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Polar substituent effects in the sodium borohydride reduction of 2- and 3- substituted fluorenones
Tetrahedron.1%2. Vol 18,PP. 323to 331. PergamonPra Ltd. Printedin NorthernIreland
POLAR SUBSTITUENT EFFECTS IN THE SODIUM BOROHYDRIDE REDUCTION OF 2- AND 3SUBSTITUTED FLUORENONES* G. G. SMITH? and R. P. BAYER Department
of Chemistry, Washington Pullman, Washington
(Received 13 March 1961; in revisedform
State University
2 October 1961)
Abs&a&-_The kinetics in the sodium borohydride reduction of fluorenone and twelve 2- and 3substituted fluorenones were determined at three temperatures in isopropyl alcohol and the entropies and enthalpies of activation calculated. A linear Hammett up plot was obtained using meta and para 0 constants. The positive p value (p = G2.65) confirmed the nucleophilicity of sodium borohydride. Deviations of the 2-methoxy and 2-aminofluorenone from the Hammett correlation were explained by electron delocalization through the unsubstituted ring to the reaction site in the pound state. The reduction reaction to a considerable extent destroys these interactions at the transition state stage.
9-fluorenones has been determined by borohydride reduction. The interest in fluorenones is an of previous studies made in these laboratories of polar substituent and proximity effects of carbonyl compounds in rigid systems. Previously, migratory aptitudes in substituted phenanthraquinones were determined.’ Other studies have been made on the effect of structural changes upon reactivity of aldehydes and ketones using different reagents, 2 but the mechanisms of these reactions appears to be more complex than does that of sodium borohydride reduction.2J*2e The discovery of sodium borohydride by Schlesinger et aL3 provided a reagent which was not only useful synthetically but has been shown to be valuable as a measure of carbonyl reactivity. 4 Various studies have indicated the kinetics of this reaction to be simple second order with no detectable side reactions.4u*5 had no mechanGarrett and Lyttle 5a found that a change in alkali concentration istic effect on the sodium borohydride reduction of 3-a-hydroxy-1 I-a- acetoxySodium borohydride has been used as a reducing agent pregnam-20-one in dioxane. for preparative purposes primarily in water and methanol solution. It reacts with
THE substituent
studying extension
their
effect
in 2- and 3- substituted
sodium
* This research was supported by a grant from the National Science Foundation, G-6042. Grateful acknowledgement is hereby given. Abstracted from a thesis presented to the Graduate School, Washington State University by R. P. Bayer in partial fulfillment of the requirements for the Ph. D. degree, November, 1960. t Present address: Chemistry Department, Utah State University, Logan, Utah. 10 G. G. Smith and D. G. Ott, J. Amer. Chem. Sot. 77.2342 (1955); b G. G. Smith and D. G. Ott, I&f. 77, 2325 (1955); o G. G. Smith and G. 0. Larson, Ibid. 82, 99 (1960). *J. D. Dickinson and C. Eabom, J. Chem. Sot. 3641 (1959); b G. H. Stempel. Jr., and G. S. SchalTel, (1941); d W. p. /. Amer. Chem. Sot. 66,1158 (1944); c F. P. Price, Jr., and L. P. Hammet, Ibtif. 63.2387 Jencks, Ibid. 81,475 (1959). ’ B. M. Anderson and W. P. Jencks, Ibid. 82, 1773 (1960). s H. I. Schlesinger, H. C. Brown, H. R. Hoekstra and L. R. Rapp, /. Amer. Chem. Sot. 75, 199 (19~3). 4~ E. H. Jensen, A Srudy an Sodium Borohydride NYT Nordisk Forlag Arnold Busck, Copenhagen (1954); b H. C. Brown, 0. H. Wheeler, K. Ichikawa, Terrahedron 1,214 (1957); 0 H. C. Brown and K. Ichikawa, Ibid. 1, 221 (1957). h E. R. Garrett and K. A. Lyttle, J. Amer. Chem. Sot. 75, 6051 (1953); ( H. C. Brown, E. J. Mead and B. C. Subba Rao, Ibid. 17, 6209 (1955). 323
324
G. G. SMITH
and R. P. BAYER
these solvents, however, complicating the kinetic study. Brown et aL5 b found sodium borohydride to be moderately soluble in isopropyl alcohol; in this medium no base was necessary and alcoholysis was not appreciable. Thus it was concluded that a study of the rates of reduction of substituted fluorenones by sodium borohydride in isopropyl alcohol was a suitable system to evaluate substituent effects and carbonyl reactivity in a system in which the carbonyl group is held rigidly coplanar with the ring. Fluorenone and a few substituted fluorenones have been reduced with sodium borohydride to tluorenols .‘j However, no published study has been made on the kinetics of the reaction. For the most part the reduction of fluorenones with sodium borohydride is straightforward but a few fluorenones failed to give the expected product.6 The purpose of the investigation on the rate of reduction of substituted fluorenones was to : (a) evaluate the substituent effect in a ring system where the reactive carbonyl was held essentially coplanar with the substituted aromatic ring, (b) verify that sodium borohydride is a nucleophilic reagent in carbonyl reductions, and (c) investigate the proximity effect of ortho substituents in a ring system where the neighboring substituent and the reactive carbonyl are held close and coplanar to one another. This last objective will be discussed in a subsequent paper. DISCUSSION
OF ANALYTICAL
PROCEDURES
AND RESULTS
Two methods
were tried to determine the sodium borohydride reduction rates of the substituted fluorenones: spectrophotometric and titrimetric. In the former, the fraction of ketone present at any time, t, was determined by the intensity of the R-band characteristic of the carbonyl group. ’ In the latter,’ the fraction of sodium borohydride present at any time was determined by titration of an aliquot of the reaction The spectrophotometric method proved far superior to the titrimetric mixture. method because of the better reproducibility of the spectral method. Attempts to compare the rate constants for fluorenone reduction by both methods failed since The indicator the titrimetric method gave erratic results which were not reproducible. end point could not be accurately determined because of the color of the ketone and precipitation of the fluorenol. The spectrophotometric method was shown to be completely satisfactory for this study by comparing the specific rate constants determined for benzophenone at several concentrations with those obtained by the titrimetric method. The average rate constants obtained at 25” by the two methods were: 22.7 + 0.4 and 20.9 f 0.5, respectively. The rates of reduction were measured several times at one concentration of ketone and sodium borohydride. However, only the mean value and the standard deviation of the arithmetric mean are listed in Table 1. Changing the initial concentration of the ketone or borohydride had no significant effect on the rate constant. The activation enthalpies and entropies for each compound were calculated in the usual manner from the slope obtained by plotting the reciprocal of the absolute temperature against log k, - log T. b M. S. Newman and W. B. Lutz,/. Amer.
Chem. Sot. 78,2469 (1956); b H.-L. Pan and T. L. Fletcher, Ibid. (1956); c H.-L. Pan and T. L. Fletcher, J. Org. Chem. 23, 799 (1958). 7 A. E. Gillam and E. S. Stern, An Introduction to Electronic Absorption Spectroscopy in Organic Chemistry (2d ed.) p. 126. Edward Arnold, London (1957). 78,4812
Polar substituent effects in the sodium borohydride reduction of 2- and 3-substituted fluorenones TABLE
1.
