Conformational Studies in Ester Hydrolysis

CONFORMATIONAL STUDIES IN ESTER HYDROLYSIS

BY P. S. RADHAKRISHNAMURTI AND PRAKASH C. PATRA (Department of Chemistry, Khallikote College, Berhampur (Gm.), Orissa] Received July 5, 1969

(Communicated by Prof. S. V. Anantakrishnan, F.A.sc., r.N.r.)

INTRODUCTION

THE School of Anantakrishnan 1-6 has made extensive investigations on hydrolytic reactions for the last two decades and arrived at valuable findings regarding structure and reactivity, and role of solvent on the reactions. In the present investigation a few cyclic esters have been subjected to both acid and alkaline hydrolysis in alcohol-water and dimethyl sulfoxide-water mixtures. The effect of the dimethyl sulfoxide on the alkaline hydrolysis of a series of benzoates and salicylates has also been studied.

EXPERIMENTAL All the solvents were purified as in earlier papers, while the esters were invariably freshly prepared and distilled before use. Dimethyl sulfoxide was used after purification by the method of Roberts. 7 The physical constants of the esters are given below. Bornyl acetate b.p. 226° C., Iso-bornyl acetate b.p. 125° C./75 mm., Cyclohexyl acetate b.p. 175° C., Cyclopentyl acetate b.p. 153° C., methyl salicylate b.p. 222.9° C., ethyl salicylate b.p. 234° C., Iso-propyl salicylate b.p. 120 0-22 0 C./18 mm., iso-butyl salicylate b.p. 130 0-2 0 C./18 mm., Methyl benzoate b.p. 198° C., Ethyl benzoate b.p. 213° C., benzyl benzoate b.p. 323° C. Preparation of materials and rate measurements.—Preparation of solu- tions and rate measurements were as described in previous publications (loc. cit.).

RESULTS AND DISCUSSION . The first order rate constants in the case of acid hydrolysis and the second order rate constants in the case of alkaline hydrolysis for cyclo-pentyl, cyclo-hexyl, bornyl and iso-bornyl acetates are given below, for both alcohol- water mixtures and dimethyl sulfoxide-water mixtures. AS 181 182 P. S. RADHAKRISHNAMURTI AND PRAKASH C. PATRA

TABLE I

Rates of acid hydrolysis in aqueous-alcohol and aqueous-dimethyl sulfoxide

k x 10 4 min.—' Temp. 50°C. Acid--*HBr. Solvent Bornyl Iso-bornyl Cyclo-hexyl Cyclo-pentyl acetate acetate acetate acetate

DMSO°•water (V/V):

85:15 3.667 2.905 .. ., 75 :25 4.668 4.061 5.560 5•994 65:35 11.230 8•619 12.780 ..

55:45 .. .. 17.690 Alcohol-water (V/V): 75: 25 1.252 0•856 1.849 2.587 65 :35 1.824 1.300 2.593 4.389 55 :45 2.440 .. 5•473 5.778

a — Dimethylsulfoxide.

Rates of alkaline hydrolysis in aqueous-alcohol and aqueous dimethyl sulfoxide

mole ' min. ' Temp. 50 C. Alkali—*NaOH kx1U3 1 — — ° Name of esters Alcohol-water (75 : 25 v/v) DMsO•water (75 : 25 v/v)

Boinyl acetate 356•6 7992 L•o•bornyl acetate 282.7 4932 Cyclohexyl acetate 982.5 12084 Cvclooentvl acetate .. 1359 15822

The following facts emerge from the experimental results.

1. The reactivity is cyclo-pentyl > cyclohexyl acetate; and bornyl > iso-bornyl acetate. 2. The reactions in dimethylsulfoxide—water mixtures are consider- ably faster than in alcohol—water mixtures. Conformational Studies in Ester Hydrolysis 183 3. Increase of water increases the rate in both dimethyl sulfoxide- water; and alcohol-water mixtures in acid hydrolysis. This is novel as in alkaline hydrolysis increase of dimethyl sulfoxide increases the rate. 4. Alkaline hydrolysis is faster than acid hydrolysis. 5. Influence of structure is more pronounced in alkaline hydrolysis than in acid hydrolysis. With this background one has to attempt to rationalize the above facts. Cyclopentyl acetate reacts faster than cyclohexyl acetate both in acid hydrolysis and in alkaline hydrolysis. The explanation has to be traced to strain energy differences. The reactivity of cyclic compounds is markedly influ- enced by variation in the size of the ring. The results of the present investigations, namely, the greater reactivity of cyclopentyl over cyclohexyl acetate are in accord with the earlier investigations on the effect of the ring size on the reactivity of alicyclic compounds. It has been proposed that the effect of the ring size on chemical reactivity can be accounted for in terms of I strain—the increase in internal strain in a cyclic structure resulting from alterations in bond angles and constellations which acccmpany a charge in the co-ordination number of a ring atom in the course of a reaction. Of the two major sources of internal strain, generally recognised in the cyclo-alkanes, or their derivatives, namely, the distortion of bond angles from the preferred values and the deviation of the C-H bond constellations from the preferred staggered arrangements, the former appears to be the major source of strain in the 3- or 4-membered rings and the second factor (the constellation effect) is of major importance in the common rings.8, 9

