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The reaction of dicarboxylic acids containing ether linkages with alkaline earth metals
J in,.~,, m¢~/. ( h e m . . 1974. Vol. 36, pp. 2033 2038. Pergamon Press. Printed in Great Britain.
THE R E A C T I O N OF D I C A R B O X Y L I C ACIDS C O N T A I N I N G ETHER L I N K A G E S WITH A L K A L I N E E A R T H METALS MASAHIRO MIYAZAKI, YASUAKI SHIMOISHI, HARUO MIYATA and KYOJI TOEI Department of Chemistry. Faculty of Science. Okayama University. 3-1-1, Tsushimanaka. Okayama-shi 700. Japan
( Received 4 December 1973) Abstract Four dicarboxylic acids (Reagents 1, 11. 111 and IV) containing ether linkages, HOOCCH20(CH2CH2OJ, CHzCOOH (n = 0 3), were synthesized. The acid dissociation constants and their chelate stability constants with alkaline earth metals were measured by pH titratitm method at an ionic strength ~ = 0.10 and at 25-0 + 0.1°C. As the total sum of the number of oxygen atoms of ether linkages and carbon atoms approaches infinity, the value of the ratio of the first to the second acid dissociation constant comes near to four, Therefore, it indicates that the molecules behave statistically, when the number of atoms between two carboxyl groups approaches infinity. The decreasing order of the stability constants of those chelates ,Aith alkaline earth metals is as follow,: Reagents I and 11 (n = 0and ll; Ca > Sr > Ba > Mg Reagent 111 (n = 21: Ca > Sr - Ba > Mg Reagent IV(n - 3): Sr Ba > Ca > Mg.
INTRODUCTION
EXPERIMENTAL
WHEN Katayama et a/.[1] studied previously the reaction of ortho-substituted phenylazo chromotropic acids with alkaline earth metals, they pointed out that the calcium chelate of phenylazo chromotropic acid substituted by - O C H 2 C O O H at the ortho position was more stable than the magnesium, strontium and barium chelates. On the other hand, GEDTA[2, 3] in which ether linkages are introduced to EDTA, can form a more stable chelate with calcium than with magnesium. On the basis of these facts, the authors have tried to synthesize dicarboxylic acids containing ether linkages and to determine the stability constants of the chelates with alkaline earth metals, especially to investigate the difference between the calcium and magnesium chelates. The dicarboxylic acids containing ether linkages used in this experiment are shown in Table 1.
Synthesis ol dicarboxylic acids containing ether linkages Reagent 1. The commercial reagent of guaranteed-reagent grade was recrystallized from acetone unti! its melting point became constant 143 143.5°C (143-143.5°C[4])). Reagent ll. Reagent II was synthesized according to the method of Abe et al.[4]. HOCH2CH2OCH2CH2OCH2CH2OH
Reagent 1
HOOCCH2OCH2COOH Di(carboxy)methyl ether
Reagent 11
HOOCCH2OCH2CH2OCH2COOH
Reagent 11I
HOOCCH20CH2CH2OCHzCHzOCH2COOH
1,2-Bis-(carboxymethoxy)ethane Di{carboxymethoxy)ethyl ether
HOOCCH20CH2CH2OCH2CH2OCH2CH2OCH2COOlq Di[flqcarboxymethoxy)ethoxylethane 2033
J.I.N.C., Vol. 36, No. 9
H
11
Commercial triethylene glycol was fractionated once. The distillate of b.p. 120 124°C/0-4 mm Hg {128 133°C/2 mm Hg[4]) was used. In a four-necked flask fitted with a dropping funnel, a thermometer, a mechanical stirrer and a reflux condenser were placed 420 g of conc nitric acid (specific gravity 1-38) and 0.40 g of ammonium metavanadate. The mixture was gradually heated with slow stirring until the temperature rose to about 70°C and the ammonium metavanadate was completely dissolved.
Table 1. Dicarboxylic acids containing ether linkage>
Reagent IV
HNO., + NH,VO,)
2034
MASAHIRO MIYAZAKI, YASUAKI SHIMOISHI, HARUO MIYATA and KYOJI T6EI
To the mixture were added 10 g of triethylene glycol with stirring at that temperature for 30 min. Then 90 g of triethylene glycol were added to this reaction solution dropwise for 3 hr at 70 + 2°C. After adding triethylene glycol, heating was continued at that temperature for 8 hr to complete the oxidation. Then the reflux condenser and the dropping funnel were removed, and one of two necks was connected to a waterpump to evacuate at 95-100°C (the bath temperature), until the brown vapor of NO2 was no longer observed. A large quantity of water was added to the blue-green viscous liquid obtained, and nitric acid was removed completely by a rotary evaporator. This procedure was continued until no nitric acid could be found in the water distilling over. When the blue-green viscous liquid was allowed to stand in a refrigerator, white crystals deposited. It was recrystallized from acetone until its melting point became constant 74.5-75.5°C (78-79°C[4])). Found: C, 40.93; H, 5.87 per cent. Calc. for C6H1oO6; C, 40.45; H, 5.66 per cent. Reagent IlL Commercial diethylene glycol was fractionated once. The distillate of b.p. 106-110.5°C/0.5 mm Hg (113-115°C/3 mm Hg[5]) was used. The synthetic scheme is as follows: HOCH2CH2OCH2CH2OH Na ) NaOCH2CH2OCH2CH2ON a CICH2COOCH31j H 3 C O O C C H 2 O C H 2 C H 2 O C H 2 C H 2. H+ OCH2COOCH3 III
In a three-necked flask fitted with a shield stirrer, a reflux condenser with a calcium chloride tube, and a dropping funnel were placed 200 ml of anhydrous xylene and 8.7 g (0-38 g atom) of sodium metal. The mixture was heated directly. When the sodium metal melted, it was dispersed as granules by vigorous stirring. Heating was stopped and to the mixture were added dropwise 20g (0.19mole) of diethylene glycol from the dropping funnel for 30 min. After the heating had been stopped, 41-2 g(0.38 mole) of methyl chloroacetate were added dropwise to the solution from the dropping funnel for 30 min. The solution was allowed to reflux for 30 min to complete the reaction. Xylene was then added to the solution to extract the ester formed, and the xylene extract was filtered to remove the salt formed. The xylene extract was concentrated by a rotary evaporator to eliminate xylene. The red-orange viscous liquid obtained was extracted with ether. After evaporating the ether under reduced pressure, the residue was vacuum-distilled b.p. 137-142°C/0.5 mm Hg (147-152°C/1 mm Hg[5]). In an egg-plant type flask fitted with a reflux condenser were placed 50 g of the ester obtained, 50 g of water and 7 g of cation exchange resin (Amberlite IR-120-B). The mixture was refluxed at a bath temperature of 150°C for 7 hr. After reaction w~/s complete, the resin was removed by filtration and the filtrate treated with active carbon. From the filtrate methanol and water were removed by distillation under reduced pressure and the residue was allowed to reach constant weight in a vacuum desiccator. Reagent III is a colorless viscous liquid. Found: C, 43.15; H, 6.66 per cent. Calc. for C8H1407 : C, 43.25; H, 6.35 per cent. Reagent I V. Triethylene glycol was fractionated once. The distillate of b.p. 120-124°C/0.4 mm Hg (128-133°C/2 mm Hg [4]) was used.