SE~ONDORDERCONSTANTS
FORTHEREAC~ONOFSODILW
BOROHYDRIDEWI-III
325
SUBS~UTED
FLUORENONE.3INISOPROPYLALCOHOL
Amax (mu)
Fluorenone
i
log
_I__-_ 2-CN” 2-Br
390 400
2.842 2.554
2-Cl
404
2.508
385
2-F
2.292
3-Cl
375
2449
3-Br
370
2.524
3-F
375
2.390
H
380
i 2.412
2-OCH,
430
2.508
I
I
2-CH,
I
400 ’ 2409
3-CH,
’
375
2.452
I 2-NH, 3-OCH,
490 380
k, x 10m (1 /mole-set)
Temp E
2.680 2.913
(“C) 25.0 25.0 35.0 45.0 0.8 25.0 35.0 0.5 25.0 35.0 25.0 35.0 45.0 25.0 35.0 45.0 25.0 35.0 45.0 0.5 17.2 25.0 35.0 25.0 35.0 45.0 25.0 35.0 45.0 25.0 35.0 45.0 25.0 25.0 35.0 45.0
!
8484*4 1186 * 2341 * 4235 St 183.3 f 1020 f
! 1948 k i 121.8 ! 683.3 *f ; 1272*
19 6 14 3.1 11
Relative Rate (25”) 76.3 IO.7
AH: (kco//mole)
I
11.2
ASS (e.u.)
-25.3
: I 9.17
10 4.1 14.7 j 11
11.0
-26.1 I
6.14
10.7
4.56
Il.0
/
--27.5
3.91
10.6
:
-29.3
1.73
12.2
-28.1
I 793.6 & 23.8 1444*13 192.3 $ 0.6 389.3 + I.6 743.7 & 5.3 17.OhO.2 63.8 f 1.1 Ill.2 I 1.8 211.5 * 2.6 97.8 + 0.6 198.1 i_ 1.8 393.3 * 3.9 70.7 ..&0.4 145.7 * 1.1 283.9 f 2.4 35.5 1: 0.4
I
-25.6
I Ia0
11.7
--28.2
0.880
12.5
-25.8
0.636
12.5
0.319
12.4
!
-26.3
--28.3 I
145 _1:0.75 25.5 + 1.8 46.1
0.200 0.130
10.6
;
-36.1
o Deviations are standard deviations of the arithmetic mean from three determinations. b The rate is an initial rate hecause of complex formation shortly after the reaction was initiated. DISCUSSION
OF
RESULTS
Fluorenone (AH: = 1 l-7 kcal and AS: = -28.2 e.u.) is 4.89 times as reactive as benzophenone (AH:: = 13.3 kcal and AS: = -26 e.u.) in reduction at 25”. This is consistent with the observations of Dickinson and Eaborn2” and Price and Hammett2c that the more rigid the structure of a ketone, the more reactive it is in carbonyl In this instance, the difference in reactivity appears to be reflected addition reactions. in both the enthalpy and entropy of activation. Therefore, in the freely rotating system the reduced rate can perhaps be attributed to the “damping” of resonance 5
G. G. Smnn and R. P. BAYER
326
interactions between the phenyl groups and the carbonyl group in benzophenone and the difference in solvation between the two reactions systems. Figure 1 shows a Hammett ploP for the kinetic data at 25”. The linearity with most of the 2- and 3-substituted fluorenones using meta and para a constants, respectively, appears to be very good. Contrasted to these results are those of Dickinson and Eaborn who showed that the 2- and 3-substituted fluorenoneP and substituted benzophenones ab failed to follow a Hammett up correlation in their rate studies on oxime formation. The lack of correlation here may be accounted for by the two-step course of these reactions and the influence of pH.ld The p value for the sodium borohydride reduction of substituted fluorenones is +2*65 which is evidence for a fairly polar transition state and a nucleophilic attack of the hydride ion on the carbonyl as proposed by Brown et aL4b The polar transition state would require a high degree of solvation. The deviation of 2-methoxy- and 2-aminofluorenone from the Hammett correlation in sodium borohydride reduction is interesting, and the extent of this deviation is well outside experimental error. Recently, Dickinson and Eabomso observed the same effect for the 2-methoxy group (the 2-amino was not studied) while studying the rates of reaction of some substituted 9-bromofluorenes with potassium iodide in acetone. The deviation of the 2-methoxy- and Zaminofluorenone could, in part, be explained on second-order mesomeric affects as observed with meta substituents in the phenyl system.sb However, the affect in the fluorenone system is considerably greater because of the direct conjugative interaction between a donor (-R) group and the C=O group as illustrated in structures I, IIa, IIb. 0-
&rx+ I
0-
0-
cd& - bx+ no
nb
The reduction will, to a considerable extent, destroy these interactions at the transition stage and therefore, it would be anticipated that the strong -R substituents (F, OCH,, NH& in both the 2- and 3-position would react more slowly than expected from the operation solely of “Ar-Y” inductive effects.sC The results bear this out (Fig. 1). Taft’s a”-valuesBe, which more exactly represent Ar-Y inductive effects, are also plotted in Fig. 1 for these three substituents. (The other a0 values were not plotted because their variance from a constant is very slight.) The deviation is greater when a” values are used which amplifies the point that there is considerable mesomeric influence of the strong -R substituents in the ground state that is to a considerable extent destroyed at the transition state stage. The low entropy value of 3-methoxy (-36-l e.u.) may appear surprising because of the distance of the substituent from the reaction site. However, it is logical in light of the above discussion on the importance of mesomeric stabilization of the ground state. In a polar medium such as isopropyl alcohol, solvation is likely to be important WH.
H. Jaffe. Chem. Reo. 53, 191 (1953); * J. D. Dickinson and C. Eabom, J. Chem. Sot. 3036 (1959). k J. D. Dickinson and C. Eabom, /. Chem. Sot. 3574 (1959); b R. W. Taft, Jr. and I. C. Lewis, J. Amer. Chem. Sot. 81.5343 (1959); c R. W. Taft, Jr.,/. Phys. Chem. 64. 1805 (1960).
Polar substituent effects in the sodium borohydride reduction of 2- and 3-substituted fluorenones
327
in determining the over-all entropy term. The solvation of substituted fluorenone in the highly polar transition state is probably independent of the substituent, but in the ground state large differences in solvation around the carbonyl as the substituent is varied could be expected. The largest solvation would be expected for those molecules having electron-withdrawing groups; in these cases solvation in the ground state and transition state would not be appreciably different, and, therefore, AS’ would be fairly high (less negative). In those compounds having electron-donating
.3
FIG. I. Hammett plot of rate constants at 25” for the sodium borohydride reduction of 2- and 3-substituted fluorenones. @ Represent points using Taft u” values.
groups attached to the ring the solvation in the ground state would be low and the amount of solvent “frozen out” in the transition state would be large leading to a very low entropy term. Even though the 3-methoxyfluorenone deviates considerably from this correlation, it is difficult to conclude that the meta and paru reaction constants are differentlO If it is assumed that they are different, the best reaction constant for metu substituents would still be +2-65 and for thepuru substituent +2-98. However, correlation of the puru substituted fluorenone with p = +2*98 does not appear to be significantly better than with p = +2*65. On first considering this mesomeric deviation, it appears that a new (Tconstant should be calculated for the 2-methoxy (and also 2-amino) group in this system, such as is required forf -amino andp-hydroxy groups. From out data, the new Qconstants would be uz-Yeo = -0.021 and uz_Nu = -0.264. Although these constants do not give an exact correlation for the data :f Dickinson and EaborneD for the reaction of Pbromofluorenes with potassium iodide in acetone, they are a considerable improvement over the standard constants. I0J. Hine, 1. Amer.
