Observations on the stereochemistry of reduction of 2,6- dimethylcyclohexanones

Article abstract of DOI:10.1139/v98-154

The reduction of cis-2,6-dimethylcyclohexanone with NaBH₄ in methanol is shown to produce predominantly the axial alcohol, an unexpected result based upon prior reports and current paradigms for similar cyclohexanone reductions. This finding pr

Full text of DOI:10.1139/v98-154

1
308
Obs e rva tions on the s te re oc he m is try of
re duc tion of 2 ,6 -dim e thylc yc lohe xa none s
Thom a s E. Good win, J e nn ife r M. Me a c ha m , a nd Ma rk E. Sm ith
Abstract: The reduction of cis-2,6-dimethylcyclohexanone with NaBH in methanol is shown to produce
4
predominantly the axial alcohol, an unexpected result based upon prior reports and current paradigms for similar
cyclohexanone reductions. This finding prompted a careful and systematic investigation of the NaBH and LiAlH
4
4
reductions of cis- and trans-2,6-dimethylcyclohexanones in various solvents, with additional results contrary to
literature reports. Possible explanations for these discrepancies are given, an unusual solvent effect is noted, the rate of
epimerization versus reduction is examined, molecular modeling results are reported, and an important caveat is offered
for future stereochemical studies of this nature.
Key words: cyclic ketone reduction, stereochemistry, molecular modeling.
Résumé : On démontre que la réduction de la cis-2,6-diméthylcyclohexanone par le NaBH dans le méthanol conduit
4
d’une façon prépondérante à l’alcool axial; ce résultat est inattendu sur l’on se base sur les rapports antérieurs et sur
les paradigmes actuels proposés pour les réductions de cyclohexanones semblables. Cette observation nous a amenés à
réexaminer d’une façon soignée et systématique les réductions des cis- et trans-2,6-diméthylcyclohexanones par le
NaBH et le LiAlH dans divers solvants; on a obtenu d’autres résultats sont contraires à ceux rapportés
4
4
antérieurement. On présente diverses propositions pour expliquer ces différences; on note un effet de solvant inhabituel,
on a examiné la vitesse d’épimérisation par rapport à la vitesse de réduction, on rapporte des résultats de modélisation
moléculaire et on présente une mise en garde pour les futures études stéréochimiques de cette nature.
Mots clés : réduction de cétone cyclique, stéréochimie, modélisation moléculaire.
[
Traduit par la Rédaction] Goodwin et al. 1311
based on relative GC retention times and analysis of
0 MHz NMR spectra. Garner (3) found that reduction of 1
with NaBH in methanol yielded two alcohols in a ratio of
6
The stereochemical course of the reduction of cyclic ke-
4
tones, especially cyclohexanones, has been a topic of intense
theoretical and practical interest for decades (for a conve-
nient tabular listing of examples, see ref. 1). In general,
6
8:32; by analogy to the earlier work, the major isomer was
assumed to be equatorial alcohol 2 (see Scheme 1).
When we repeated the reduction of cis-2,6-dimethyl-
sterically undemanding reducing agents such as LiAlH and
4
cyclohexanone with NaBH in methanol, the axial alcohol 3
4
NaBH are known to approach simple cyclic ketones prefer-
4
was clearly the major product, an unexpected result based
upon prior reports and current paradigms for similar
cyclohexanone reductions (see Discussion). We have care-
fully and systematically reexamined the NaBH and LiAlH
entially along what is apparently the more hindered axial
trajectory, thus leading to the equatorial alcohol as the major
reaction product. This tendency can be reversed by using re-
agents or substrates that are more sterically demanding. Re-
duction of cis-2,6-dimethylcyclohexanone (1) can yield two
diastereomeric alcohols (2 and 3). The trans isomer (4) pro-
vides diastereomers 5 and 6, which are easily interconverted
by a ring flip, thus yielding for all practical purposes only
the more stable conformer 5. In a seminal paper, Wigfield
and Phelps (2) reported that reduction of the cis isomer 1
4
4
reductions of cis- and trans-2,6-dimethylcyclohexanones and
report herein additional results that are not entirely in accord
with prior reports. Possible explanations for the
discordances are given, an unusual solvent effect is noted,
the rate of epimerization versus reduction is examined, mo-
lecular modeling results are reported, and an important ca-
veat is offered for other stereochemical studies of this
nature.
with NaBH in 2-propanol gave a 2:3 alcohol ratio of 62:38.
4
Assignment of equatorial alcohol 2 as the major product was
Received April 1, 1998.
1
The reduction of a mixture of cis- and trans-2,6-
dimethylcyclohexanones was performed using LiAlH4 in
T.E. Goodwin, J.M. Meacham, and M.E. Smith.
Department of Chemistry, Hendrix College, Conway,
AR 72032, U.S.A.
both diethyl ether and THF, as well as with NaBH in both
4
2
methanol and 2-propanol. As much as possible, reaction
1Author to whom correspondence may be addressed.
Telephone: (501) 450-1252. Fax: (501) 450-3829. E-mail:
Goodwin@Hendrix.edu
conditions were standardized (see Experimental). The prod-
uct mixtures were directly analyzed by GC–MS before any
solvent evaporation, since we experienced product loss with
Can. J. Chem. 76: 1308–1311 (1998)
© 1998 NRC Canada

