THE CHROMIC ACID OXIDATION OF ALIPHATIC SECONDARY ALCOHOLS—SUBSTITUENT EFFECTS AND THE MECHANISM

By N. VENKATASUBRAMANIAN * AND G. SRINIVASAN (Department of Chemistry, Virekananda College, Madras-4) Received March 24, 1969

(Communicated by Prof. S. V. Anantakrishnan, F.A.se.)

ABSTRACT

The mechanism of the chromic acid oxidation of a number of sub- stituted propan-2-ols has been studied in aqueous acetic acid medium. Electron withdrawing substituents retard the reaction considerably while electron-releasing substituents accelerate the reaction. A gocd correlation exists between the rate and Q* values. The p * value is —1 • 60. The results are * interpreted in terns of a rate-determining abstraction of the secondary hydrogen as a hydride anion.

INTRODUCTION

EvEN THOUGH chromic acid has been extensively used as an oxidising agent for well over a century for both preparative and analytical purposes and three monographsl-3 have appeared on the subject, it is generally recog- nised that a complete and satisfactory picture of the mechanism of the chromic acid oxidation of secondary alcohols is yet to emerge.

Considerable work has been carried out in this direction by Westheimer, 4

Rocek,5 . 6 Kwart,7,8 Stewart9,10 and their colleagues and also from these laboratories .1'

The mechanism proposed by Westheimer and his associates . for the oxidation of isopropyl alcohol involves a prior formation of a chromate ester (monoisopropyl chromate) followed by a rate-determining proton loss to any available base (probably a water molecule).

* To whom all enquiries should be addressed. 1 Al

2 N. VENKATASUBRANIANIAN AND G. SRINIVASAN

H' + HCz 0, = H.CrO. CHI JC' H • H.CrO.° Cw`C/H •HIO CH3OH cit( 'p•CT0,H C13 \H H CH, ^^^^ -- "C=O+BH +HCrO3 C^ ^0 C103,H CMs In strongly acid solutions the protonated ester was supposed to be formed. Evidences, both direct and indirect, have since been put forth for the for- mation of an ester in the equilibrium step.'E -14 The work of Kwart and his group'." and also of Stewart and Leer° has shown that the Hammett reaction constant p for the oxidation of aryl methyl carbinols and of aryl trifluoromethyl carbinols was —1.01—a negative value that could not be rationalized easily on the basis of a rate-controlling proton abstraction from the a-carbon of a preformed chromate ester.

Kwart8 has considered an internal proton transfer from a chromate ester as the more probable mechanism for this oxidation.

+ +

R' "H Q RAC: H••0

-.i RICO + 1 S CZ0%

However, Stewart and Lee10 are of the opinion that it should be difficult to decide about the electron-flow in a cyclic mechanism of the above type and propose that the observed negative P value would arise due to the developing carbonyl group in the electron-deficient transition state being stabilised by electron-donating substituents.

An alternative mechanism for the oxidation was proposed by Roceks and by one of the present authors" wherein the hydrogen on the secon- dary carbon atom was lost as a hydride anion.

1+Cx,O^ R >C=o +HCroeliz0 R' \_Q1- H .f V R

The present kinetic work was undertaken to determine the structural influences on the rate of the oxidation of aliphatic secondary alcohols, espe- cially for the reason that the conjugative influences of a substituent (as in the trifluoromethyl carbinols) on the developing double bond in the transi- tion state would be absent and the polar effects to be considered would mainly Chromic Acid Oxidation of Aliphatic Secondary Alcohols 3

be inductive in origin. The effect of substituents on the oxidation of aliphatic primary alcohols has already been studied by Rocek.a

EXPERIMENTAL Reagents.—All the alcohols used in this investigation are of the extra pure variety (Fluka AG/Koch-Light/K and K) and were distilled from an all-glass apparatus. Large head and tail fractions were rejected and fractions distilling at the literature temperatures were collected. 2-Amino-l-phenyl ethanol (Cilag-Chemie) and 4-Chloro-benzhydrol (Koch-light) were used as such.