The synthetic scheme is as follows: HOCH]CH2OCH2CH2OCH2CH2OH NaOCH2CHzOCH2CH2OCH2CH2ONa C1CH2COOCH~I~ HaCOOCCH2OCH2CH2OCH2CH 2. OCH2CH2OCH2COOCH a H* ) IV The synthetic procedure was similar to that for Reagent III. The dimethyl ester of IV boils at 163-168°C/0.4 mm Hg (172-174°C/1 mm Hg[5]). Reagent IV is a colorless viscous liquid. Found: C, 45.00; H, 7.07 per cent. Calc. for CloHlaOa: C, 45-11; H, 6.82 per cent. Reagent solution Reagents I and lI were dried at 60°C in vacuo before use. Reagents III and IV were dried to constant weight in a vacuum desiccator. These reagents were dissolved in distilled water. The stock solutions of these reagents were standardized by potentiometric titration with a standard 0.10 M potassium hydroxide solution. The 0.10M potassium hydroxide was standardized by hydrogen potassium phthalate titrimetrically. The stock solutions of metal ions were prepared by dissolving Mg(NO3) 2 . 6H20, Ca(NO3) 2 . 4H20, Sr(NO3) 2 and Ba(NOa) 2 of guaranteed-reagent grade. The concentrations of the Mg(II) and Ca(II) solutions were determined by chelatometric titration, while the concentrations of the Sr(II) and Ba(II) solutions were determined by the usual gravimetric method. pH titration apparatus The pH titration apparatus is illustrated in Fig. 1. The titration cell was a double-walled glass vessel and the titration temperature was maintained at 25.0 _+ 0-1°C by the circulation of water from a thermostat bath. Purified nitrogen gas was introduced into the titration cell, and the titration was carried out under nitrogen. The electrode used was a Metrohm combined glass electrode EA125. The syringe used was an Agla micrometer syringe and the total volume of this syringe was 0-5 ml. The piston of this syringe was depressed by rotating the micrometer, and the 0.10 M potassium hydroxide was added dropwise into the titration
E~
~
2><5. Fig. 1. Micro-titration apparatus. A, Metrohm Precision Compensator E388; B, Metrohm combinedglass electrode EA125; C, Thermometer; D, N 2 gas; E, 25°C water from a thermostat bath; F, volume 10ml; G, Magnetic stirrer; H, Laboratory jack; I, Agla micrometer syringe.
Chelates of dicarboxylic acids having - O - linkages cell. The m i n i m u m volume that can be titrated by this
micrometer syringe is 2 × 10-4 ml. The pH-meter used was a Metrohm Precision Compensator E388. The body of the titration cell was moved up and down by a laboratory jack. pH titration method
The acid dissociation and chelate stability constants were calculated from titration curves obtained by titrating solutions (10 ml) in the presence and in the absence of metal ions
with 0.10 M potassium hydroxide. The titration was carried out at 25.0 ___0.1°C and the ionic strength # = 0-10(KNO3). The observed pH-meter readings were converted into the actual hydrogen-ion concentration by comparison w i t h the stoichiometric dissociation constant of acetic acid[6].
CALCULATION Acid dissociation constants
When the dicarboxylic acid is represented as H2L, the acid dissociation equilibrium is as follows: H z L ~Ko. - H L - + H +, H L - K.~ ~ L 2- + H +. K,, and Ka2 are given by the following formula [ H L - ] [H + ] [H2L ] '
K,,
1 Ka '
-
[ L 2 - ] [ H +] [HL-]
Ka2
RESULTS AND DISCUSSION Synthesis
Reagents llI and IV can also be synthesized by the method of Abe et al. [5], but especially in the case of the synthesis of IV, the starting material, pentaethylene glycol, is expensive and not easily obtainable. On the other hand, the method given here is easy in comparison with the former method; the reaction time is shorter, and the starting material is cheaper. Titration curves
The titration curves for Reagent 1 in the presence and in the absence of alkaline earth metal ions are illustrated in Fig. 2. In this figure, the titration curves for Reagent I in the presence of magnesium and barium ions are intermediate between the titration curves for Reagent I alone and for the strontium ion. The titration curves for Reagents II, III and IV are similar to that for Reagent I in Fig. 2. The inflection at a = 2 in the titration curve of the ligand in Fig. 2 shows the complete dissociation of the two carboxyl protons of Reagent I. The titration curve in the presence of metal ion shows a lower pH value than that of the ligand only. Here a depression of the titration curves indicates the formation of the metal chelate species. Acid dissociation constants
AKa~ + B
The acid dissociation constants of the four reagents are summarized in Table 2. In Table 2, the pKa, and
A = 2TL - T°H - [ H + ] + [ O H - ] [H+]2(ToH + [H +] - [ O H - ] ) ' B =
2035
TL - T°" - [H +] + [OH-] [H+](ToH + [m +] - [OH-])
10
where TL represents the total concentration of ligand species, and Ton represents the total concentration of the base added to the system. [H +] is measured with the pH-meter, and [OH-] is calculated from [H+].
