each of which may be primary, secondary or tertiary. Of diamines of natural occurrence the ptomaines, putrescine, (tetramethylenediamine) and cadaverine, (pentamethylenediamine) are best known. These substances are produced in the putrefaction of proteins by a wide variety of agents and occur in cheese and in brewer's yeast. Putrescine is derived from arginine via ornithine, cadaverine from lysine" H2NC (:NH). (CHz)3. CH(NH~). COgH ~ arginine H2N. (CH~)4- CH(NH.). CO.H ~ lysine
HgN(CH.)4NH 2 putrescine
H~N(CH~)sNH. cadaverine
Diamines are extensively used in the synthesis of medicinal chemicals such as anti-malarials and ganglionic blocking agents. Certain of the polymethylenediamines, e.g. hexamethylenediamine, are made on a large scale for conversion to polymers (e.g. nylon).
(i) Preparation Diamines may be prepared by methods analogous to those used for simple amines (Vol. IB, pp. 112 et seq.).
4~
GLYCOLS
12
(I) By the reaction of ammonia or an amine with a halogenoalkylamine (Org. Synth., Coll. Vol. h i , 1955, p. 254). Diamines can be prepared from ammonia or an amine and a dihalogenoalkane but the method is not normally satisfactory as further alkylation occurs, e.g. with the formation of cyclic dimers such as piperazine derivatives. Gabriel's method may be applied to the synthesis of diamines in which one or both amino groups are primary (H. E. French et al., J. Amer. chem. Soc., 1945, 57, 882; J. C. Sheehan and W. A. Bolhofer, ibid., 195o, 72, 2786; Org. Synth., Coll. Vol. III, 1955, p. 256) :
.~. co\
<~CO/NK+ Br(CH2,aBr
~.
co\ ~/CO2H
R'NH"+ "~/'C0" ( I'~/CO~N(CH~)nNR~ - > HgN(CH')nNR' + ~'~'C09H (2) By the reduction of a bifunctional compound. (a) Dinitriles may be converted to diamines with a variety of reducing agents, thus decane-I,IOdiamine can be obtained from sebaconitrile with hydrogen and Raney nickel in liquid ammonia (Org. Synth., Co11. Vol. nI, 1955, p. 229) or with lithium aluminium hydride (A. E. Finholt, A. C. Bond and H. I. Schlesinger, J. Amer. chem. Soc., 1947, 69, 1199). Aminonitriles are also convenient starting materials and may be reduced by controlled hydrogenation (E. Strack and H. Schwaneberg, Bet., 1932, 65, 71o; 1933, 66, I33O), by sodium ill ether over potassium bicarbonate (W. McMeeking and T. S. Stevens, J. chem. Soc., 1933, 347) or, in the case of tertiary aminoacetonitriles, sodium and alcohol (M. S. Bloom et al., J. Amer. chem. Soc., 1945, 67, 539); lithium aluminium hydride may also be employed (H. E. Zaugg and B. W. Horrom, ibid., 1953, 75, 292). For further information on the preparation of diamines from aminonitriles, see F. C. Whitmore et al., ibid., 1944, 66, 725; W. Huber et al., ibid., 1945, 67, 1618; A. A. Goldberg and W. Kelly, J. chem. Soc., I947, 1360. (b) By reduction of nitroamines (R. L. Heath and J. D. Rose, ibid., 1947, 1486). (c) By reduction of dioximes (E. Strack and H. Schwaneberg, Bet., 1934, 67, lOO6) or the oximes of aminoketones (D. S. Breslow et al., J. Amer. chem. Soc., 1944, 66, 1921). (d) By catalytic reductive amination of glycols or aminoalcohols (R. C. Schryer, U.S.P., 2,754,33o/I956 ), or aminoketones. A number of ~oo-diamines have been prepared by reductive amination of bis(cyanoalkoxy)alkanes (A. Hrubesch, G.P., 823,295/1951): (CH i-CH~OCHg. CH2CN)~
Ht +Ni NH.
>
HO(CH2)4OH
+ H2N(CH2)3NH9
6
NITROGEN
41
ANALOGUES
and of alkyl lactims (Bad. Anilin u. Soda Fabrik, B.P., 824,419/1957): I
CHz(CHg)nC(OR)'I~
Hs+ NiNH. -> H~.N(CHg.) n + 9.NH~
(3) From the amides of dicarboxylic acids by the Hofmann reaction (Vol. IB, p. ~7)(4) From the azides of dicarboxylic acids by the Curtius reaction (Vol. IB, p. IIS). (5) N-Substituted ethylenediamines can be obtained from ethyleneimine and primary or secondary amines, under anhydrous conditions in the presence of aluminium chloride (G. H. Coleman and J. E. Callen, J. Amer. chem. Soc., 1946, 58, 2oo6).