Chem. Sot. 81, 1126 (1959).
328
G.
G. SMITH
and R. P. BAYER
Taft” has suggested that it is more sound theoretically to apply the following equation rather than to attempt to calculate a new substituent constant for each reaction or reaction type: log k/k, = crp + Y This equation (in the present study) attributes the effect of the substituent on the rate to the sum of both polar effects and the additional resonance effects through the unsubstituted ring. ‘I? is this additional resonance effect (not normally encountered in meta substitution) and ap is the polar effect. Thus, Yz_yeo is equal to -0.340 in the case of the reaction of 2-methoxy-9-bromo-fluorene with potassium iodide in acetone at -0W” (the rate data for 2-Me0 was extrapolated to O$W). In the sodium borohydride reduction of 9-fluorenones, Y2_1Jreois equal to -0.435 at 0”. These differences appear to reflect the difference in nucleophilicity of the iodide and borohydride ions. It is concluded that in the sodium borohydride reduction of 2- and 3-substituted fluorenones a good correlation of the rate is obtained by a Hammett ap plot using meta and para substituent constants. The +2-65 value for p indicates a fairly polar transition state with a transfer of a hydride ion from boron to carbon being rate determining. That the deviation of strong -R (F, OCH,, NH,) in both the 2- and 3-positive can logically be explained by mesomerism through the unsubstituted ring in the ground state which is destroyed in the transition state. The low entropy term for the 3-methoxy derivative is explained on the basis of a considerable change in the solvation from the ground state to the activated state. Further discussion of the mechanism of sodium borohydride reduction will be given in a subsequent paper. EXPERIMENTAL Sodium borohydride (98+ %) obtained from Metal Hydride, Incorporated, was used without further purification. This is justifiable since the impurities are known not to interfere with the reaction kinetics and standard solutions were not made gravimetrically, but rather by mixing excess sodium borohydride with isopropyl alcohol, filtering the mixture and standardizing by the iodate method. Isopropyl alcohol was dried over calcium hydride and sodium borohydride and distilled, b.p. 79-79.5” (697 mm). Preparation ofjluorenones. Very few substituted fluorenonesarecommerciallyavailable. However, they were prepared by well known procedures. Therefore, their syntheses are only briefly mentioned and reference is made to their syntheses in Table 2. Each were sublimed and recrystallized from ethanol and dried in uacuo before use, with exception of 2- and 3-methyl-and 3-methoxyfluorenones which were not subtimed but only recrystallized from ethanol. 2-Fluoro-, 2-bromo- and 2-nitrofluorenones were prepared by the oxidation of the respective fluorene compound with sodium dichromate in acetic acid. 2-Nitrofluorenone was reduced with stannous chloride and hydrochloric acid to the 2arninofluorenone, and Z-cyano-, Zchloro-, and 2-methoxyfluorenones were obtained from this compound by standard methods. 2-Aminofluorenone was also utilized for the preparation of 3-bromofluorenone by bromination to 2-amino-3-bromofluorenone and subsequent diazotization and deamination. 2-Methylfluorenone was obtained from the oxidation of 2-methylfluorene with pentyl nitrite. 2-Methylfluorene was prepared by acetylation of fluorene to 2-acetylfluorene followed by a Kindler modification of the WiUgerodt reaction, hydrolysis to the acid, and decarboxylation by distillation in the presence of calcium oxide. Muterids.
** R.
W. Taft, Jr., Sreric Eficrs York (1956).
in Organic Chrmisrry (Edited
by M. S. Newman)
p. 633.
John Wiley, New
Polar substituent effects in the sodium borohydride
329
reduction of 2- and 3-substituted fluorenones
3-Methyl- and 3-methoxyfluorenone were both prepared by a similar method. pToluenesulfonylanthranilic acid was prepared and its acid chloride subjected to Friedel-Crafts conditions in the presence of toluene and anisole, respectively. Hydrolysis of the crude product with concentrated sulfuric acid afforded the respective 2-aminobenzophenones. The benzophenones were subjected to a modified Gomberg reaction in 21 N sulfuric acid to afford 3-methyl- and 3-methoxytluorenone, respectively. 3-Chlorofluorenone was prepared by a Sandmeyer reaction with 3-amino-fluorenone and cuprous chloride. 3-Amino and 3-fluorofluorenones were gratefully received from Dr. Fletcher.‘* TABLE 2. PHYSICAL PROPERTIESOF SUBSTITUTED FLUORENONES
M.p. (“C) Fluorenone
2-Cyan0 2-Bromo 2-Chloro’ 2-Fluorof 3-Chloro 3-Bromo 3-Amino‘ 3-Fluoro’ 2-Methoxy t-Methyl 3-Methyl 2-Amino 3-Methoxy
Observed”
Literature
173-174 149-150 126-127 117-118 156157 165-165.5 162-162.5 132-132.5L 78-79 92.5.-93.5 69-70 158-159 99.5-100
173” 149” 123’8” 117s 157” 165.5-l 66b*h 159-1&Y 128.5-128‘ 77-78” 91-92* 66.5”. 68b 158* 1OCP
I
DAll mp corrected. b J. D. Dickinson and C. Eaborn, J. Chem. Sot. 2337 (1959). ’ Prepared by R. Haugwitz. 6 C. Courtot, Ann. C/tint. (10). 14, 1450 (1930). r I. M. Heilbron, D. H. Hey and R. Wilkinson, J. Chem. Sot. 141, 113 (1938). 1 This ketone was prepared by the oxidation of 2-fluorofluorene which was kindly provided by Dr. T. L. Fletcher, University of Washington. 0 E. D. Bergmann H. Hoffmann and D. Winters Eer. deut. them. Ges. 66,46 (1933). h Ref. 66. I This ketone was gratefully received by Dr. T. L. Fletcher, University of Washington. ) N. Ishikawa, M. Okawaki and M. Hayashi, Ytiki Gdsei Kagaku Ky6koi-Shi 15, 34 (1958); Absrr. 52, 5349 (1958). L Purified further by sublimation and recrystallization from ethanol. * Ref. 12. m F. Ullman and E. Mallet, Ber. a&t. them. Ges. 31, 1694 (1898).
Chem.