Goodwin et al.
1309
Table 1. Relative percent of reduction products from 2,6-
dimethylcyclohexanones.
Scheme 1. Reduction products from 2,6-dimethylcyclohexanones.
Compound no.
(2 + 3):5
Reagent–solvent
A. LAH–THF
Method
2:3
GC–MS
NMR
GC–MS
NMR
GC–MS
NMR
GC–MS
NMR
49:51
49:51
53:47
54:46
29:71
33:67
50:50
54:46
80:20
79:21
80:20
79:21
80:20
79:21
75:25
71:29
B. LAH–Et O
2
C. NaBH –MeOH
4
D. NaBH –i-PrOH
4
use of a rotary evaporator. Product mixtures were also ana-
lyzed by H NMR spectroscopy. Before preparation of NMR
samples, the dried product solutions were placed in a hood
to allow selective solvent evaporation at the ambient temper-
ature.
1
Our LiAlH4 data disagree with a tabulated 2:3 ratio of
2:38 in the literature (6), although the origin of that ratio is
6
not clear and may be a mistaken citation of the Wigfield and
6
Phelps data (2) using NaBH in 2-propanol. Our results are,
4
however, in line with those of Boone and Ashby (7), who
Table 1 shows the ratio of products from reduction of cis-
observed that LiAlH reduction of the closely related cis,cis-
4
2
,6-dimethylcyclohexanone as determined by both GC–MS
4
-tert-butyl-2,6-dimethylcyclohexanone in THF gave 53%
of the equatorial alcohol (axial hydride addition).
The table also lists the ratio of products (2 + 3) derived
from reduction of cis-2,6-dimethylcyclohexanone to that
product 5) from the trans isomer. This ratio is of interest
3
and NMR. Very little stereoselectivity is evident for reduc-
tion of the cis ketone with the notable exception of the
NaBH reduction in methanol for which our ratios are simi-
4
lar to those reported by Garner (3). In contrast, however, to
the earlier assumption for this reductant–solvent combina-
tion, it is clear that the axial alcohol 3 predominates over the
(
when compared to the ratio of reactant ketones (see footnote
1
2
). The GC–MS and H NMR spectral analyses reveal a
equatorial alcohol 2 in the product mixture as shown by
constant ratio for entries A, B, and C, suggesting little if any
epimerization of the reactant ketones before reduction. The
1
3
00 MHz H NMR spectral analysis and integration. Spe-
cifically, the HCOH methine hydrogen for isomer 2 appears
as a triplet (J = 9.6 Hz) at δ 2.70, while that for isomer 3 ap-
pears as a broad singlet at δ 3.53, thus they are easily distin-
guished. The analogous hydrogen for alcohol 5 appears as a
exception is entry D (NaBH in 2-propanol), where the pro-
4
portion of alcohol 5 in the product mixture is higher than
that of ketone 4 in the reactant mix. This phenomenon has
been noted previously (2a). This discrepancy was found to
be even more pronounced in a more dilute solution of 2-
propanol (see footnote 5) where a (2 + 3):5 ratio of 84:16
was determined by GC–MS, although the 2:3 ratio was es-
sentially unchanged relative to entry D in Table 1. The
NaBH4 reduction of 2,6-dimethylcyclohexanones in 2-
propanol is apparently significantly slower than for the other
three reductant–solvent combinations, a difference which be-
comes even more pronounced upon dilution. This rate de-
crease then allows epimerization to take place prior to
reduction, giving rise to variable results.
4
doublet of doublets (J = 7.7, 4.1 Hz) at δ 3.32).
There is less consonance between our ratios for reduction
of the cis isomer with NaBH in 2-propanol and the 62:38
4
ratio reported previously (2). This reaction was run again in
our laboratories under the more dilute conditions and longer
reaction time used in the former work (5), to provide a 2:3
5
ratio of 49:51 as determined by GC–MS. In view of the
product loss in this reaction when using a rotary evaporator,
it is possible that differential evaporation of isomers 2 and 3
gave rise to the apparent predominance of 2 reported by ear-
lier workers. Support for this conclusion is evidenced in en-
try D of Table 1, which reports essentially no selectivity by
GC–MS, but a slight excess of alcohol 2 by NMR integra-
tion after solvent evaporation, a result more in line with the
prior report (2).
Boone and Ashby (7) have presented clear evidence that
equatorial α-methyl substituents on a cyclohexanone ring
2
The mixture of cis- and trans-2,6-dimethylcyclohexanones was obtained from Aldrich and was labeled as 98% pure. By GC–MS, a cis:trans
ratio of 80:20 was found, remarkably close to the 81:19 ratio reported by Garner (3) in 1993. A ratio of 79:21 by integration of the H NMR
1
spectrum of a CDCl solution was also observed. As the results in Table 1 and discussion in the text reveal, minor ratio discrepancies of this
3
sort are common, and thus are at least partly related to idiosyncrasies of the two measurement techniques.
3
4
The values in Table 1 represent an average of duplicate, simultaneous reactions. The NMR ratios for the two LAH–THF reactions were
5
1:49 and 48:52. Otherwise, agreement was excellent between duplicate runs, with differences in relative product percentages between each
pair of reactions averaging 0.4 for GC–MS analysis and 0.7 for NMR analysis.
A similar chemical-shift trend and coupling pattern was reported for the analogous acetates (4a). Coupling constants for the HCOH methine
hydrogen were calculated on MMX-minimized structures using PCMODEL (Serena Software) and are in good agreement with experimental
1
values: 2 (t, J = 10.1 Hz), 3 (t, J = 1.8 Hz), and 5 (dd, J = 10.1, 4.6 Hz). The H NMR calculation using PCMODEL is based on a modified
Karplus algorithm (4b). The 13C NMR spectral assignments for alcohols 2, 3, and 5 have been reported (4c).
5
6
The ketone mix (89 µL) and NaBH (29 mg) were reacted in 3.2 mL of 2-propanol for 23 h.
4
K. Houk. Personal communication.
©
1998 NRC Canada