(ii) Properties The aliphatic diainines are liquids or low-melting solids, which fume slightly in air, absorb carbon dioxide, and form stable hydrates. They have a peculiar odour, which resembles ammonia and recalls piperidine. (iii) Reactions The reactions of diamines are similar to those of aliphatic mono-amines. They form salts; those members with primary and secondary amino groups react with acid chlorides and anhydrides to form acyl derivatives, and with isocyanides to give ureas. The typical reactions of aliphatic amines with nitrous acid are observed, except that 1,2-diprimary amines tend to form epoxides. The diamines and their derivatives are starting materials for the preparation of a number of heterocyclic systems. 1,2- and 1,3-Diamine hydrochlorides may be converted into pyrrolidines and piperidines, respectively (cf. Rodd, C.C.C., Ist Edn., Vol. IVa, 1957, p. 32). Among other systems I
I
which can be obtained are 1,3-diazacycloalkenes, HN(CH~)nN:CR (ibid., pp. 302, 304, 312, 1295, I594), 2,3-dihydro-I,4-diazepins (ibid., p. I595), and higher polyazacyclanes (ibid., p. 1629; H. Sletter and E. E. Roos, Ber., 1954, 87, 566). Diamines readily form linear polymers in reactions with bifunctional compounds. Thus with dibasic acids they give polyamides, with di-isocyanates polyureas, and with dihalogenoalkanes polyamines. Diamines readily co-ordinate with metallic salts to form complex ions related to those formed by ammonia. Thus ethylenediamine gives salts of the type, [Co.(HgNCH~CHgNH~)3]
$e$
3 x|
and [Cu.(HzNCH~CH~NH2)~]
ee 2X e
42
GLYCOLS
12
F o r further information on the stability a n d stereochemistry of such coordination compounds, see A. E. Martell and M. Calvin, " C h e m i s t r y of the Metal Chelate Compounds", Prentice Hall, New York, 1952; " T h e Chemistry of the Co-ordination C o m p o u n d s " (Ed. J. C. Bailar, jr.), Reinhold, New York, 1956.
(iv) Individual atiphatic diamines Methylenediamine, CH,(NH2)~, is, like its oxygen analogue, very unstable. Its salts are obtained on acid hydrolysis of methylenediformamide (P. Knudsen, Ber., 1914, 47, 2698). Tetra-alkylmethylenediamines, t~2NCH,~tZ,, can be obtained by the reaction of a dialkylamine with formaldehyde, a methylene dihalide, or chloromethyl sulphate (J. Houben and H. R. Arnold, ibid., 19o8, 4 I, 1565; R. Damiens, Ann. chim., 1951, 6, 835 ) . N,N,N',N'-Tetramethylmethylene diamine, b.p. 82-84o/76o mm., gives With hydrogen chloride in N,N-dimethylformamide (chloromethyl)dimethylamine; other tetra-alkyl derivatives react similarly (H. Bohme, W. Lehners and G. Kreitzer, Ber., 1958, 91, 340). Ethane-I,2-diamine, ethylenediamine, H2N(CH2) ,NH,, m.p. 8.5 ~ b.p. 116.5 ~ forms a hydrate, m.p. I o ~ b.p. I 18 ~ Anhydrous ethylenediamine may be obtained by heating the complex [Zn.