Extension of I strain concept to the five- or six-membered rings has indicated that the reactions involving a change in the co-ordination from 4-3 (reaction of S N 1 and free radical types) and from 4-5 (reaction of S N2 and E2 types forming the activated complexes) are strongly favoured in the strained rings, (viz., 5- and 7-membered) but proceed more slowly in the strain free cyclohexyl compounds. This generalisation is particularly applicable to the present studies. Further in the tetrahedrally bound cyclopentyl acetate there arise C-H bond oppositions which give rise to considerable conformational strain approximately 1 k.cal. bond opposition. Accurate heat of combustion data show that cyclopentane which is 6-7 k.cals. more strained than cyclohexane can exist in a relatively strain free conformation with all t C-H 184 P. S. RADHAKRISHNAMURTI AND PRAKASH C. PATRA bonds nicely staggered. When there is a change from spa to sp 2 at one of the carbon atoms (as in the doubly bonded carbon atom or a carbonium ion or in the transition state of the S N2 or E2 reaction) four of these bond oppositions disappear .corresponding to 4 k.cals. This relief of conformational strain, presumably, more than outweighs the angular strain involved in a change from sp 3 to sp. 2 It might, however, be argued that since the normal angle in cyclopentane, i.e., 108° is very close ' rather to the tetrahedral angle than to 120° angle in the sp 2 configuration, the angular strain should consequently work against the change to sp. 2 But the change of sp 3—^sp 2 takes place quite easily, as the results of a number of investigations show. Hence, the angular strain one can only be of minor importance when compared to conformational has, of course, to assume that the slight puckering of the cyclopentane ring strain, does not affect the bond opposition significantly. In the six-membered ring the situation is different. In the " chair " form of cyclohexane there is complete staggering of the C—H bonds with no bonds in opposition. When the configuration of one of the carbon atoms is changed from sp 3 to sp 2 two bond opposition will be created as can be seen from a consideration of models. This change will therefore cost energy and will be resisted. Hence the slow rate of reaction with cyclohexyl acetate. It should be emphasised that many other factors such as F strain, entropy factors and the like might affect the relative rates of hydrolysis of the two esters. It is only proper that the I strain could be an important factor that could be invoked to give a simple picture of the observed order of reactivity. In bornyl and iso-bornyl acetates the cyclohexane ring is fixed as the boat conformation by the presence of CMe 2 bridge. 10

Me Me r'ie Mc

ak y rle oak_

BQRNY4 ACETATE Aso BORNYL AQETATF Conformational Studies in Ester Hydrolysis 185

Bornyl acetate has its acetoxy group in the boat-axial conformation and the acetoxy group and the methyl group on the adjacent carbon atoms are cis. The higher rate of bornyl than isc-bornyl acetate shows that the boat-axial acetoxy group is not appreciably much hindered whereas the primary steric effect of the gem dimethyl group is responsible for the lower kinetic rate with iso-bornyl acetate.

In the solvolysis of tosylates for these ring systems as well as in the oxidation of iso-bornyl and bornyl alcohols, iso-bornyl system reacts faster than bornyl system. 11-13 It is important to note the difference in the reactivity in the present investigation, where in it is found that bornyl system reacts faster than iso-bornyl system and this finding is quite in consonance with the results obtained by Chapman and coworkers in alkaline hydrolysis of these acetates.

Solvent effect.—It is seen that the reactions are faster with increasing water content of the medium. Prima facie it appears that it is against a positive ion-dipole mechanism as postulated by Amis for acid hydrolysis of esters, where in for such reactions the reaction rates decrease by increasing dielectric constant. But by invoking the correlation between mole fraction of water and rate constant one can explain the observed results. For plot- ting log10K. against mole fraction of water it was decided to use log 10 K N rather than log10K. calculated at volume percentage. 14

KN = 1,000 N Vc 4^:7

Where E N is the total number of moles of the solvent and V is the volume of the solution in millilitres. Linearity has been observed for log, oK N against mole fraction of water.

Although the reciprocal of the dielectric constant shows linearity with log10K, the mole fraction of water has apparently got a better relationship and thus has a wide range of applicability. The deviations are probably caused by the cumulative effect of the differences in solute-solvent inter- actions and electrostatic field. The mole fraction of water has been found to have a linear relationship with log 10K. values of ionisation reactions by Hudson and Saville. 15

It was of interest to compute the molecular radii on the basis of Amis treatment and also by Laidler and Landskroener theory for acid hydrolysis, 186 P. S. RADHAKRISHNAMURTI AND PRAKASH C. PATRA

Amis treatnient. 1 '—According to the Amis theory for ion-dipolar reactions Zeµ lnk' D_D = lnk' D =„ + DKTr 2 •

'r' values computed from the above equation are quite reasonable. The slopes are negative against the postulate by Amis for acid hydrolysis, but the r values are reasonable. The abnormality can be easily explained by invoking dependence on mole fraction of water as stated earlier.