8
g-,
"-7
Stability constants
13n
When the metal ion is represented as M 2÷, the chelate formation equilibrium is as follows:
I 6
K
M 2 + + L 2- ~- ML.
K is given by the following formula K -
/4
[ML] TL - F [MZ+][L 2-] -[L 2 ](F + Tu-
TL)
[L2_ ] = 2TL -- Ton - [H +] + [OH-] [H +] 2[H+] 2 , -4 K~ K~,. K ~ F=[
L2-]
[H+]
EH+Y 1
I+~+K,,.K,~]
w h e r e Tu r e p r e s e n t s t h e total c o n c e n t r a t i o n of t h e m e t a l ion.
3
0
[ I
I
O*
2
Fig. 2. Titration curyes of the di(carboxy)methyl ether chelate system at 25°C, # = 0.10. L, ligand only: [L] = 1.258 × 10 -3 M ; [ M g ] = 2.678 × 10-3 M ; [ C a ] = 2.508 × 10- 3 M; [Sr] = 2.546 × 10-3 M; [Ba] = 2.520 × 10- 3 M. *a is moles of base added per mole of ligand.
MASAHIRO MIYAZAKI, YASUAKI SHIMOISHI, HARUO MIYATA a n d KYOJI TOE1
2036
T a b l e 2. Acid dissociation constants, t = 25.0 _+ 0-1°C, p = 0.10 (KNO3}
i;
Reagent*
3 4 5 6 7 8 9 10 11 12 13 14
pK,
pK,~
l
2-73
3.92
II
2.99
3.83
Ill
3-03
3.80
IV
3.05
3.80
Reagent-',Malonic acid Succinic acid Glutalic acid Adipic acid Pimelic acid Suberic acid Azelaic acid Sebacic acid
pK,~[7]
pK,:[7]
pK~[8]
pKa,[8 ]
2.97 4.18 4.31 4.44 4.51 4.53 4-56 4.5~
5-75 5.67 5.43 5.45 5-51 5.52 5.53 5.54
2-83 4.19 4.34 4.42 4.48 4.52 4.55
5.69 5.48 5-42 5.41 5.42 5-40 5.41
* n is the total sum of the number of oxygen atoms of ether linkages and carbon atoms. + n is the number of carbon atoms.
I
I
I
I
I
I
I
5.0
4.0
3.13
3.0 ~
o
-
o
0
I
I
0.5
1.0
I
I
I
1.5 2.0 2.5 zln×lO
I
I
3.0
3.5
Fig. 3. Relation between pK, and 1In. 0, Ingold's plots; ~ , Ninomiya's plots, where n is the number of carbons; O, authors' plots, where n is the total sum of the number of oxygen atoms of ether linkages and the number of carbon atoms. pKa2 values correspond to the dissociation of the two carboxyl protons respectively. The pK, values of the four reagents are plotted against the reciprocal of the total sum of the number of oxygen atoms of ether linkages and carbon atoms in the reagents (Fig. 3). In this figure, it is obvious that the pK,'s of the reagents, as a whole, are smaller than those of the aliphatic dicarboxylic acids. This indicates that the large electronegativity of the - O - atom introduced as ether linkages enhances the dissociation of the acids.
The ApK, = pKa2 - pKa, becomes smaller as the number of carbons of the aliphatic dicarboxylic acids increases. When the number of carbons becomes infinite, namely at 1In = 0, ApKa is equal to 0-6, i.e. Kal/Ka2 is equal to 4, meaning that the molecule behaves statistically. This is similar to the pK a of the reagents. When the total sum of the number of oxygen atoms of efher linkages and carbon atoms approaches infinity, namely at 1/n = 0, ApK, is equal to 0.6, i.e. K,,/Ka2 is equal to 4. The molecules of the reagents also behave statistically. In Fig. 3, Ninomiya's plots[7] are shifted from those given by Ingold[8]. In the case of Ninomiya and T6ei [7], the aliphatic dicarboxylic acid molecules favor the pliable model, because the dilute dicarboxylic acids (2.5 × 10 -3 M) are titrated in concentrated electrolytes, namely at the ionic strength # = 0.10. In the case of Gane and Ingold[8], the aliphatic dicarboxylic acid molecules prefer the rigid model, because the pKa's of the dilute dicarboxylic acids are measured in pure water and extrapolated to irtfinite dilution. Therefore, the aliphatic dicarboxylic acid molecules behave theoretically. In the other hand, it is thought that the molecules of the reagents favor the rigid model and behave theoretically, because the - O - atom introduced as ether linkages is hydrophilic, though the reagents are titrated in the concentrated electrolytes, namely at the ionic strength/~ = 0.10.