The fluorenols, for product study, were prepared by reduction of the ketones with an excess of sodium borohydride. The physical properties of these alcohols are listed in Table 3. Kinetics measurements. The rate constant was obtained for sodium borohydride reduction of benzophenone in isopropyl alcohol by both the titrimetric and spectrophotometric methods. The activation enthalpies and entropies were determined for 13 fluorenones whose rates of reduction were studied by the spectrophotometric method. Titrimetric method. This method involved the titration of aliquots removed from the reaction mixture at appropriate intervals for residual borohydride by the potassium iodate method.ti*6 A known volume of standard isopropyl alcohol solution of borohydride (50 ml) was placed in a 200 ml glass stoppered round-bottom flask, immersed in a constant temp bath several hours prior to the experiment; the reactants were also kept at a constant temp for several hours. A 50 ml volume of If T. L. Fletcher, M. J. Namkung, W. H. Wetzel and H. -L. Pan, J. Org. Chem. 25,1342 (1960).
144’5-145
140-141
135-136
100
94” 90.5 99”
3-MethyP
2-Amino 3-Methoxy Hydrogen
157.5’ 160” 144-145‘ 143-144” 143.5-144.5’ 144-145” 201-201.5’ 120” 84.5-85‘
169.5-170.5’ 171-172’
129-130’ ! 1420
’ 128”
77.99
!
I I
:
: 77.99
, 72.06
I
%JBsTITUTED
77.71 I 4.53 I
:I::
’1 4.54 I
78.18 1 4.53 71.94 l 4.19 i
!?-FLUORENOL9
;
i
-
I
/
-
~ 7
i 9.49 I
I
i I::;:
9.16
9.31 16.50
(1Analyses by Alfred Bernhardt Mikroanalytischcs Laboratorium im Max-Planck-Institut, Muelheim (Ruhr) Germany. AU analytical samples were sublimed in oocuo for final purification. Reduction according to the method of H. -L. Pan and T. L. Fletcher, J. Org. Chem. 23, 79 (1958). c Yields are based on recrystallized product. d All mp are corrected. a C. Cow-tot and J. Moreaux. C.R. Acad. Sci., Paris 217. 506 (1943). r C. H. Courtot and C. Vignati, Bull. Sot. Chim. 41, 58 (1927); C/tern. Absrr. 21, 1643 (1921). g C. Courtot and C. Vignati, C.R. Acud. Sci.,.Puris 184, 1179 (1927); C/tern. Absrr. 21, 3616 (1927). therefore, the yield reported is that given in the literature. ’ This compound has been reported as having been prepared by sodium borohydridc reduction: * Ref. 6c. j K. Suzuki, S. Kajigaeshi and M. Sano, Yiki Gdsei Kuguku KyOkui-Shi 16, 82 (1958); Chem. Abstr. 52, 10019 g (1958). t Obtained pure without recrystallization. t Ref. b, Table 2. m C. L. Arcus and M. M. Coombs, J. Chem. Sot. 3977 (1954).
122 -122.5
143.5-144.5
145-145.5
91.8
2-Methyl
i
/ 165.5-166
I i
169-169.5 160-160.5
87”
76 95 98
946
93.3 99
’
! /
; I
3-Fluoro 2-Methoxyk
3-Bromo
3-Chloro
2-Chloro 2-Fluoro
2-cyan0 2-B;omo
Fluorenol
TABLE 3.
Polar substituent effects in the sodium borohydride
reduction of 2- and 3-substituted fluorenones
331
the ketone in isopropyl alcohol was rapidly added to the borohydride solution with vigorous mixing. As the reaction proceeded, 10 ml aliquots were pipetted into a solution of 25 ml of a 025 N standard potassium iodate and 2 ml of 2 N NaOH (mixing was accomplished with the aid of a magnetic stirrer) at appropriate intervals. After 1 min mixing, 2 g of potassium iodide was added, followed by 12 ml of 2 N H,SO,. The iodine solution was covered with a watch glass and placed in a dark place for 2-3 min. Distilled water (250 ml) was added and the solution titrated with 0.1 N standard thiosulfate solution. From the volume of thiosulfate used, the amount of unreacted sodium borohydride and unreacted ketone were calculated. The rate constant was then computed for the reaction. The rate constants for the three determinations made for benzophenone were 20.7 x lo-‘, 20.4 x 10.’ and 21.6 x lo-’ l/mole-see using a ketone concentration of OG400 M and sodium borohydride concentrations of 0.0238 M, 0.0213 M, and 0.0218 M, respectively. Specrrophotomerric merhocf. This method involved use of a Beckman Model DU Spectrophotometer to determine the amount of unreacted ketone in the reaction of ketone with sodium borohydride in isopropyl alcohol at various temperatures and concentrations. It was found to be the simpler and more accurate of the two methods. The height of the carbonyl peak (R-band) was used as a measure of the concentration of ketone present at any time. In the spectrophotometric measurements, Beer’s Law was applicable and the reduction products were found not to interfere at the wave lengths used. Sodium tetraisopropylborate had no effect on the carbonyl peak. The rate constants for two determinations made for benzophenone were 22.3 x lo-’ and 23.1 x lOma l/mole-set using ketone concentrations of 0.0266 M and O0tOO M, respectively, and sodium borohydride concentrations of 0.0290 M and 0.0214 M, respectively. These are considered in good agreement with the titration method. Analyticalprocedure for borohydride. In a 500 ml Erlenmeyer flask was placed 0.25 N standard potassium iodate (25-50 ml) with 2 N NaOH (2-5 ml). The alcoholic solution of sodium borohydride (l&25 ml) was added and the solution thoroughly mixed by swirling for approximately 2 min. Finally, 2 g of potassium iodide was added followed immediately by 12-15 ml of 5 N H,SO,. The flask was covered with a watch glass and placed in a dark place for 2-3 min. Distilled water (250 ml) was added and the iodine-iodide solution was titrated with standard thiosulfate solution (0.1 N) using starch indicator. Determination of the rate constant. Standard solutions of sodium borohydride and of ketone in isopropyl alcohol were prepared and equilibrated in the thermostat. Concentrations were corrected for changes in density of isopropyl alcohol, using data in the International Critical Tables. A known volume of ketone solution (2-15 ml) was placed in a reaction flask immersed in the thermostat. A known volume of sodium borohydride solution (l-5 ml) was added to the ketone solution and mixing was accomplished with the aid of an automatic pipette. An aliquot was placed in the spectrophotometer. The temp of the cell compartment was regulated within *0.05” by circulating water from a thermostat through the custom-built jacketed cell compartment. Measurements of the percentage transmission were made beginning 1i-3 min after the initiation of the reaction and generally continued until the reaction had proceeded beyond one half-life. Using Seer’s Law, the concentration was calculated for appropriate time intervals. The concentrations of the ketone and borohydride were doubled and some cases trebled without a significant change in the rate. A linear plot was obtained from a plot of the quantity a%
log 6 -$+
against the time t which passed through
the origin. In this expression a is the initial molar concentration of ketone, b is the initial molar concentration of sodium borohydride and x is the amount of sodium borohydride which has reacted at time I. Rates were determined at 3 temperatures (four for fluorenone) and in triplicate wherever it was feasible. Mean values and standard deviations of the arithmetic mean are listed in Table 1. AcknowIe&ements-The authors are greatly appreciative to the National Science Foundation for financial support and to Dr. T. L. Fletcher for 3-amino-, 3-fluoro, and Cfluorofluorenones and 2fluorofluorene used in this study.