(H,NCH2),]**C20, e e, obtained from the hydrate and zinc oxalate, at 2oo ~ in vacuo (J. C. Bailar, J. Amer. chem. Soc., 1934, 56, 955)- It is strongly alkaline and has an ammoniacal odour. Acetyl-, m.p. 5 I~ b.p. 128~ mm.; diacetyl-, m.p. 173~ propionyl-, b.p. 13o~ ram.; dipropionyl-, m.p. 189~ dibutyryl-ethylenediamine, m.p. 191 ~ N-Methyl-, b.p. 115-116~ N,N-dimethyl-, b.p. lO7~ N,N'-dimethyl-, b.p. 119~ N,N,N'-trimethyl-, b.p. 14o~ N,N,N',N'-tetramethyl-, b.p. 121~ N-ethyl-, b.p. 129131~ N,N-diethyl, b.p. 144-145~ N-octyl-, m.p. 29-31~ N-decyl, m.p. 36-37o; N-dodecyl-, m.p. 36-38o; N-tetradecyl-, m.p. 42-43~ ~-hexadecyl-, m.p. 55-57~ •-octadecyl-ethylenediamine, m.p. 64-65 ~ Propane-I,2-diamine, propylenediamine, C H s . C H ( N H , ) . C H ~ N H , , b.p. 119I2O ~ has been resolved into its optical enantiomorphs, [a]D +34 .8o (F. P. Dwyer, F. L. Garvan and A. Shulman, ibid., 1959, 81, 29o). Butane-I,2-diamine, butylenediamine, CH 3 -CH,. CH(NH,) 9C H , N H , , b.p. I3514 o~ Butane-2,3-diamine, CHs.CH(NH,).CH(NH2).CH3, DL-isomer, b.p. 5758016o rnm., n~5 1"44o8, l.(+)-isomer, b.p. 58-59~ mm., n~5 1-4462, [0e]~5 + 29-48, meso-isomer, b.p. 59-6o~ ram., n~5 1-442o (F. H. Dichey, W. Fickett and H. J. Lucas, ibid., 1952, 74, 944). Butane-l,3-diamine, CH3-CH(NH~). CH~.CH~NH 2, b.p. 141~
occo-Potymethy lened ia mines Propane-I,3-diamine, trimethylenediamine, H2N(CH,.)sNH ,, b.p. 136-137~ 76o mm., diacetyl deriv., m.p. IOI ~ hydrochloride, m.p. 246-247 ~ Butane-I,4-diamine, tetramethylenediamine, putrescine, H , N ( C H i ) i N H ,, m.p. 27 ~ b.p. 158-159 ~ occurs in many products of bacterial decomposition. It is found in urine and faeces of patients suffering from cystinuria. The tetramethyl deriva-
6
I~ITROGEN ANALOGUES
43
tire, (H3C),N(CH2)4N(CH~)2, occurs in henbane (Hyoscyamus). N,N'-bis(3-aminopropyl)butane-I,4-diamine, spermine, HzN(CH2)3NH(CH,)4NH(CH2)3NH,, m.p. 66 ~ b.p. 15 o~ is present in fresh human semen (P. Schreiner, Ann., 1878, 194, 68) and was possibly first isolated by Van Leeuwenhoek in 1678. It may by synthesized from putrescine (H. P. Schultz, J. Amer. chem. Soc., 1948, 7o, 2666), and forms crystalline salts, the phosphate being characteristic. A second polyamine, 3-aminopropylbutane-I,4-diamine, spermidine, H,N(CH,) 3NH(CH2)4NH ,, accompanies spermine in many tissue extracts (0. Rosenheim et al., Biochem. J., 1927, 21, 97). Pentane-I,5-diamine, cadaverine, H~N(CH2)sNHz, b.p. I78-I8O ~ occurs frequently with putrescine and like it has a foul smell. The tetramethyl deriv., b.p. I9O-I9 I~ is obtained from the bis-methiodide, pentamethonium iodide, (CH3)sN.(CH2)s.N(CH3)s-2Ie, m.p. 3o2 ~ The latter and the hexamethylene analogue (see below) are ganglionic blocking agents, used for treating hypertension and for decreasing bleeding during surgical operations. Hexane-I,6-diamine, hexamethylenediamine, m.p. 42~ b.p. 196~ is manufactured on a large scale mostly for conversion to polyamide fibres(e.g, nylon 66). It is prepared by reduction of adiponitrile although other methods have been proposed (see refs. to patent literature pp. 4o-41). N,N,~',2q'-Tetramethylhexane1,6-diamine, b.p. 2o9-21o~ hexamethylene bis(trimethylammonium chloride), hexamethonium chloride, m.p. 289-291 ~ and the corresponding bromide, iodide, and tartrate are ganglionic blocking agents (see above). Heptane-I,7-diamine, m.p. 28-29 ~ b.p. 223-225~ octane-I,8-diamine, m.p. 52~ b.p. 225-226~ nonane-I,9-diamine, m.p. 37-5 ~ b.p. 258-259~ decane-I,io-diamine, m.p. 61.5 ~ b.p. I4O~ mm.; undecane-I,II-diamine, m.p. 58~ b.p. 14oI5O~ mm.; dodecane-I,I2-diamine, m.p. 66-67 ~ b.p. 187~ mm.; tridecaneI,I3-diamine, m.p. 51~ octadecane-I,I8-diamine, m.p. 93 ~