The comparison of the stability of the magnesium chelate with that of the calcium chelate The stability constants of their 1:1 chelates with alkaline earth metals (magnesium, calcium, strontium and barium) are tabulated in Table 3. The stability constants of the chelates of Reagent I with alkaline earth metals decrease as follows: calcium > strontium > barium > magnesium, the stability constants
Chelates of dicarboxylic acids having -O linkages
2037
Table 3. Stability constants of the chelates, t = 25.!) ± 0.1°C, H = 0.10{KNO3) n
Reagent*
2 3 4 5 6 7 8 9 I0 11 12 13 14
Mg
Ca
Sr
Ba
l
2.06
3.39
2-47
2.15
I1
1.9
3.15
2.40
_._ )
Ill
1-8
2.40
"~"~9
"~ 3¢ _._9
IV
1.4
2.14
2.29
2-29
* n is the t o t a l s u m of the n u m b e r of o x y g e n a t o m s ', n is tile n u m b e r of c a r b o n a t o m s .
Reagent;Oxalic acid Malonicacid Succinic acid Glutalic acid Adipic acid Pimelic acid S uberic acid Azelaic acid %cbacic acid
Mg
Ca
Sr
Ba
2.V619 i 3.0 i 0] 2-54[11] 2.31[11~ ] ~"~il2 _.8, 2.49[12] 1.25i13] 1.71!12 1.20113] 1.20113] 1.06~13 I.B[ 31 1.08,13 1.06113] 0.6[14] 2.04115 2.19116] 1.85(16]
of e t h e r l i n k a g e s a n d c a r b o n a t o m s .
of their chelates of Reagents II, III and IV with alkaline earth metals decrease as shown below:
The comparison oJ the stability constants of the reagents with those oj aliphatic dicarboxylic acids
calcium > strontium > barium > magnesium calcium > strontium = barium > magnesium strontium = barium > calcium > magnesium
From Table 3, it is clear that the reagents form more stable chelates with alkaline earth metals than do the aliphatic dicarboxylic acids. For example, Reagent I corresponds to the acid-introduced ether linkage of succinic acid, and Reagent II corresponds to the acidintroduced ether linkage of adipic acid, and there, in each case, the stability of the metal chelates is increased by the introduction of ether linkages. These results indicate the coordination of the - O - atom introduced as ether linkages. When the chelate ring is five- or six-membered, the stability of the chelate formed is highest, whereas the chelate rings formed by the aliphatic dicarboxylic acids would become five-, six- and seven-membered successively. Therefore, it is clear that the stability of the chelates of aliphatic dicarboxylic acids with alkaline earth metals become poor with an increase in the number of carbon atoms. On the other hand, when the reagents form chelates with calcium and magnesium, the stability also becomes poor with an increase in the total sum of the number of oxygen atoms of the ether linkages and the number of carbon atoms. The stability, as a whole, however, is much better than those of the aliphatic dicarboxylic acids, because the number of five-membered rings formed in a chelate is increased by the coordination of the - O - atom introduced as ether linkages with increase of the total sum of the number of oxygen atoms of ether linkages and carbon atoms. Therefore, it is thought that the reagents form stabler chelates on the basis of the total interaction between the steric factor and the coordination of the (Y atom than aliphatic dicarboxylic acids do with alkaline earth metals. On the basis of the reasons described above, the -O- atom introduced as ether linkages functions largely on the increase of the stability of four metal chelates. Especially it functions specifically for calcium.
The log K values are plotted against the reciprocal of crystal ionic radii of alkaline earth metals, 1/r,ys, ' , in Fig. 4. From this figure, all the reagents form their most unstable chelate with magnesium. Furthermore, all the reagents form a stabler chelate with calcium than they do with magnesium. This is similar to the behavior of GEDTA. Reagents I and II form especially stable chelates with calcium.
Ba Sr Ca
I'1
']
Mg
'
'
I'
3 o
I
I
[
I
I
0.8
1.0
1.2
1/-,
1.6
rcryst
Fig. 4. Plot of log K against 1/r¢,y,,. of metal ions.
©, Reage ~t 1; O, Reagent 11; ~ , Reagent I11 ,'0', Reagent I V
2038
MASAHIRO MIYAZAKI, YASUAKISH1MOISHI, HARUO MIYATAand KYOJI TO~t
Acknowledgement--The authors wish to express their gratitude to Professor Yoshiro Abe of Keio University for his kind instruction in the synthesis of 1,2-bis-(carboxy methoxy) ethane and di(carboxymethoxy)ethyl ether.
REFERENCES
1. T. Katayama, H. Miyata and K. T6ei, Bull. chem. Soc. Japan 44, 2174 (1971). 2. G. Schwarzenbach, H. Senn and G. Anderegg, Heir. chim. Acta 40, 1886 (1957). 3. J. H. Holloway and C. N. Reilly, Analyt. Chem. 32, 249 (1960). 4. Y. Abe, C. Kato, D. Higo, T. Aoki and H. Miyagawa, Yukagaku 18, 32 (1968). 5. Y. Abe, T. Aoki and H. Miyagawa, Yukagaku 20, 149 (1971).
6. H. S. Harned and F. C. Hickey, J. Am. chem. Soc. 59, 1284, 2303 (1937). 7. A. Ninomiya and K. T6ei, Nippon Kagaku Zasshi 911, 656 (1969). 8. R. Gane and C. K. Ingold, J. chem. Soc. 2153 (1931). 9. G. Schwarzenbach and G. Anderegg, Helv. Chim. Acta 40, 1773 (1957). 10. E. Gelles and R. M. Hay, J. chem. Soc. 3673, 3684, 3689 (1958). 1 !. R. W. Money and C. W. Davies, Trans. Faraday. Soc. 28, 609 (1932). 12. D. I. Stock and C. W. Davies, J. chem. Soc., 1371 (1949). 13. R. K. Cannon and A. Kibrick, J. Am. chem. Soc. 60, 2314 (1938). 14. J. Schubert and Lindenboum, J. Am. chem. Soc. 74, 3529 (1952). 15. J. M. Peacock and J. C. James, J. chem. Soc. 2233 (1951). 16. N. E. Topp and C. W. Davies, J. chem. Soc. 87 (1940).
