Oxidation of Bicyclic Secondary Alcohols

MECHANISM OF OXlDATION OF SECONDARY ALCOHOLS BY BROMINE--OXlDATION OF BICYCLIC SECONDARY ALCOHOLS

BY V. THIAGARAJAN AND N., VENKATASUBRAMANIAN (Department of Chemistry, Vivekananda College, Madras-4) Received October 3, 1967

(Communicated by Profl S. V. Anantakrishnan, F.A.SC.)

ABSTRACT

The kinetics of the bromine oxidation of borneo], isoborneol, a-norborneol and fl-norborneo] have been investigated in order lo flnd out whether the oxidation is sensitive to the configuratien of the alcohol. There is a definite and considerable variation in rale which is sho~n to arise from stereochemical consequences. The Arrhenius paralneters of the reaction have also been calculated.

THE bromine oxidation of secondary alcohols has recently been investigated by two groups of workers3, 2 Swain and co-workers favour ah acyclic mechanism (I) involving the rate-determining transfer of the secondary hydrogen as a hydride anion to brominc while Barker and associates propose a concerted mechanism (II) for the oxidation on the basis of very similar reactivity of epimeric pairs of alcohols, for e.g., cis and trans 4-tert. butyl cyclohexanol and cholestan-3-a-ol and cholestan-3-fl-ol.

Br -- Br H -- C-- O-- H : OHa --> Br- + HBr + RiCO + lisO + (I) I R ~xl'~./' 3, c ! -> RtCO+ 2HBr (II) /N~ 4"- , R O--H As the Barkcr mechanism is based on the insensitivity of the oxidation reaction to the configuration of the alcohol, we have now chosen for our investigation the following two pairs of terpenoid a]cohols--borneol and isoborneoI; a-norborneol (endo) and fi-norborneol (cxo) to determine whether this is valid for these stereoisomefic pairs also. 37 38 V. THIAGARA.IAN AND N. VENKATASUBRAMANIAN

EXPERIMENTAL AND RESULTS

The oxidations have been carried out in binary solvent mixturcs of acetic acid and water under constant ionic strength with 0-2 M. sodium acetate and also in 56~ tert. butyl alcohol--50~ aqueous acetate buffer of pH 4. The course of the reaction was studied by following lhc dis- appearance of bromine by iodometry and the reaction exhibited simple second order kineties--the reaction being of the first order with respect to the concentration of molecular bromine and to that of the alcohol. In the concentration ranges used and in the solvent mixtures, side reactions were negligible. There was little tribromide ion formation and the tate of bromination of the product ketone was very slow. V.P.C. of the oxidised solution also failed to show any bromocamphor and the kctoncs were the only products isolated. The second order rate constants for these oxidations are presented in Table I.

DISCUSSION

TABLE I Second order constants (k2 • 103 titre.mole -1 sec. -1) for the bromine oxidation of isomeric terpenoM secondary alcohols

Concentration of alcohol = 0.01860M Solvent: 70% HOAc -- 30% H~O Concentration of bromine = 0.00270M [Sodium acctate] ---- 0,2 M, t~ = 0.2

fl-nor- a-nor- Temp. borneol borneo! Borneol Isoborneol (exo) (endo)

40 ~ 2.52 72.90 37.60 66.90 45 ~ 3-66 115-60 44.90 95-21 50 ~ 5.62 152.30 59.20 129.30 *45 ~ 7.73 216.60 122.00 215.40

* Solvent: 50% tcrt. butyl alcohol--50% aqucous acetato buffer of pH 4.

Barker and associates report that the cis isomer (axial -OH group) was oxidised only 20-31k~o faster than the trans (equatorial -OH group) among the 4-tert. butyl cyclohexanols and cholestan-3-ols. We note, Mechanism of Oxidation of Secondary Alcohols by Bromine 39 however, a widely varying degree of reactivity in the compounds under investigation. The observed order of reactivity in both the solvent systems fl-norbomeol (exo) < Borneol < isoborneol < a-norbomeol (endo) I 12 25 30 clearly shows that the generalisation that there is little stereo-chemical requirement on the part of the alcohol in bromine oxidation cannot be wholly correct. The Arrhenius parameters for the oxidation (Table II) also point out certain interestŸ facts. In spite of the large difference in

TABLE II Arrhenius parameters for the oxidation of terpenoid alcohols in 70% acetic acid in the temperature range 40-50 ~ C.