Kinetic methods.—The oxidation rates were obtained by following the disappearance of Cr (VI). In a typical kinetic run 50 mI. of a 0.04 M solution of the alcohol in 70% acetic acid was mixed with 50 ml. of 0.014 M chromic acid in 70% acetic acid in thermostated reaction bottle. Both the solutions contained the calculated quantity of sodium acetate to keep the pH reasonably constant around 3.5. 5 ml. aliquots were withdrawn periodi- cally and were quenched in 20 ml. of a 0.3 M iodate-free potassium iodide containing 0.3 gm. of NaHCO 3. Then 2 ml. of 6 M sulphuric acid was added and the solution set aside for 5 minutes. The solution was then diluted to 70 ml. and titrated against standard thiosulphate using starch as an indicator.

Good straight line plots were obtained for over 60% of the reaction for all the alcohols investigated (Fig. 1).

RESULTS AND DISCUSSION

The rates of oxidation of alcohols of the type RCH 2–CHOH–CH3 where R = – OCH 3, –OC 4H9, CBHS , – NH 2, –N (CH 3) 2 and of 1-phenyl- 2-amino ethanol, 4-chlorobenzhydrol and 2-phenyl cyclohexanol were determined in acetic acid-water mixtures of different compositions at a constant pH of 3.5 between 45° C. and 60° C. The oxidation rates of alcohols where R = H, CH3, C2Hs, a-phenyl ethyl alcohol and benzhydrol have already been reported by one of us." , ' Good second-order con- stants (Table I) were obtained for over 60% of reaction in all cases—first with respect to the gross concentration of Cr (VI) and with respect to the alcohol under conditions of constant acidity—a result conforming to earlier findings. 4 N . VENKATASUBRAMANLAN AND G. SIUNIVASAN

K 0 d -e 1

5 015 Y 4- IA

05 OCH,

o - CH,NH,

^._ -0.5 0 +OS •110 tog. [a .- FiG. I FiG. 2

FiG. 1. Typical second order plots for the oxidation of (a) 1-phenylpropan-2-ol (50;o HOAC — 50°•; H30 at 45° C.) and (b) 1-,z-butoxy-propan-2-ol (60% HOAC — 40/ H=O at 50° C.). FiG. 2. Taft plot for the CrO3 oxidation of substituted secondary alcohols.

The Arrhenius parameters determined from the temperature dependence of the rate (plots of log k 2 versus 1/T) are collected in Table II.

It is evident from the results obtained that the influence of polar groups on the oxidation rate is very pronounced. It is very likely that under the conditions of the present investigations, both isopropanolamine and the dimethylamino ''compound are largely protonated • and the quaternary ammonium ions, therefore, exhibit a large retarding influence. The re- placement of the hydrogen on the methyl group of isopropyl alcohol by the •-OCH 3 and —11—OC 4H 9 —groups of strong electronegative character reduce the rate considerably. A similar retarding influence is also evident in 4-chlorobenzhydrol and 1-phenyl-2-amino-ethanol. A comparison of the rates of oxidation of isopropyl alcohol, a-phenyl ethyl alcohol and 1-phenyl- propan-2-ol also show that while a phenyl group on the reaction centre boosts Chromic Acid Oxidation of Aliphatic Secondary Alcohols 5

TABLE I Oxidation of substituted secondary alcohols in acetic acid-water mixtures

Temp. 50° C. k3 x 10° Titre-mol-1 sec-1

Solvent composition (% HOAc) Compound 50% 60% 70% 80%•

Propan-2-ol* -. 0.780 1.62 4-04 ., Butan-2-ol * .. 1.36 2.68 6.49 ,. Pentan-2-ol* .. 1.88 3.57 7-78 ... 1-Methoxy-propan-2-ol - , . 0.175 0.333 0.704 1-n-Butoxy-propan-2-ol ,. 0.189 0.305 0.505 ... Isopropanolamine ., ... 0.0972 0.205 0.420 1-Dimethylamino-propan-2-ol , . 0.218 0.401 0.820 1-Phenylpropan-2-ol 0.819 1.15 1-81 ,. a-Phenyl ethyl alcohol * - ... 8.91 18.5 44-6 1-Phenyl-2-amino ethanol , . . , 2-70 4.42 11.4 Benzhydrol* ... 11.8 16.6 34-1 ., 4-Chlorobenzhydrol -. 5.01 7.63 12.6 ... Cyclohexanol .. 1.59 3.13 6.95 ., 2-Phenyl cyclohexanol . - 1.39 2.54 4.50