THE R E A C T I O N OF D I C A R B O X Y L I C ACIDS C O N T A I N I N G ETHER L I N K A G E S WITH A L K A L I N E E A R T H METALS MASAHIRO MIYAZAKI, YASUAKI SHIMOISHI, HARUO MIYATA and KYOJI TOEI Department of Chemistry. Faculty of Science. Okayama University. 3-1-1, Tsushimanaka. Okayama-shi 700. Japan
( Received 4 December 1973) Abstract Four dicarboxylic acids (Reagents 1, 11. 111 and IV) containing ether linkages, HOOCCH20(CH2CH2OJ, CHzCOOH (n = 0 3), were synthesized. The acid dissociation constants and their chelate stability constants with alkaline earth metals were measured by pH titratitm method at an ionic strength ~ = 0.10 and at 25-0 + 0.1°C. As the total sum of the number of oxygen atoms of ether linkages and carbon atoms approaches infinity, the value of the ratio of the first to the second acid dissociation constant comes near to four, Therefore, it indicates that the molecules behave statistically, when the number of atoms between two carboxyl groups approaches infinity. The decreasing order of the stability constants of those chelates ,Aith alkaline earth metals is as follow,: Reagents I and 11 (n = 0and ll; Ca > Sr > Ba > Mg Reagent 111 (n = 21: Ca > Sr - Ba > Mg Reagent IV(n - 3): Sr Ba > Ca > Mg.
INTRODUCTION
EXPERIMENTAL
WHEN Katayama et a/.[1] studied previously the reaction of ortho-substituted phenylazo chromotropic acids with alkaline earth metals, they pointed out that the calcium chelate of phenylazo chromotropic acid substituted by - O C H 2 C O O H at the ortho position was more stable than the magnesium, strontium and barium chelates. On the other hand, GEDTA[2, 3] in which ether linkages are introduced to EDTA, can form a more stable chelate with calcium than with magnesium. On the basis of these facts, the authors have tried to synthesize dicarboxylic acids containing ether linkages and to determine the stability constants of the chelates with alkaline earth metals, especially to investigate the difference between the calcium and magnesium chelates. The dicarboxylic acids containing ether linkages used in this experiment are shown in Table 1.
Synthesis ol dicarboxylic acids containing ether linkages Reagent 1. The commercial reagent of guaranteed-reagent grade was recrystallized from acetone unti! its melting point became constant 143 143.5°C (143-143.5°C[4])). Reagent ll. Reagent II was synthesized according to the method of Abe et al.[4]. HOCH2CH2OCH2CH2OCH2CH2OH
Reagent 1
HOOCCH2OCH2COOH Di(carboxy)methyl ether
Reagent 11
HOOCCH2OCH2CH2OCH2COOH
Reagent 11I
HOOCCH20CH2CH2OCHzCHzOCH2COOH
1,2-Bis-(carboxymethoxy)ethane Di{carboxymethoxy)ethyl ether
HOOCCH20CH2CH2OCH2CH2OCH2CH2OCH2COOlq Di[flqcarboxymethoxy)ethoxylethane 2033
J.I.N.C., Vol. 36, No. 9
H
11
Commercial triethylene glycol was fractionated once. The distillate of b.p. 120 124°C/0-4 mm Hg {128 133°C/2 mm Hg[4]) was used. In a four-necked flask fitted with a dropping funnel, a thermometer, a mechanical stirrer and a reflux condenser were placed 420 g of conc nitric acid (specific gravity 1-38) and 0.40 g of ammonium metavanadate. The mixture was gradually heated with slow stirring until the temperature rose to about 70°C and the ammonium metavanadate was completely dissolved.
Table 1. Dicarboxylic acids containing ether linkage>
Reagent IV
HNO., + NH,VO,)
2034
MASAHIRO MIYAZAKI, YASUAKI SHIMOISHI, HARUO MIYATA and KYOJI T6EI
To the mixture were added 10 g of triethylene glycol with stirring at that temperature for 30 min. Then 90 g of triethylene glycol were added to this reaction solution dropwise for 3 hr at 70 + 2°C. After adding triethylene glycol, heating was continued at that temperature for 8 hr to complete the oxidation. Then the reflux condenser and the dropping funnel were removed, and one of two necks was connected to a waterpump to evacuate at 95-100°C (the bath temperature), until the brown vapor of NO2 was no longer observed. A large quantity of water was added to the blue-green viscous liquid obtained, and nitric acid was removed completely by a rotary evaporator. This procedure was continued until no nitric acid could be found in the water distilling over. When the blue-green viscous liquid was allowed to stand in a refrigerator, white crystals deposited. It was recrystallized from acetone until its melting point became constant 74.5-75.5°C (78-79°C[4])). Found: C, 40.93; H, 5.87 per cent. Calc. for C6H1oO6; C, 40.45; H, 5.66 per cent. Reagent IlL Commercial diethylene glycol was fractionated once. The distillate of b.p. 106-110.5°C/0.5 mm Hg (113-115°C/3 mm Hg[5]) was used. The synthetic scheme is as follows: HOCH2CH2OCH2CH2OH Na ) NaOCH2CH2OCH2CH2ON a CICH2COOCH31j H 3 C O O C C H 2 O C H 2 C H 2 O C H 2 C H 2. H+ OCH2COOCH3 III
In a three-necked flask fitted with a shield stirrer, a reflux condenser with a calcium chloride tube, and a dropping funnel were placed 200 ml of anhydrous xylene and 8.7 g (0-38 g atom) of sodium metal. The mixture was heated directly. When the sodium metal melted, it was dispersed as granules by vigorous stirring. Heating was stopped and to the mixture were added dropwise 20g (0.19mole) of diethylene glycol from the dropping funnel for 30 min. After the heating had been stopped, 41-2 g(0.38 mole) of methyl chloroacetate were added dropwise to the solution from the dropping funnel for 30 min. The solution was allowed to reflux for 30 min to complete the reaction. Xylene was then added to the solution to extract the ester formed, and the xylene extract was filtered to remove the salt formed. The xylene extract was concentrated by a rotary evaporator to eliminate xylene. The red-orange viscous liquid obtained was extracted with ether. After evaporating the ether under reduced pressure, the residue was vacuum-distilled b.p. 137-142°C/0.5 mm Hg (147-152°C/1 mm Hg[5]). In an egg-plant type flask fitted with a reflux condenser were placed 50 g of the ester obtained, 50 g of water and 7 g of cation exchange resin (Amberlite IR-120-B). The mixture was refluxed at a bath temperature of 150°C for 7 hr. After reaction w~/s complete, the resin was removed by filtration and the filtrate treated with active carbon. From the filtrate methanol and water were removed by distillation under reduced pressure and the residue was allowed to reach constant weight in a vacuum desiccator. Reagent III is a colorless viscous liquid. Found: C, 43.15; H, 6.66 per cent. Calc. for C8H1407 : C, 43.25; H, 6.35 per cent. Reagent I V. Triethylene glycol was fractionated once. The distillate of b.p. 120-124°C/0.4 mm Hg (128-133°C/2 mm Hg [4]) was used.