POLAR SUBSTITUENT EFFECTS IN THE SODIUM BOROHYDRIDE REDUCTION OF 2- AND 3SUBSTITUTED FLUORENONES* G. G. SMITH? and R. P. BAYER Department
of Chemistry, Washington Pullman, Washington
(Received 13 March 1961; in revisedform
State University
2 October 1961)
Abs&a&-_The kinetics in the sodium borohydride reduction of fluorenone and twelve 2- and 3substituted fluorenones were determined at three temperatures in isopropyl alcohol and the entropies and enthalpies of activation calculated. A linear Hammett up plot was obtained using meta and para 0 constants. The positive p value (p = G2.65) confirmed the nucleophilicity of sodium borohydride. Deviations of the 2-methoxy and 2-aminofluorenone from the Hammett correlation were explained by electron delocalization through the unsubstituted ring to the reaction site in the pound state. The reduction reaction to a considerable extent destroys these interactions at the transition state stage.
9-fluorenones has been determined by borohydride reduction. The interest in fluorenones is an of previous studies made in these laboratories of polar substituent and proximity effects of carbonyl compounds in rigid systems. Previously, migratory aptitudes in substituted phenanthraquinones were determined.’ Other studies have been made on the effect of structural changes upon reactivity of aldehydes and ketones using different reagents, 2 but the mechanisms of these reactions appears to be more complex than does that of sodium borohydride reduction.2J*2e The discovery of sodium borohydride by Schlesinger et aL3 provided a reagent which was not only useful synthetically but has been shown to be valuable as a measure of carbonyl reactivity. 4 Various studies have indicated the kinetics of this reaction to be simple second order with no detectable side reactions.4u*5 had no mechanGarrett and Lyttle 5a found that a change in alkali concentration istic effect on the sodium borohydride reduction of 3-a-hydroxy-1 I-a- acetoxySodium borohydride has been used as a reducing agent pregnam-20-one in dioxane. for preparative purposes primarily in water and methanol solution. It reacts with
THE substituent
studying extension
their
effect
in 2- and 3- substituted
sodium
* This research was supported by a grant from the National Science Foundation, G-6042. Grateful acknowledgement is hereby given. Abstracted from a thesis presented to the Graduate School, Washington State University by R. P. Bayer in partial fulfillment of the requirements for the Ph. D. degree, November, 1960. t Present address: Chemistry Department, Utah State University, Logan, Utah. 10 G. G. Smith and D. G. Ott, J. Amer. Chem. Sot. 77.2342 (1955); b G. G. Smith and D. G. Ott, I&f. 77, 2325 (1955); o G. G. Smith and G. 0. Larson, Ibid. 82, 99 (1960). *J. D. Dickinson and C. Eabom, J. Chem. Sot. 3641 (1959); b G. H. Stempel. Jr., and G. S. SchalTel, (1941); d W. p. /. Amer. Chem. Sot. 66,1158 (1944); c F. P. Price, Jr., and L. P. Hammet, Ibtif. 63.2387 Jencks, Ibid. 81,475 (1959). ’ B. M. Anderson and W. P. Jencks, Ibid. 82, 1773 (1960). s H. I. Schlesinger, H. C. Brown, H. R. Hoekstra and L. R. Rapp, /. Amer. Chem. Sot. 75, 199 (19~3). 4~ E. H. Jensen, A Srudy an Sodium Borohydride NYT Nordisk Forlag Arnold Busck, Copenhagen (1954); b H. C. Brown, 0. H. Wheeler, K. Ichikawa, Terrahedron 1,214 (1957); 0 H. C. Brown and K. Ichikawa, Ibid. 1, 221 (1957). h E. R. Garrett and K. A. Lyttle, J. Amer. Chem. Sot. 75, 6051 (1953); ( H. C. Brown, E. J. Mead and B. C. Subba Rao, Ibid. 17, 6209 (1955). 323
324
G. G. SMITH
and R. P. BAYER
these solvents, however, complicating the kinetic study. Brown et aL5 b found sodium borohydride to be moderately soluble in isopropyl alcohol; in this medium no base was necessary and alcoholysis was not appreciable. Thus it was concluded that a study of the rates of reduction of substituted fluorenones by sodium borohydride in isopropyl alcohol was a suitable system to evaluate substituent effects and carbonyl reactivity in a system in which the carbonyl group is held rigidly coplanar with the ring. Fluorenone and a few substituted fluorenones have been reduced with sodium borohydride to tluorenols .‘j However, no published study has been made on the kinetics of the reaction. For the most part the reduction of fluorenones with sodium borohydride is straightforward but a few fluorenones failed to give the expected product.6 The purpose of the investigation on the rate of reduction of substituted fluorenones was to : (a) evaluate the substituent effect in a ring system where the reactive carbonyl was held essentially coplanar with the substituted aromatic ring, (b) verify that sodium borohydride is a nucleophilic reagent in carbonyl reductions, and (c) investigate the proximity effect of ortho substituents in a ring system where the neighboring substituent and the reactive carbonyl are held close and coplanar to one another. This last objective will be discussed in a subsequent paper. DISCUSSION
OF ANALYTICAL
PROCEDURES
AND RESULTS
Two methods
were tried to determine the sodium borohydride reduction rates of the substituted fluorenones: spectrophotometric and titrimetric. In the former, the fraction of ketone present at any time, t, was determined by the intensity of the R-band characteristic of the carbonyl group. ’ In the latter,’ the fraction of sodium borohydride present at any time was determined by titration of an aliquot of the reaction The spectrophotometric method proved far superior to the titrimetric mixture. method because of the better reproducibility of the spectral method. Attempts to compare the rate constants for fluorenone reduction by both methods failed since The indicator the titrimetric method gave erratic results which were not reproducible. end point could not be accurately determined because of the color of the ketone and precipitation of the fluorenol. The spectrophotometric method was shown to be completely satisfactory for this study by comparing the specific rate constants determined for benzophenone at several concentrations with those obtained by the titrimetric method. The average rate constants obtained at 25” by the two methods were: 22.7 + 0.4 and 20.9 f 0.5, respectively. The rates of reduction were measured several times at one concentration of ketone and sodium borohydride. However, only the mean value and the standard deviation of the arithmetric mean are listed in Table 1. Changing the initial concentration of the ketone or borohydride had no significant effect on the rate constant. The activation enthalpies and entropies for each compound were calculated in the usual manner from the slope obtained by plotting the reciprocal of the absolute temperature against log k, - log T. b M. S. Newman and W. B. Lutz,/. Amer.
Chem. Sot. 78,2469 (1956); b H.-L. Pan and T. L. Fletcher, Ibid. (1956); c H.-L. Pan and T. L. Fletcher, J. Org. Chem. 23, 799 (1958). 7 A. E. Gillam and E. S. Stern, An Introduction to Electronic Absorption Spectroscopy in Organic Chemistry (2d ed.) p. 126. Edward Arnold, London (1957). 78,4812
Polar substituent effects in the sodium borohydride reduction of 2- and 3-substituted fluorenones TABLE
1.