Laidler and Landskroener treatment".—The equation:

2 1 _ 1 3G 1 S= 2.303 (2kT) [bA bB — 2b 3

_ E2 ( 2bx3 — 2bAbx2 — 4bAGX 9 212 kTbA \ bx3

becomes on substitution using the values for acid hydrolysis of esters.

Gx = 9.1 x 10-14 sq.cm., bA = 1.7 x 10 -8 cm.

107>< 104 S = bx3T (2bx 3 — 3.4bx — 47.41).

A plot of log10K. vs. 1/D are all linear. Using the slope, bx values have been computed and they are quite reasonable for acid hydrolysis of esters.

TABLE 11

Temperature = 50° C.

Name Acqueous alcohol (rev) Aqueous-D\1 O (v,'v) of the esters rX108 cm. bx (1) rX10$ cm. fx (1)

Bornyl acetate 1.189 3•075 1•629 4.10

Cyclohexyl acetate ..^ 1•000 3.079 1•701 4.00 C,yclopentyl acetate .. ^I1.120 3.076

One important difference in the acid and alkalire hydrolysis in dimethyl >,llfoxide-water mixtures is that rates increase with water content in acid Conformational Studies in Ester hydrolysis 187 hydrolysis whereas, as found by Roberts (loc. cit.) with increase of dimethyl sulfoxide content the reaction rate increases in alkaline hydrolysis. Alkaline hydrolysis of benzoates and salicylates.—A systematic study, to evaluate p values, has been made for benzoates and salicylates. The rate constants are given in Table III.

TABLE 111

Kx 10 2 in 1 mole 1 min."' Temp 5G° C. Esters Alcoho:-eater DMSO water Rd. rate (75 25 v/v) (75 : 25 nn^v)

Benzyl benzoate 69.96 6282 90 Meth)1 benzoate 56.06 5344 95

Ethyl benzoate 48.60 .. Methyl salicylate 34•28 Ethyl salicylate 31.38 .. Iso-propylsalicylate 17.82 ..

Iso-1 utyl salicylate 29.18 ..

The p values are + 0.5 and + 1.5 for benzoates and salicylates respec- tively. All salicylates are reacting slower than benzoates. The reaction is faster in dimethyl sulfoxide-water mixtures compared to alcohol-water mixtures. But the effect of dimethyl sulfoxide is pronounced in alkaline hydrolysis for the obvious reason, of the diminution of OH- ion solvation as a result of the competition between this anion and the dimethyl sulfoxide molecules for the water molecules and to an increase in the transition state solvation.

REFERENCES

1. Anantakrishnan, S. V. and Proc. Ind. Acad. Sci., 1950, 32, 338. Nair, P. M. 2. -- and Anantaraman, Ibid., 1959, 49, 86 and 174. A. V. 3. — and Radhakrishna- Ibid., 1960, 53, 30. murti, P. S. 4, ----- .. Ibid., 1961, 54, 327. 188 P. S. RADHAKRISIINAMURTI AND PRAKASH C. PATRA

5. Anantakrishnan, S. V. and Proc. Ind. Acad. Sci., 1967, 55, 299. Venkataratnam, R. V. 6. Ibid., 1967, 56, 40. 7. Roberts, D. D. J. Org. Chem., 1966, pp. 4037. 8. Pitzer, K. S. Science, 1945, 101, 2635. 9. Kilpatrick, J. E., Pitzer, J. Amer. Chem. Soc., 1947, 69, 2483. K. S. and Spitzer, R. 10. Chapman, N. B., Parker, J. Chem. Soc., 1960, 3634. R. E. and Smith, P. J. A. 11. Brown, H. C. and Ham, G. J. Amer. Chem. Soc., 1956, 78, 2735.

12. Heck, R. and Prelog, V. . . He/v. Chim. Acta, 1955, 38, 1541. 13. Wiberg, K. B. Oxidation in Organic Chemistry, Academic Press, New York, London, 1965, pp. 165. 14. Scatchard, G. New York Acad. Sci., 1940, 39, 341. 15. Hudson, R. F. and J. Chem. Soc., 1955, pp. 4119. Saville, B.

16. Amis, E. S. Solvent Efectsf on Reaction Rates and Mechanisms, Acade- mic Press, New York, London, 1966, pp. 66. 17. Laidler, K. J. and Trans. Faraday Soc., 1956, 52, 200. Landskroener, P. A.