Reduction of 2- and 4-alkylcyclohexanones with sodium borohydride in alcohol solvents: The effect of the solvent on the stereochemistry.

Bruce A. Hathaway *

Abstract: A solvent effect has been demonstrated in the reduction of 2- and 4-alkylcyclohexanones with sodium borohydride in alcohol solvents. The proportion of cis-alcohol product decreases as the size and bulk of the solvent increases.

Key Words: Borohydride, reduction, alkylcyclohexanones, stereochemistry 

Introduction

Previously (Hathaway 1998), we have reported a solvent effect in the reduction of 2,6-dimethylcyclohexanone and 2-methylcyclohexanone with sodium borohydride in alcohol solvents. We now report that this solvent effect is general with reductions of other 2-alkylcyclohexanones, as well as with 4-alkylcyclohexanones. The reduction of ketones with sodium borohydride in an alcohol solvent is a common reaction to prepare an alcohol. Reduction of alkylcyclohexanones gives a mixture of cis and trans alcohol products.

Experimental Procedures and GC Conditions

A solution of 0.50 grams of the ketone in the 10 mL alcohol solvent was stirred at room temperature. Sodium borohydride (0.10 grams) was added, and the reaction mixture was stirred for 30 minutes. The reaction mixture was diluted with water, and then extracted with two, 10 mL portions of hexane. The combined hexane layers were washed with 10 mL of distilled water, dried with magnesium sulfate, filtered, and the solvent was removed to yield the crude product. Proton NMR spectra of the products were recorded at 300 MHz in [CDCI.sub.3]. The C-1 methine protons were integrated to determine the relative amounts of each isomer. GC conditions: Carbowax column (30 m, 0.53 mm i.d.), column temperature at 110[degrees]C, injector and detector temperature at 200[degrees]C, flow rate at 5 mL/min, 0.4 [micro]L of a dilute solution of the alcohols in hexane was injected.

Results

Gas chromatography (GC) clearly separates the two isomers, but obviously doesn't tell which isomer is which. The earlier literature assigned the isomers by relative GC retention times (Wigfield and Phelps 1974). The order of elution of the isomers was found to be dependent on the type of GC column used. The C-1 methine hydrogens for the cis and trans isomers are clearly separated in the NMR spectra, and the chemical shifts of those hydrogens are known for many of the pure isomers (Pouchert and Campbell 1974). NMR spectra of the products for several of the experiments were recorded. In all cases, the chemical shift of the C-1 methine proton of the cis isomer is more deshielded (larger ppm value) than the methine proton of the trans isomer. The results of these analyses are shown in the following tables. The appearances of the peaks of each methane resonance also differs. The C-1 methine proton of the cis isomer appears as a broad singlet, while the methine proton of the trans isomer appears as a multiplet. Th is is consistent with the Karplus relationship. The C-1 methine proton of the cis isomer is gauche to the hydrogens on C-2 and C-6, which would give rise to very small coupling constants at best, while the C-1 methine proton of the trans isomer is anti to the C-2 hydrogen and the axial C-6 hydrogen, which produces large coupling constants.

Discussion

As shown in Table 1, the proportion of cis-isomer decreases as the size and bulk of the alcohol solvent increases. Although the effect is not large, it is reproducible, as the results shown in Table i have been repeated many times. Table 2 shows very good agreement between the NMR and GC results. Since the proportion of cis-alcohol increases when a more bulky reducing agent is used (Carey and Sundberg 1990), the solvent must not be increasing the bulk of the reducing agent. Apparently, the bulkier solvents must be blocking the approach of the borohydride ion somewhat from the equatorial side of the ketone. This could be the result of hydrogen-bonding of the alcohol solvent to the carbonyl oxygen of the ketone.

Table 1

GC Analyses of Reductions of Alkylcyclohexanones: % cis Alcohol Formed

Alkyl Group  Methanol  95%Ethanol  Isopropyl alcohol  t-Butyl alcohol

2-Methyl       49.8       39.8           37.5              32.0
2-Ethyl        49.7       43.7           39.7              37.1
2-Propyl       49.9       43.9           41.7              39.0
2-Isopropyl    54.8       50.5           44.0              36.4
2-Butyl        51.4       44.4           42.8              40.4
2-t-Butyl      80.1       68.6           65.8              65.2
4-Methyl       26.9       22.7           20.6              15.3
4-t-Butyl      19.7       14.9           13.3               8.9
Table 2

Comparison of NMR and GC Analyses of Reduction of Alkylcyclohexanones: %
cis Alcohol Formed

Alkyl Group  Solvent      % cis alcohol by NMR  % cis alcohol by GC

2-Methyl     95% ethanol          39.3                 39.8
2-Ethyl      t-butanol            34.1                 37.1
2-Propyl     t-butanol            37.6                 39.0
2-Isobutyl   t-butanol            34.8                 36.4
2-Butyl      t-butanol            39.5                 40.4
2-t-Butyl    methanol             80.3                 80.1
4-Methyl     95% ethanol          20.6                 22.7
4-t-Butyl    t-butanol            5.4                   8.9
Table 3

Proton NMR Chemical Shifts of C-1 Methine Hydrogens of
Alkylcyclohexanols

Alkyl Group  cis-isomer (ppm)  trans-isomer (ppm)

2-Methyl           3.76               3.10
2-Ethyl            3.90               3.22
2-Propyl           3.86               3.19
2-Isopropyl        4.08               3.70
2-Butyl            3.86               3.19
2-t-Butyl          4.21               3.46
4-Methyl           3.91               3.51
4-t-Butyl          4.01               3.50

Acknowledgments

The authors acknowledge the support of the National Science Foundation ILI Grant 9650399. The authors thank Bjorn Olesen for helpful discussions.

Literature Cited

Carey, F. A. and Sundberg, R. J. 1990. Advanced Organic Chemistry, 3rd Edition; Plenum: New York, Part B, pages 241-244.

Hathaway, B. A. 1998. J. Chem. Educ., 75: 1623-4.

Pouchert, C. I. and Campbell, J. R. 1974. The Aldrich Library of NMR Spectra, Aldrich Chemical Company, Inc.: Milwaukee, WI, Volume 1, pages 114-116.

Wigfield, D. C. and Phelps, D. J. 1974. I Amer. Chem. Soc., 96: 543-549