* From Venkatasubramanian ll

TABLE II Arrhenius parameters for the oxidation of secondary alcohols in 70% HOAc

Compound E. k.cal./mole A S e.u,

1-Methoxy-propan-2-ol - - 15.4 -32 1-n-Butoxy-propan-2-ol .. 12.5 -40 1-Phepyl propan-2-ol * ... 11.4 -41 Isopropanolamine •. 12.9 -49 1-Dimethylaminopropan-2-ol . - 15.1 -32 1-Phenyl-2-amino ethanol - - 16.3 -24 4-Chlorobenzhydrol .. 12-0 -36 2-Phenyl cyclohexanol . - 11.1 -40

• In 60 % HOAc. 6 N. VENKATASUBRAMANIAN AND G. SRINIVASAN the rate of oxidation considerably, the rate drops when this is insulated from it. 2-Phenyl cyclohexanol exhibits an identical trend. It should also be mentioned here that the effect of a chlorine substituent is so pronounced that the oxidation of 1, 3-dichloro-propan-2-ol did not proceed at all even after twenty-four hours in 70% acetic acid at 50° C. and trans-2-chloro- cyclohexanol was oxidised so sluggishly that less than 4% of CrO 3 was con- sumed in 26 hours under the above conditions. These results thus confirm the earlier findings that the chromic acid oxidation of alcohols is strongly inhibited by electron-withdrawing substituents even in systems where there is no possibility of any conjugative stabilisation of the developing carbonyl double bond. There exists a good linear relationship between the rate constants for the oxidation and the Taft a* values of the –CH 2R groups (Fig. 2). This linear relationship justifies that the oxidations compared proceed by one and the same mechanism. A p* = —1.6 is obtained showing that con- siderable positive charge resides on the a-carbon atom in the transition state (the point, corresponding to a-phenyl ethyl alcohol does not fall in the line because this compound is different and has both inductive and resonance effects operating). As was pointed out by Rocek, 6 the equilibrium

ROH + H 2CrO 4 R–O–CrO 3H + H2O should be insensitive to structural -_ changes in the alcohol moiety, as in esteri- fications involving sulphuric acid. 1 ' One can thus conclude that the observed p* arises only out of the differential effects of the substituents in the second stage of the Westheimer mechanism, viz., the rate-determining loss of the secondary hydrogen. A mechanism very similar to the proton abstraction from the acid chromate ester has been proposed for the base catalysed conversion of benzyl nitrate to benzaldehyde.