SE~ONDORDERCONSTANTS
FORTHEREAC~ONOFSODILW
BOROHYDRIDEWI-III
325
SUBS~UTED
FLUORENONE.3INISOPROPYLALCOHOL
Amax (mu)
Fluorenone
i
log
_I__-_ 2-CN” 2-Br
390 400
2.842 2.554
2-Cl
404
2.508
385
2-F
2.292
3-Cl
375
2449
3-Br
370
2.524
3-F
375
2.390
H
380
i 2.412
2-OCH,
430
2.508
I
I
2-CH,
I
400 ’ 2409
3-CH,
’
375
2.452
I 2-NH, 3-OCH,
490 380
k, x 10m (1 /mole-set)
Temp E
2.680 2.913
(“C) 25.0 25.0 35.0 45.0 0.8 25.0 35.0 0.5 25.0 35.0 25.0 35.0 45.0 25.0 35.0 45.0 25.0 35.0 45.0 0.5 17.2 25.0 35.0 25.0 35.0 45.0 25.0 35.0 45.0 25.0 35.0 45.0 25.0 25.0 35.0 45.0
!
8484*4 1186 * 2341 * 4235 St 183.3 f 1020 f
! 1948 k i 121.8 ! 683.3 *f ; 1272*
19 6 14 3.1 11
Relative Rate (25”) 76.3 IO.7
AH: (kco//mole)
I
11.2
ASS (e.u.)
-25.3
: I 9.17
10 4.1 14.7 j 11
11.0
-26.1 I
6.14
10.7
4.56
Il.0
/
--27.5
3.91
10.6
:
-29.3
1.73
12.2
-28.1
I 793.6 & 23.8 1444*13 192.3 $ 0.6 389.3 + I.6 743.7 & 5.3 17.OhO.2 63.8 f 1.1 Ill.2 I 1.8 211.5 * 2.6 97.8 + 0.6 198.1 i_ 1.8 393.3 * 3.9 70.7 ..&0.4 145.7 * 1.1 283.9 f 2.4 35.5 1: 0.4
I
-25.6
I Ia0
11.7
--28.2
0.880
12.5
-25.8
0.636
12.5
0.319
12.4
!
-26.3
--28.3 I
145 _1:0.75 25.5 + 1.8 46.1
0.200 0.130
10.6
;
-36.1
o Deviations are standard deviations of the arithmetic mean from three determinations. b The rate is an initial rate hecause of complex formation shortly after the reaction was initiated. DISCUSSION
OF
RESULTS
Fluorenone (AH: = 1 l-7 kcal and AS: = -28.2 e.u.) is 4.89 times as reactive as benzophenone (AH:: = 13.3 kcal and AS: = -26 e.u.) in reduction at 25”. This is consistent with the observations of Dickinson and Eaborn2” and Price and Hammett2c that the more rigid the structure of a ketone, the more reactive it is in carbonyl In this instance, the difference in reactivity appears to be reflected addition reactions. in both the enthalpy and entropy of activation. Therefore, in the freely rotating system the reduced rate can perhaps be attributed to the “damping” of resonance 5
G. G. Smnn and R. P. BAYER
326
interactions between the phenyl groups and the carbonyl group in benzophenone and the difference in solvation between the two reactions systems. Figure 1 shows a Hammett ploP for the kinetic data at 25”. The linearity with most of the 2- and 3-substituted fluorenones using meta and para a constants, respectively, appears to be very good. Contrasted to these results are those of Dickinson and Eaborn who showed that the 2- and 3-substituted fluorenoneP and substituted benzophenones ab failed to follow a Hammett up correlation in their rate studies on oxime formation. The lack of correlation here may be accounted for by the two-step course of these reactions and the influence of pH.ld The p value for the sodium borohydride reduction of substituted fluorenones is +2*65 which is evidence for a fairly polar transition state and a nucleophilic attack of the hydride ion on the carbonyl as proposed by Brown et aL4b The polar transition state would require a high degree of solvation. The deviation of 2-methoxy- and 2-aminofluorenone from the Hammett correlation in sodium borohydride reduction is interesting, and the extent of this deviation is well outside experimental error. Recently, Dickinson and Eabomso observed the same effect for the 2-methoxy group (the 2-amino was not studied) while studying the rates of reaction of some substituted 9-bromofluorenes with potassium iodide in acetone. The deviation of the 2-methoxy- and Zaminofluorenone could, in part, be explained on second-order mesomeric affects as observed with meta substituents in the phenyl system.sb However, the affect in the fluorenone system is considerably greater because of the direct conjugative interaction between a donor (-R) group and the C=O group as illustrated in structures I, IIa, IIb. 0-
&rx+ I
0-
0-
cd& - bx+ no
nb
The reduction will, to a considerable extent, destroy these interactions at the transition stage and therefore, it would be anticipated that the strong -R substituents (F, OCH,, NH& in both the 2- and 3-position would react more slowly than expected from the operation solely of “Ar-Y” inductive effects.sC The results bear this out (Fig. 1). Taft’s a”-valuesBe, which more exactly represent Ar-Y inductive effects, are also plotted in Fig. 1 for these three substituents. (The other a0 values were not plotted because their variance from a constant is very slight.) The deviation is greater when a” values are used which amplifies the point that there is considerable mesomeric influence of the strong -R substituents in the ground state that is to a considerable extent destroyed at the transition state stage. The low entropy value of 3-methoxy (-36-l e.u.) may appear surprising because of the distance of the substituent from the reaction site. However, it is logical in light of the above discussion on the importance of mesomeric stabilization of the ground state. In a polar medium such as isopropyl alcohol, solvation is likely to be important WH.
H. Jaffe. Chem. Reo. 53, 191 (1953); * J. D. Dickinson and C. Eabom, J. Chem. Sot. 3036 (1959). k J. D. Dickinson and C. Eabom, /. Chem. Sot. 3574 (1959); b R. W. Taft, Jr. and I. C. Lewis, J. Amer. Chem. Sot. 81.5343 (1959); c R. W. Taft, Jr.,/. Phys. Chem. 64. 1805 (1960).
Polar substituent effects in the sodium borohydride reduction of 2- and 3-substituted fluorenones
327
in determining the over-all entropy term. The solvation of substituted fluorenone in the highly polar transition state is probably independent of the substituent, but in the ground state large differences in solvation around the carbonyl as the substituent is varied could be expected. The largest solvation would be expected for those molecules having electron-withdrawing groups; in these cases solvation in the ground state and transition state would not be appreciably different, and, therefore, AS’ would be fairly high (less negative). In those compounds having electron-donating
.3
FIG. I. Hammett plot of rate constants at 25” for the sodium borohydride reduction of 2- and 3-substituted fluorenones. @ Represent points using Taft u” values.
groups attached to the ring the solvation in the ground state would be low and the amount of solvent “frozen out” in the transition state would be large leading to a very low entropy term. Even though the 3-methoxyfluorenone deviates considerably from this correlation, it is difficult to conclude that the meta and paru reaction constants are differentlO If it is assumed that they are different, the best reaction constant for metu substituents would still be +2-65 and for thepuru substituent +2-98. However, correlation of the puru substituted fluorenone with p = +2*98 does not appear to be significantly better than with p = +2*65. On first considering this mesomeric deviation, it appears that a new (Tconstant should be calculated for the 2-methoxy (and also 2-amino) group in this system, such as is required forf -amino andp-hydroxy groups. From out data, the new Qconstants would be uz-Yeo = -0.021 and uz_Nu = -0.264. Although these constants do not give an exact correlation for the data :f Dickinson and EaborneD for the reaction of Pbromofluorenes with potassium iodide in acetone, they are a considerable improvement over the standard constants. I0J. Hine, 1. Amer.