The synthetic scheme is as follows: HOCH]CH2OCH2CH2OCH2CH2OH NaOCH2CHzOCH2CH2OCH2CH2ONa C1CH2COOCH~I~ HaCOOCCH2OCH2CH2OCH2CH 2. OCH2CH2OCH2COOCH a H* ) IV The synthetic procedure was similar to that for Reagent III. The dimethyl ester of IV boils at 163-168°C/0.4 mm Hg (172-174°C/1 mm Hg[5]). Reagent IV is a colorless viscous liquid. Found: C, 45.00; H, 7.07 per cent. Calc. for CloHlaOa: C, 45-11; H, 6.82 per cent. Reagent solution Reagents I and lI were dried at 60°C in vacuo before use. Reagents III and IV were dried to constant weight in a vacuum desiccator. These reagents were dissolved in distilled water. The stock solutions of these reagents were standardized by potentiometric titration with a standard 0.10 M potassium hydroxide solution. The 0.10M potassium hydroxide was standardized by hydrogen potassium phthalate titrimetrically. The stock solutions of metal ions were prepared by dissolving Mg(NO3) 2 . 6H20, Ca(NO3) 2 . 4H20, Sr(NO3) 2 and Ba(NOa) 2 of guaranteed-reagent grade. The concentrations of the Mg(II) and Ca(II) solutions were determined by chelatometric titration, while the concentrations of the Sr(II) and Ba(II) solutions were determined by the usual gravimetric method. pH titration apparatus The pH titration apparatus is illustrated in Fig. 1. The titration cell was a double-walled glass vessel and the titration temperature was maintained at 25.0 _+ 0-1°C by the circulation of water from a thermostat bath. Purified nitrogen gas was introduced into the titration cell, and the titration was carried out under nitrogen. The electrode used was a Metrohm combined glass electrode EA125. The syringe used was an Agla micrometer syringe and the total volume of this syringe was 0-5 ml. The piston of this syringe was depressed by rotating the micrometer, and the 0.10 M potassium hydroxide was added dropwise into the titration
E~
~
2><5. Fig. 1. Micro-titration apparatus. A, Metrohm Precision Compensator E388; B, Metrohm combinedglass electrode EA125; C, Thermometer; D, N 2 gas; E, 25°C water from a thermostat bath; F, volume 10ml; G, Magnetic stirrer; H, Laboratory jack; I, Agla micrometer syringe.
Chelates of dicarboxylic acids having - O - linkages cell. The m i n i m u m volume that can be titrated by this
micrometer syringe is 2 × 10-4 ml. The pH-meter used was a Metrohm Precision Compensator E388. The body of the titration cell was moved up and down by a laboratory jack. pH titration method
The acid dissociation and chelate stability constants were calculated from titration curves obtained by titrating solutions (10 ml) in the presence and in the absence of metal ions
with 0.10 M potassium hydroxide. The titration was carried out at 25.0 ___0.1°C and the ionic strength # = 0-10(KNO3). The observed pH-meter readings were converted into the actual hydrogen-ion concentration by comparison w i t h the stoichiometric dissociation constant of acetic acid[6].
CALCULATION Acid dissociation constants
When the dicarboxylic acid is represented as H2L, the acid dissociation equilibrium is as follows: H z L ~Ko. - H L - + H +, H L - K.~ ~ L 2- + H +. K,, and Ka2 are given by the following formula [ H L - ] [H + ] [H2L ] '
K,,
1 Ka '
-
[ L 2 - ] [ H +] [HL-]
Ka2
RESULTS AND DISCUSSION Synthesis
Reagents llI and IV can also be synthesized by the method of Abe et al. [5], but especially in the case of the synthesis of IV, the starting material, pentaethylene glycol, is expensive and not easily obtainable. On the other hand, the method given here is easy in comparison with the former method; the reaction time is shorter, and the starting material is cheaper. Titration curves
The titration curves for Reagent 1 in the presence and in the absence of alkaline earth metal ions are illustrated in Fig. 2. In this figure, the titration curves for Reagent I in the presence of magnesium and barium ions are intermediate between the titration curves for Reagent I alone and for the strontium ion. The titration curves for Reagents II, III and IV are similar to that for Reagent I in Fig. 2. The inflection at a = 2 in the titration curve of the ligand in Fig. 2 shows the complete dissociation of the two carboxyl protons of Reagent I. The titration curve in the presence of metal ion shows a lower pH value than that of the ligand only. Here a depression of the titration curves indicates the formation of the metal chelate species. Acid dissociation constants
AKa~ + B
The acid dissociation constants of the four reagents are summarized in Table 2. In Table 2, the pKa, and
A = 2TL - T°H - [ H + ] + [ O H - ] [H+]2(ToH + [H +] - [ O H - ] ) ' B =
2035
TL - T°" - [H +] + [OH-] [H+](ToH + [m +] - [OH-])
10
where TL represents the total concentration of ligand species, and Ton represents the total concentration of the base added to the system. [H +] is measured with the pH-meter, and [OH-] is calculated from [H+].