C6 H5 - 0 N0: —^ CC H S CHo + td + Ht $: 1 H

The P for this reaction was found to be + 3.4. The close similarity between the above mechanism and the Westheimer mechanism and their different P values make the loss of the secondary hydrogen as a proton highly improbable in the latter mechanism. An alternative to the Westheimer mechanism is the proposal of Kwart and later Stewart, viz., the unimolecular decomposition of the chromate Chromic Acid Oxidation of Aliphatic Secondary Alcohols 7 ester. If this mechanism were to be taken as an internal proton transfer from the secondary carbon atom to the oxygen of the Cr (VI), as was proposed by Kwart, this would be untenable for (i) water would certainly be a stronger base than an oxygen atom in the chromate; (ii) the protonation of the chromic acid part at increased acidity should actually lead to a rate- diminution, contrary to experimental findings and most important of all; (iii) the a-carbon would at no stage be electron-deficient. The transition state in such a case would have actually more of a carbanion character, against the observed negative P values.* However, if one rules out proton transfer, the other alternative can only be that the hydrogen on the secondary carbon atom is lost as a hydride ion (in as much as the chromic acid oxi- dation of alcohols does not exhibit the usual characteristics of a free radical mechanism). We feel, therefore, that the observed experimental results can only be explained on the basis of a mechanism that involves the rate-determining loss of the secondary hydrogen as a hydride anion as in the original Rocek mechanism or in a unimolecular decomposition of the chromate ester as proposed by Stewart and Lee. 1° Although it is a vexing problem to deter- mine the direction of electron-flow in a cyclic machanism, the fact that con- siderable positive charge is created in the transition state points more to a hydride ion loss than a proton loss. Evidences have also accumulated in recent literature substantiating this point of view. Bell18 is of the view that the unusually large kulkD ratios obtained by Stewart and Lee for the ring-substituted aryl trifluoro_ methyl carbinols is indicative of a hydride ion loss. The easy oxidative decarboxylation of a-hydroxy acids by chromic acid to the corresponding aldehydes rather than to the a-keto acids indicate an electron-deficient carbon atom bearing the carboxyl group. 19 A linear free energy relation- ship between the chromic acid oxidation of cyclanols and the borohydride reduction of the corresponding cyclanones also point to similar transition states for the two reactions. 20 A convincing evidence of most recent origin is the work of Burstein and Ringold 2' who have shown the simi- larity of keq/kax ratios in the DDQ oxidation (involving essentially a hy- dride ion loss) and in the chromic acid oxidation of steroidal allyl alcohols.

* It has been argued that any transition state with a developing carbonyl double bond will always be electron-deficient. It must, however, be pointed out that the electron pair of the original C—H bond are just in the process of being shared with the oxygen atom and hence the possibility of any large positive charge on the a-carbon is extremely remote. 8 N. VENKATASUBRAMANIAN AND G. SRINIVASAN

REFERENCES

1. Stewart, R. .. Oxidation Mechanisms, Benjamin, W. A., New York, 1964. 2. Waters, W. A. .. Mechanisms of Oxidation of Organic Compouncss, Methuen and Co., Ltd., London, 1964. 3. Wiberg, K. B. .. Oxidation in Organic Chemistry, Academic Press, N.Y., London, 1965. 4. Westheimer, F. H. and J. Amer. Chem. Soc., 1958, 80, 3030 and references cited Graham, G. T. E. therein. 5. Rocek, J. and Krupicka, J. Collection Czech. Chem. Communs., 1958,, 23, 2068. 6. Rocek, J. .. Ibid., 1960, 25, 1052. 7. Kwart, H. and Francis, P. S. J. Amer. Chem. Soc., 1955, 77, 4907. 8. .. Ibid., 1959, 81, 2116. 9. Stewart, R. and Lee, D. G. Ibid., 1964, 86, 3051. 10. .. Can. J. Chem., 1964, 42, 439. 11. Venkatasubramanian, N. Proc. Ind. Acad. Sci., 1960, 53, 80. and Anantakrishnan, S. V.

12. Rocek, J., Westeimer, F. H., Hely. Chico. Acta, 1962, 45, 2554. Eschenmoser, A., Mo1do- vanyi, L. and Schreiber, J. 13. Wiberg, K. B. and Schafer, J. Amer. Chem. Soc., 1967, 89, 455. H. 14. Stewart, R. and Lee, D. G. J. Org. Chem., 1967, 32, 2868. 15. Venkatasubramanian, N. J. Sci. Industr. Res., 1961, 20, 385, 541. 16. Kianing, U. .. Acta Chem. Scand., 1958, 12, 576. 17. Buncel, L. E. and Bourns, Can. J. Chem., 1960, 38, 2457. A.N. 18. Bell, R. P. .. Disc. Farad. Soc., 1965, 39, 16. 19. Sundaram, S. .. Ph.D. Thesis, University of Madras, India, 1967. 20. Venkatasubramanian, N. Proc. Ind. Acad. Sci., 1967, 65, 30. and Srinivasan, G. 21. Burstein. S. H. and Ringold, J. Amer. Chem. Soc., 1967, 89, 4722. H. J.