Chem. Sot. 81, 1126 (1959).
328
G.
G. SMITH
and R. P. BAYER
Taft” has suggested that it is more sound theoretically to apply the following equation rather than to attempt to calculate a new substituent constant for each reaction or reaction type: log k/k, = crp + Y This equation (in the present study) attributes the effect of the substituent on the rate to the sum of both polar effects and the additional resonance effects through the unsubstituted ring. ‘I? is this additional resonance effect (not normally encountered in meta substitution) and ap is the polar effect. Thus, Yz_yeo is equal to -0.340 in the case of the reaction of 2-methoxy-9-bromo-fluorene with potassium iodide in acetone at -0W” (the rate data for 2-Me0 was extrapolated to O$W). In the sodium borohydride reduction of 9-fluorenones, Y2_1Jreois equal to -0.435 at 0”. These differences appear to reflect the difference in nucleophilicity of the iodide and borohydride ions. It is concluded that in the sodium borohydride reduction of 2- and 3-substituted fluorenones a good correlation of the rate is obtained by a Hammett ap plot using meta and para substituent constants. The +2-65 value for p indicates a fairly polar transition state with a transfer of a hydride ion from boron to carbon being rate determining. That the deviation of strong -R (F, OCH,, NH,) in both the 2- and 3-positive can logically be explained by mesomerism through the unsubstituted ring in the ground state which is destroyed in the transition state. The low entropy term for the 3-methoxy derivative is explained on the basis of a considerable change in the solvation from the ground state to the activated state. Further discussion of the mechanism of sodium borohydride reduction will be given in a subsequent paper. EXPERIMENTAL Sodium borohydride (98+ %) obtained from Metal Hydride, Incorporated, was used without further purification. This is justifiable since the impurities are known not to interfere with the reaction kinetics and standard solutions were not made gravimetrically, but rather by mixing excess sodium borohydride with isopropyl alcohol, filtering the mixture and standardizing by the iodate method. Isopropyl alcohol was dried over calcium hydride and sodium borohydride and distilled, b.p. 79-79.5” (697 mm). Preparation ofjluorenones. Very few substituted fluorenonesarecommerciallyavailable. However, they were prepared by well known procedures. Therefore, their syntheses are only briefly mentioned and reference is made to their syntheses in Table 2. Each were sublimed and recrystallized from ethanol and dried in uacuo before use, with exception of 2- and 3-methyl-and 3-methoxyfluorenones which were not subtimed but only recrystallized from ethanol. 2-Fluoro-, 2-bromo- and 2-nitrofluorenones were prepared by the oxidation of the respective fluorene compound with sodium dichromate in acetic acid. 2-Nitrofluorenone was reduced with stannous chloride and hydrochloric acid to the 2arninofluorenone, and Z-cyano-, Zchloro-, and 2-methoxyfluorenones were obtained from this compound by standard methods. 2-Aminofluorenone was also utilized for the preparation of 3-bromofluorenone by bromination to 2-amino-3-bromofluorenone and subsequent diazotization and deamination. 2-Methylfluorenone was obtained from the oxidation of 2-methylfluorene with pentyl nitrite. 2-Methylfluorene was prepared by acetylation of fluorene to 2-acetylfluorene followed by a Kindler modification of the WiUgerodt reaction, hydrolysis to the acid, and decarboxylation by distillation in the presence of calcium oxide. Muterids.
** R.
W. Taft, Jr., Sreric Eficrs York (1956).
in Organic Chrmisrry (Edited
by M. S. Newman)
p. 633.
John Wiley, New
Polar substituent effects in the sodium borohydride
329
reduction of 2- and 3-substituted fluorenones
3-Methyl- and 3-methoxyfluorenone were both prepared by a similar method. pToluenesulfonylanthranilic acid was prepared and its acid chloride subjected to Friedel-Crafts conditions in the presence of toluene and anisole, respectively. Hydrolysis of the crude product with concentrated sulfuric acid afforded the respective 2-aminobenzophenones. The benzophenones were subjected to a modified Gomberg reaction in 21 N sulfuric acid to afford 3-methyl- and 3-methoxytluorenone, respectively. 3-Chlorofluorenone was prepared by a Sandmeyer reaction with 3-amino-fluorenone and cuprous chloride. 3-Amino and 3-fluorofluorenones were gratefully received from Dr. Fletcher.‘* TABLE 2. PHYSICAL PROPERTIESOF SUBSTITUTED FLUORENONES
M.p. (“C) Fluorenone
2-Cyan0 2-Bromo 2-Chloro’ 2-Fluorof 3-Chloro 3-Bromo 3-Amino‘ 3-Fluoro’ 2-Methoxy t-Methyl 3-Methyl 2-Amino 3-Methoxy
Observed”
Literature
173-174 149-150 126-127 117-118 156157 165-165.5 162-162.5 132-132.5L 78-79 92.5.-93.5 69-70 158-159 99.5-100
173” 149” 123’8” 117s 157” 165.5-l 66b*h 159-1&Y 128.5-128‘ 77-78” 91-92* 66.5”. 68b 158* 1OCP
I
DAll mp corrected. b J. D. Dickinson and C. Eaborn, J. Chem. Sot. 2337 (1959). ’ Prepared by R. Haugwitz. 6 C. Courtot, Ann. C/tint. (10). 14, 1450 (1930). r I. M. Heilbron, D. H. Hey and R. Wilkinson, J. Chem. Sot. 141, 113 (1938). 1 This ketone was prepared by the oxidation of 2-fluorofluorene which was kindly provided by Dr. T. L. Fletcher, University of Washington. 0 E. D. Bergmann H. Hoffmann and D. Winters Eer. deut. them. Ges. 66,46 (1933). h Ref. 66. I This ketone was gratefully received by Dr. T. L. Fletcher, University of Washington. ) N. Ishikawa, M. Okawaki and M. Hayashi, Ytiki Gdsei Kagaku Ky6koi-Shi 15, 34 (1958); Absrr. 52, 5349 (1958). L Purified further by sublimation and recrystallization from ethanol. * Ref. 12. m F. Ullman and E. Mallet, Ber. a&t. them. Ges. 31, 1694 (1898).
Chem.