8
g-,
"-7
Stability constants
13n
When the metal ion is represented as M 2÷, the chelate formation equilibrium is as follows:
I 6
K
M 2 + + L 2- ~- ML.
K is given by the following formula K -
/4
[ML] TL - F [MZ+][L 2-] -[L 2 ](F + Tu-
TL)
[L2_ ] = 2TL -- Ton - [H +] + [OH-] [H +] 2[H+] 2 , -4 K~ K~,. K ~ F=[
L2-]
[H+]
EH+Y 1
I+~+K,,.K,~]
w h e r e Tu r e p r e s e n t s t h e total c o n c e n t r a t i o n of t h e m e t a l ion.
3
0
[ I
I
O*
2
Fig. 2. Titration curyes of the di(carboxy)methyl ether chelate system at 25°C, # = 0.10. L, ligand only: [L] = 1.258 × 10 -3 M ; [ M g ] = 2.678 × 10-3 M ; [ C a ] = 2.508 × 10- 3 M; [Sr] = 2.546 × 10-3 M; [Ba] = 2.520 × 10- 3 M. *a is moles of base added per mole of ligand.
MASAHIRO MIYAZAKI, YASUAKI SHIMOISHI, HARUO MIYATA a n d KYOJI TOE1
2036
T a b l e 2. Acid dissociation constants, t = 25.0 _+ 0-1°C, p = 0.10 (KNO3}
i;
Reagent*
3 4 5 6 7 8 9 10 11 12 13 14
pK,
pK,~
l
2-73
3.92
II
2.99
3.83
Ill
3-03
3.80
IV
3.05
3.80
Reagent-',Malonic acid Succinic acid Glutalic acid Adipic acid Pimelic acid Suberic acid Azelaic acid Sebacic acid
pK,~[7]
pK,:[7]
pK~[8]
pKa,[8 ]
2.97 4.18 4.31 4.44 4.51 4.53 4-56 4.5~
5-75 5.67 5.43 5.45 5-51 5.52 5.53 5.54
2-83 4.19 4.34 4.42 4.48 4.52 4.55
5.69 5.48 5-42 5.41 5.42 5-40 5.41
* n is the total sum of the number of oxygen atoms of ether linkages and carbon atoms. + n is the number of carbon atoms.
I
I
I
I
I
I
I
5.0
4.0
3.13
3.0 ~
o
-
o
0
I
I
0.5
1.0
I
I
I
1.5 2.0 2.5 zln×lO
I
I
3.0
3.5
Fig. 3. Relation between pK, and 1In. 0, Ingold's plots; ~ , Ninomiya's plots, where n is the number of carbons; O, authors' plots, where n is the total sum of the number of oxygen atoms of ether linkages and the number of carbon atoms. pKa2 values correspond to the dissociation of the two carboxyl protons respectively. The pK, values of the four reagents are plotted against the reciprocal of the total sum of the number of oxygen atoms of ether linkages and carbon atoms in the reagents (Fig. 3). In this figure, it is obvious that the pK,'s of the reagents, as a whole, are smaller than those of the aliphatic dicarboxylic acids. This indicates that the large electronegativity of the - O - atom introduced as ether linkages enhances the dissociation of the acids.
The ApK, = pKa2 - pKa, becomes smaller as the number of carbons of the aliphatic dicarboxylic acids increases. When the number of carbons becomes infinite, namely at 1In = 0, ApKa is equal to 0-6, i.e. Kal/Ka2 is equal to 4, meaning that the molecule behaves statistically. This is similar to the pK a of the reagents. When the total sum of the number of oxygen atoms of efher linkages and carbon atoms approaches infinity, namely at 1/n = 0, ApK, is equal to 0.6, i.e. K,,/Ka2 is equal to 4. The molecules of the reagents also behave statistically. In Fig. 3, Ninomiya's plots[7] are shifted from those given by Ingold[8]. In the case of Ninomiya and T6ei [7], the aliphatic dicarboxylic acid molecules favor the pliable model, because the dilute dicarboxylic acids (2.5 × 10 -3 M) are titrated in concentrated electrolytes, namely at the ionic strength # = 0.10. In the case of Gane and Ingold[8], the aliphatic dicarboxylic acid molecules prefer the rigid model, because the pKa's of the dilute dicarboxylic acids are measured in pure water and extrapolated to irtfinite dilution. Therefore, the aliphatic dicarboxylic acid molecules behave theoretically. In the other hand, it is thought that the molecules of the reagents favor the rigid model and behave theoretically, because the - O - atom introduced as ether linkages is hydrophilic, though the reagents are titrated in the concentrated electrolytes, namely at the ionic strength/~ = 0.10.