1
310
Can. J. Chem. Vol. 76, 1998
retard axial approach of LiAlH . A simple, yet compelling
LiAlH4 in diethyl ether or THF, or with NaBH4 in 2-
propanol, there is apparently a very close balance between
factors that hinder and (or) encourage axial and equatorial
hydride addition thus leading to little stereoselectivity. With
4
steric rationalization for this trend is that with each addi-
tional equatorial α-alkyl group, a new 1,3-diaxial-type inter-
action exists between the incoming axial nucleophile and a
C—H bond on a rotamer of the alkyl group, thus disfavoring
this approach trajectory (e.g., for cis-2,6-dimethylcyclo-
hexanone, four such interactions would exist: one from each
axial hydrogen on carbons 3 and 5, and one from each α-
methyl). When the “nonbonded” electron isodensity surface
NaBH in methanol, however, formation of the axial alcohol
4
3 predominates. In an earlier mechanistic study on ketone
reductions with NaBH in a protic solvent, Wigfield and
4
Gowland (12) found a kinetic order of 1.5 with respect to 2-
propanol. Therefore, solvent clearly can play a role in the
(
the molecule’s “electron cloud”) from 3-21G(*) ab initio
NaBH reduction mechanism. Perhaps interaction of cis-2,6-
4
calculations is examined, an increasing steric bias against
axial approach of a nucleophile is observed as α-substitution
increases.
dimethylcyclohexanone with methanol results in a subtle
conformational shift, which increases the dihedral angle be-
tween the axial α-hydrogens and the carbonyl, thus leading
to increased equatorial approach of the reducing agent.
Whatever the reason, the solvent-dependent stereoselectivity
reported herein provides further evidence of the important
7
An explanation for the usual avoidance of equatorial ap-
proach of a small nucleophile to the carbonyl carbon of an
unhindered cyclic ketone invokes torsional strain with
neighboring axial α-hydrogens (8). Anh (9a) has proposed
that axial approach of the nucleophile is most favorable
when the axial α-hydrogens are closer to being perpendicu-
lar to the plane of the carbonyl group (the “flattening rule”),
thus maximizing the n-σ* interaction between the unshared
electron pair of the nucleophile and the antibonding orbital
role that the solvent plays in NaBH reductions. Finally, a
4
caveat is proffered: our experience suggests that similar
studies of reduction stereochemistry should analyze isomer
ratios before solvent evaporation is attempted, to avoid pos-
sible alteration of product ratios through differential rates of
evaporation.
8
of each axial α-C—H bond (the “antiperiplanar effect”).
To examine flattening in the present case, the dihedral an-
gle has been determined between an axial α-hydrogen and
the carbonyl for cyclohexanone, 2-methylcyclohexanone,
and cis-2,6-dimethylcyclohexanone on structures generated
by geometry optimization using AM 1 semi-empirical calcu-
lations, followed by single-point 3-21G(*) ab initio calcula-
tions. The angles are 105.1°, 111.0°, and 113.1°,
respectively, thus leading to a correct prediction of an in-
creased equatorial approach of the nucleophile with α-sub-
stitution based on Anh’s flattening rule.
All reductions were run in duplicate for 1 h on 89 µL
(
82.3 mg; 0.652 mmol) of a commercial mixture (Aldrich)
of cis- and trans-2,6-dimethylcyclohexanones (see footnote
) and an excess of the reducing agent (0.738 mmol of
LiAlH or 0.714 mmol of NaBH ) with stirring in 1 mL of
2
4
4
solvent. In all cases, the ketones were added with caution to
a stirring mixture of the reducing agent in the chosen solvent
Nucleophilic additions to carbonyl groups are often con-
sidered to result from an interaction between the HOMO of