The fluorenols, for product study, were prepared by reduction of the ketones with an excess of sodium borohydride. The physical properties of these alcohols are listed in Table 3. Kinetics measurements. The rate constant was obtained for sodium borohydride reduction of benzophenone in isopropyl alcohol by both the titrimetric and spectrophotometric methods. The activation enthalpies and entropies were determined for 13 fluorenones whose rates of reduction were studied by the spectrophotometric method. Titrimetric method. This method involved the titration of aliquots removed from the reaction mixture at appropriate intervals for residual borohydride by the potassium iodate method.ti*6 A known volume of standard isopropyl alcohol solution of borohydride (50 ml) was placed in a 200 ml glass stoppered round-bottom flask, immersed in a constant temp bath several hours prior to the experiment; the reactants were also kept at a constant temp for several hours. A 50 ml volume of If T. L. Fletcher, M. J. Namkung, W. H. Wetzel and H. -L. Pan, J. Org. Chem. 25,1342 (1960).
144’5-145
140-141
135-136
100
94” 90.5 99”
3-MethyP
2-Amino 3-Methoxy Hydrogen
157.5’ 160” 144-145‘ 143-144” 143.5-144.5’ 144-145” 201-201.5’ 120” 84.5-85‘
169.5-170.5’ 171-172’
129-130’ ! 1420
’ 128”
77.99
!
I I
:
: 77.99
, 72.06
I
%JBsTITUTED
77.71 I 4.53 I
:I::
’1 4.54 I
78.18 1 4.53 71.94 l 4.19 i
!?-FLUORENOL9
;
i
-
I
/
-
~ 7
i 9.49 I
I
i I::;:
9.16
9.31 16.50
(1Analyses by Alfred Bernhardt Mikroanalytischcs Laboratorium im Max-Planck-Institut, Muelheim (Ruhr) Germany. AU analytical samples were sublimed in oocuo for final purification. Reduction according to the method of H. -L. Pan and T. L. Fletcher, J. Org. Chem. 23, 79 (1958). c Yields are based on recrystallized product. d All mp are corrected. a C. Cow-tot and J. Moreaux. C.R. Acad. Sci., Paris 217. 506 (1943). r C. H. Courtot and C. Vignati, Bull. Sot. Chim. 41, 58 (1927); C/tern. Absrr. 21, 1643 (1921). g C. Courtot and C. Vignati, C.R. Acud. Sci.,.Puris 184, 1179 (1927); C/tern. Absrr. 21, 3616 (1927). therefore, the yield reported is that given in the literature. ’ This compound has been reported as having been prepared by sodium borohydridc reduction: * Ref. 6c. j K. Suzuki, S. Kajigaeshi and M. Sano, Yiki Gdsei Kuguku KyOkui-Shi 16, 82 (1958); Chem. Abstr. 52, 10019 g (1958). t Obtained pure without recrystallization. t Ref. b, Table 2. m C. L. Arcus and M. M. Coombs, J. Chem. Sot. 3977 (1954).
122 -122.5
143.5-144.5
145-145.5
91.8
2-Methyl
i
/ 165.5-166
I i
169-169.5 160-160.5
87”
76 95 98
946
93.3 99
’
! /
; I
3-Fluoro 2-Methoxyk
3-Bromo
3-Chloro
2-Chloro 2-Fluoro
2-cyan0 2-B;omo
Fluorenol
TABLE 3.
Polar substituent effects in the sodium borohydride
reduction of 2- and 3-substituted fluorenones
331
the ketone in isopropyl alcohol was rapidly added to the borohydride solution with vigorous mixing. As the reaction proceeded, 10 ml aliquots were pipetted into a solution of 25 ml of a 025 N standard potassium iodate and 2 ml of 2 N NaOH (mixing was accomplished with the aid of a magnetic stirrer) at appropriate intervals. After 1 min mixing, 2 g of potassium iodide was added, followed by 12 ml of 2 N H,SO,. The iodine solution was covered with a watch glass and placed in a dark place for 2-3 min. Distilled water (250 ml) was added and the solution titrated with 0.1 N standard thiosulfate solution. From the volume of thiosulfate used, the amount of unreacted sodium borohydride and unreacted ketone were calculated. The rate constant was then computed for the reaction. The rate constants for the three determinations made for benzophenone were 20.7 x lo-‘, 20.4 x 10.’ and 21.6 x lo-’ l/mole-see using a ketone concentration of OG400 M and sodium borohydride concentrations of 0.0238 M, 0.0213 M, and 0.0218 M, respectively. Specrrophotomerric merhocf. This method involved use of a Beckman Model DU Spectrophotometer to determine the amount of unreacted ketone in the reaction of ketone with sodium borohydride in isopropyl alcohol at various temperatures and concentrations. It was found to be the simpler and more accurate of the two methods. The height of the carbonyl peak (R-band) was used as a measure of the concentration of ketone present at any time. In the spectrophotometric measurements, Beer’s Law was applicable and the reduction products were found not to interfere at the wave lengths used. Sodium tetraisopropylborate had no effect on the carbonyl peak. The rate constants for two determinations made for benzophenone were 22.3 x lo-’ and 23.1 x lOma l/mole-set using ketone concentrations of 0.0266 M and O0tOO M, respectively, and sodium borohydride concentrations of 0.0290 M and 0.0214 M, respectively. These are considered in good agreement with the titration method. Analyticalprocedure for borohydride. In a 500 ml Erlenmeyer flask was placed 0.25 N standard potassium iodate (25-50 ml) with 2 N NaOH (2-5 ml). The alcoholic solution of sodium borohydride (l&25 ml) was added and the solution thoroughly mixed by swirling for approximately 2 min. Finally, 2 g of potassium iodide was added followed immediately by 12-15 ml of 5 N H,SO,. The flask was covered with a watch glass and placed in a dark place for 2-3 min. Distilled water (250 ml) was added and the iodine-iodide solution was titrated with standard thiosulfate solution (0.1 N) using starch indicator. Determination of the rate constant. Standard solutions of sodium borohydride and of ketone in isopropyl alcohol were prepared and equilibrated in the thermostat. Concentrations were corrected for changes in density of isopropyl alcohol, using data in the International Critical Tables. A known volume of ketone solution (2-15 ml) was placed in a reaction flask immersed in the thermostat. A known volume of sodium borohydride solution (l-5 ml) was added to the ketone solution and mixing was accomplished with the aid of an automatic pipette. An aliquot was placed in the spectrophotometer. The temp of the cell compartment was regulated within *0.05” by circulating water from a thermostat through the custom-built jacketed cell compartment. Measurements of the percentage transmission were made beginning 1i-3 min after the initiation of the reaction and generally continued until the reaction had proceeded beyond one half-life. Using Seer’s Law, the concentration was calculated for appropriate time intervals. The concentrations of the ketone and borohydride were doubled and some cases trebled without a significant change in the rate. A linear plot was obtained from a plot of the quantity a%
log 6 -$+
against the time t which passed through
the origin. In this expression a is the initial molar concentration of ketone, b is the initial molar concentration of sodium borohydride and x is the amount of sodium borohydride which has reacted at time I. Rates were determined at 3 temperatures (four for fluorenone) and in triplicate wherever it was feasible. Mean values and standard deviations of the arithmetic mean are listed in Table 1. AcknowIe&ements-The authors are greatly appreciative to the National Science Foundation for financial support and to Dr. T. L. Fletcher for 3-amino-, 3-fluoro, and Cfluorofluorenones and 2fluorofluorene used in this study.