Alcohols AE K.ca]s. PZ AS e.u.

Exo norborneol (ti) II -9 5"110 ~ 104 --32.53

Borneol I 1.4 3.501 .x 105 --30.76

Isoborncol 11 "8 1.097 X I0e --26.43 Endo norborneol (a) 12 "2 2"419 X 106 --24"86 rates, the break-up of the rates into the Arrhenius parameters shows that the activation energies arc roughly the same and that it is the frequency (entropy) factor that vades significantly. This would mean that the important bond breaking process in all the four alcohols have about the same energy requirements. However, certain additional influences operate in the alcohols under investigation. Figure 1 shows these influences in the system. Ir is well known that in the non-methyl substituted bicyclo [2, 2, 1]-- heptanes (norbornanes) the boat-equatorial exo alcohol is more stablr than the corresponding endo isomer. The stability conditions reverse themselves with the introduction of geminal dimethyl groups at position 7. Asa result, the boat-equato¡ isobomeol is less stable than borneol (with a boat-axial OH group). ~ The fast tate with endo (c0 norborneol is the result of influence ~ while a similar situation in borneol is counteracted by the hindrancc to attack by a bromine molecule at the sr hydrogcn 40 V. THIAGARAJAN AND N. VENKATASUBRAMANIAN

by the gcminal dimethyl group e. This results in a lowcring in rate. The increase in rate with isoborneol over cxo norborneol (/3) is neccssarily due to influence d (which seems to be considerable indeed). Thc existence of a profound steric hindrance between the syn C~ methyl group anda f~o. H H ...... exo. P. ~orborneol endo-(- rtorJ~orneol

H~ ----b ..... ~3H H I-1 Bornect Iso~oa~~oL FIG. 1 a, b--Rate.enhancing relief of strain in the transition state. c--Rate-retarding steric strain in transition state. d --Rate-enhancing relief of steric strain in the tarnsition state. substituent at C2 is also seen in the work of Whceler and co-workcrs.4 ~-Fenchocamphorone is 13 times Iess reactive in cyanohydrin formation than norcamphor asa result of its gem-dimethyl group on the methylene bridge. Camphor with an additional methyl group at the bridge-head (carbon 1) is even less reactive by a factor of 18. It is the reversal of such a strain-producing influence that seems to be responsible for the large increase in rate in isoborneol. In addition to these steric influences, onc has the inductive effect of the methyl groups in the second pair of compounds, which would facilitate the loss of the secondary hydrogen as an anion. This, however, is not likely to be large as this would work against the loss of the hydroxylic hydrogen as a proton. The foregoing reasonings that the difference in reactivity in this series arise essentially out of large differential primary steric influences in the transition state are anaply justified by the values of the entropy factors. The frequency factor and the entropy of activation vary in the predicted order. Ir is thus seen, from the present investigations, that oxidations with bromine are not insensitive to the stereochemistry of the a!coho!s and that Meehanism of Oxidation of Secondary Aleohols by Bro 41 this cannot be unequivocally invoked to distinguish between the twt; mechanisms proposed. Note added h7 proof. Since this paper was aeeepted for publication, a new meehanism for the oxidation of seeondary aleohols by bromine, involving a rate-determimng transfer of the seeondary hydrogen asa proton has been proposed (Deno, N.C., and Potter, N.H., J. Aro. Chem. Soe., 1967, 89, 3555), but this new proposal does not alter the above discussion Jn any way.

AC KNOWLEDGEMENT

The authors thank Dr. Sukh Dev for a generous gift of borneol and isoborneel and Messrs. Fluka AG, Switzerland, for a-norborneol.

REFERENCES 1. Swain, C. G., Wiles, R. A. J. Aro. Chem. Soc., 1961, 85, 1945. and Bader, R. F. 2. Barker, I. R. L., Overend J. Chem. Soc., 1964, 3263. W. G. and Rees, C. W. 3. Hanack, M. .. Conformation Theory, Academic Press, New York, 1965, 292. 4. Wheeler, O. H., Cetina, R. J. Org. Chem., 1957, 22, 1153. and Zabicky, J. Z.