the nucleophile and the LUMO of the carbonyl group. It is
at the ambient temperature (approx. 20°C). The NaBH re-
ductions were cautiously quenched with 3 M HCl (1 mL),
diluted with saturated NaCl solution (1 mL), and extracted
4
7
of interest to note that the absolute value of the LUMO for
with diethyl ether (3 × 1 mL). The LiAlH reactions were
4
cyclohexanone, 2-methylcyclohexanone, and cis-2,6-
dimethylcyclohexanone is greater on the face of the ring
corresponding to axial approach of the nucleophile, thus
suggesting preferred nucleophilic approach from that direc-
tion. As α-substitution increases, however, steric factors may
become more decisive than these orbital interactions. Nota-
bly, when the 2,6-dimethylcyclohexanone mixture was re-
cautiously quenched with H O (two drops), aqueous NaOH
2
solution (15%; six drops), and again with H O (two drops),
2
then filtered over Celite, which was rinsed with diethyl ether
(4 mL). Ether solutions were dried over anhydrous Na SO .
2
4
The GC–MS analysis was carried out using a Hewlett
Packard 5890 Series II chromatograph with an HP 5971A
mass selective detector. The capillary column was an HP-5
(cross-linked 5% phenyl methyl silicone) with a length of
duced with the bulky reducing agent Li(s-Bu) BH in THF,
3
none of product 2 could be detected, thus demonstrating that
3
0
0 m, an inner diameter of 0.25 mm, and a film thickness of
.25 µm. Baseline separation was achieved for all three alco-
9
axial bond formation on ketone 1 is sterically disfavored.
hol products with an initial temperature of 60°C (hold
0
0
.5 min), followed by a 4°C/min ramp to 90°C (hold
.5 min), then a 10°C/min ramp to 100°C. The starting ke-
For reduction of cis-2,6-dimethylcyclohexanone with
tones were not detected in any of the product mixtures. The
7
All ab initio calculations were carried out using MacSpartan Plus from Wavefunction, Inc.
8
Another popular and useful hypothesis proposed by Cieplak (10a) assumes an electron-poor transition state for nucleophilic addition to a
carbonyl, thence leading to reaction preferentially antiperiplanar to the best electron-donating vicinal bond. (For a review of arguments for
and against the Cieplak model, see ref. 10b; for a cogent commentary and new data, see ref. 10c.).
Throughout Discussion, an assumption has been made that the reduction of the cyclic ketones proceeds via the more stable chair conform-
ers, yet it is possible that the less populous chair conformer is reduced more rapidly (cf. ref. 11). Examination of the nonbonded electron
isodensity surface from 3-21G(*) calculations for the less stable chairs of 2-methylcyclohexanone, and cis-2,6-dimethylcyclohexanone re-
veals a clear steric preference for formation of the equatorial alcohol (axial approach of the nucleophile), which upon chair flip to the more
stable conformer provides the axial alcohol. This is the same major product that would be expected from reduction of the more stable ketone
conformer if the reaction outcome is controlled primarily by steric factors.
9
©
1998 NRC Canada

Goodwin et al.
1311
1H NMR spectra were obtained on a Varian Gemini
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early experimental assistance of E. Hurst, J. Green, and A.
Guinn is appreciated. The National Science Foundation – In-
strumentation Laboratory Improvement Program, Research
Corporation, and The Roy and Christine Sturgis Charitable
and Educational Trust are thanked for funding the purchase
of an NMR spectrometer. The GC–MS instrumentation was
provided by a generous grant from the Hewlett Packard
Foundation.
1
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©
1998 NRC Canada