The comparison of the stability of the magnesium chelate with that of the calcium chelate The stability constants of their 1:1 chelates with alkaline earth metals (magnesium, calcium, strontium and barium) are tabulated in Table 3. The stability constants of the chelates of Reagent I with alkaline earth metals decrease as follows: calcium > strontium > barium > magnesium, the stability constants
Chelates of dicarboxylic acids having -O linkages
2037
Table 3. Stability constants of the chelates, t = 25.!) ± 0.1°C, H = 0.10{KNO3) n
Reagent*
2 3 4 5 6 7 8 9 I0 11 12 13 14
Mg
Ca
Sr
Ba
l
2.06
3.39
2-47
2.15
I1
1.9
3.15
2.40
_._ )
Ill
1-8
2.40
"~"~9
"~ 3¢ _._9
IV
1.4
2.14
2.29
2-29
* n is the t o t a l s u m of the n u m b e r of o x y g e n a t o m s ', n is tile n u m b e r of c a r b o n a t o m s .
Reagent;Oxalic acid Malonicacid Succinic acid Glutalic acid Adipic acid Pimelic acid S uberic acid Azelaic acid %cbacic acid
Mg
Ca
Sr
Ba
2.V619 i 3.0 i 0] 2-54[11] 2.31[11~ ] ~"~il2 _.8, 2.49[12] 1.25i13] 1.71!12 1.20113] 1.20113] 1.06~13 I.B[ 31 1.08,13 1.06113] 0.6[14] 2.04115 2.19116] 1.85(16]
of e t h e r l i n k a g e s a n d c a r b o n a t o m s .
of their chelates of Reagents II, III and IV with alkaline earth metals decrease as shown below:
The comparison oJ the stability constants of the reagents with those oj aliphatic dicarboxylic acids
calcium > strontium > barium > magnesium calcium > strontium = barium > magnesium strontium = barium > calcium > magnesium
From Table 3, it is clear that the reagents form more stable chelates with alkaline earth metals than do the aliphatic dicarboxylic acids. For example, Reagent I corresponds to the acid-introduced ether linkage of succinic acid, and Reagent II corresponds to the acidintroduced ether linkage of adipic acid, and there, in each case, the stability of the metal chelates is increased by the introduction of ether linkages. These results indicate the coordination of the - O - atom introduced as ether linkages. When the chelate ring is five- or six-membered, the stability of the chelate formed is highest, whereas the chelate rings formed by the aliphatic dicarboxylic acids would become five-, six- and seven-membered successively. Therefore, it is clear that the stability of the chelates of aliphatic dicarboxylic acids with alkaline earth metals become poor with an increase in the number of carbon atoms. On the other hand, when the reagents form chelates with calcium and magnesium, the stability also becomes poor with an increase in the total sum of the number of oxygen atoms of the ether linkages and the number of carbon atoms. The stability, as a whole, however, is much better than those of the aliphatic dicarboxylic acids, because the number of five-membered rings formed in a chelate is increased by the coordination of the - O - atom introduced as ether linkages with increase of the total sum of the number of oxygen atoms of ether linkages and carbon atoms. Therefore, it is thought that the reagents form stabler chelates on the basis of the total interaction between the steric factor and the coordination of the (Y atom than aliphatic dicarboxylic acids do with alkaline earth metals. On the basis of the reasons described above, the -O- atom introduced as ether linkages functions largely on the increase of the stability of four metal chelates. Especially it functions specifically for calcium.
The log K values are plotted against the reciprocal of crystal ionic radii of alkaline earth metals, 1/r,ys, ' , in Fig. 4. From this figure, all the reagents form their most unstable chelate with magnesium. Furthermore, all the reagents form a stabler chelate with calcium than they do with magnesium. This is similar to the behavior of GEDTA. Reagents I and II form especially stable chelates with calcium.
Ba Sr Ca
I'1
']
Mg
'
'
I'
3 o
I
I
[
I
I
0.8
1.0
1.2
1/-,
1.6
rcryst
Fig. 4. Plot of log K against 1/r¢,y,,. of metal ions.
©, Reage ~t 1; O, Reagent 11; ~ , Reagent I11 ,'0', Reagent I V
2038
MASAHIRO MIYAZAKI, YASUAKISH1MOISHI, HARUO MIYATAand KYOJI TO~t
Acknowledgement--The authors wish to express their gratitude to Professor Yoshiro Abe of Keio University for his kind instruction in the synthesis of 1,2-bis-(carboxy methoxy) ethane and di(carboxymethoxy)ethyl ether.
REFERENCES
1. T. Katayama, H. Miyata and K. T6ei, Bull. chem. Soc. Japan 44, 2174 (1971). 2. G. Schwarzenbach, H. Senn and G. Anderegg, Heir. chim. Acta 40, 1886 (1957). 3. J. H. Holloway and C. N. Reilly, Analyt. Chem. 32, 249 (1960). 4. Y. Abe, C. Kato, D. Higo, T. Aoki and H. Miyagawa, Yukagaku 18, 32 (1968). 5. Y. Abe, T. Aoki and H. Miyagawa, Yukagaku 20, 149 (1971).
6. H. S. Harned and F. C. Hickey, J. Am. chem. Soc. 59, 1284, 2303 (1937). 7. A. Ninomiya and K. T6ei, Nippon Kagaku Zasshi 911, 656 (1969). 8. R. Gane and C. K. Ingold, J. chem. Soc. 2153 (1931). 9. G. Schwarzenbach and G. Anderegg, Helv. Chim. Acta 40, 1773 (1957). 10. E. Gelles and R. M. Hay, J. chem. Soc. 3673, 3684, 3689 (1958). 1 !. R. W. Money and C. W. Davies, Trans. Faraday. Soc. 28, 609 (1932). 12. D. I. Stock and C. W. Davies, J. chem. Soc., 1371 (1949). 13. R. K. Cannon and A. Kibrick, J. Am. chem. Soc. 60, 2314 (1938). 14. J. Schubert and Lindenboum, J. Am. chem. Soc. 74, 3529 (1952). 15. J. M. Peacock and J. C. James, J. chem. Soc. 2233 (1951). 16. N. E. Topp and C. W. Davies, J. chem. Soc. 87 (1940).