Computational and experimental structure-reactivity relationships: evidence for a side reaction in Alpine-Borane reductions of d-benzaldehydes

Article abstract of DOI:10.1016/j.tetlet.2009.09.109

Extraordinary stereoselectivity, approaching 100%, has been reported in the reductions of d-benzaldehydes by B-isopinocampheyl-9-borabicyclo[3.3.1]nonane (Alpine-Borane). This is likely because of the extreme size disparity of groups on either side of the carbonyl. Here, we present a structure-reactivity study whereby the reductions of variably substituted d-benzaldehydes are explored using highly sensitive measures for enantiomeric excess and relative reactivity. These results are compared to the relative rates predicted from density functional calculations. The results indicate that 2,6-disubstitution adversely affects the stereoselectivity by means of a non-selective reduction via the dehydroboration product of Alpine-Borane, 9-borabicyclo[3.3.1]nonane.

Full text of DOI:10.1016/j.tetlet.2009.09.109

Tetrahedron Letters 50 (2009) 6803–6806
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Tetrahedron Letters
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Computational and experimental structure–reactivity relationships:
evidence for a side reaction in Alpine-Borane reductions of d-benzaldehydes
*
Hui Zhu, N. Soledad Reyes, Matthew P. Meyer
School of Natural Sciences, University of California, Merced, PO 2039, Merced, CA 95344, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Extraordinary stereoselectivity, approaching 100%, has been reported in the reductions of d-benzalde-
hydes by B-isopinocampheyl-9-borabicyclo[3.3.1]nonane (Alpine-Borane). This is likely because of the
extreme size disparity of groups on either side of the carbonyl. Here, we present a structure–reactivity
study whereby the reductions of variably substituted d-benzaldehydes are explored using highly sensi-
tive measures for enantiomeric excess and relative reactivity. These results are compared to the relative
rates predicted from density functional calculations. The results indicate that 2,6-disubstitution
adversely affects the stereoselectivity by means of a non-selective reduction via the dehydroboration
product of Alpine-Borane, 9-borabicyclo[3.3.1]nonane.
Received 4 August 2009
Revised 17 September 2009
Accepted 18 September 2009
Available online 24 September 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Stereoselective reduction of prochiral carbonyl-containing com-
pounds is one of the most highly developed classes of asymmetric
conversions; however, the substrate range of a particular conver-
sion is often difficult to predict.1 Stereoselective reactions can suf-
fer an attenuation of selectivity via three primary routes: (1) close
competition between diastereomeric transition states, (2) post-
reaction racemization through a symmetric intermediate, and (3)
the active participation of a non-selective side reaction. Nowhere
is this consideration more evident than in stereoselective reduc-
tions of prochiral ketones by B-isopinocampheyl-9-borabicy-
clo[3.3.1]nonane (Alpine-Borane). The availability of natural
olefins bearing stereogenic centers coupled with the reactivity of
organoboranes has made asymmetric organoboranes an important
source of chirality in stereoselective syntheses. Some of the first
examples of chirality transfer via organoboranes performed by
Midland et al. illustrated the potential of these compounds to per-
form stereoselective reductions with high yields and selectivities.
In particular, Alpine-Borane was found to reduce d-benzaldehydes
with very high selectivity, often approaching 100% enantiomeric
excess.2 Disappointingly, further studies on the substrate range
of this compound showed it to be much less effective in reducing
aralkyl ketones and most dialkyl ketones. Midland subsequently
showed that the application of high static pressures to the reaction
yielded improved selectivity in most previously intractable reac-
tions, accompanied by a similarly impressive rate enhancement.3,4
Based on this observation, Midland surmised that the origin of ste-
reoselectivity degradation in the Alpine-Borane reduction of ke-
tones is due to competitive non-selective reduction via 9-BBN,
the dehydroboration product of Alpine-Borane (Fig. 1). This
hypothesis was later validated by observing the transfer of 9-
BBN from Alpine-Borane to competing alkenes in solution.5,6 Fur-
thermore, Brown et al. found that the exclusion of solvent from
the reduction of ketones provided similar gains in selectivity.7
These observations are consistent with the putative side reaction,
given that the volume of activation for dehydroboration (TS3) is
likely to be large and positive and the relative entropy of solvation
for the two dissociation products is likely to be higher than that for
the single progenitor species.
H OH
B
O
H
RL
RL
RS
RS
O
TS1
RL
RS
HO
RL
H
B
O
H
H
RS
RS
RL
TS2
TS3
H
B
B
* Corresponding author. Tel.: +1 209 228 2982.
E-mail address: mmeyer@ucmerced.edu (M.P. Meyer).
Figure 1. Possible competing rate-determining transition states in the Alpine-
Borane reduction of prochiral ketones and d-aldehydes.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.109

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H. Zhu et al. / Tetrahedron Letters 50 (2009) 6803–6806
The substrate range of Alpine-Borane, however, is far from
the resulting amounts of alkyl-substituted benzyl alcohols were
determined via distinct methyl resonances. The 13C NMR was per-
formed on the initial reactant and resulting product mixtures using
calibrated 90° pulse widths and relaxation times that were 5ÂT1
for the resonance of interest with the longest relaxation time. This
value was calibrated using an inversion recovery experiment with
calibrated pulse widths. This method was chosen over HPLC detec-
tion of product and reactant ratios because HPLC could not resolve
each of the eleven reactants and products with baseline resolution.
Numerous comparisons of experimentally determined kinetic
isotope effects with those predicted from computational models
using density functional theory have validated the use of the
B3LYP density functional in arriving at meaningful representations
of the transition structure.11–15 As a point of comparison with our
empirical determination of relative rates, we computed the transi-
tion structures for preferred re attack of (R)-Alpine-Borane upon
the eleven variably substituted benzaldehydes shown in Figure 2.
The reactant aldehydes were also optimized. Frequency calcula-
tions upon the reactant and transition structures allowed for the
estimation of the relative free energies of activation (DDGà). Using
the Eyring equation, the relative rates were derived. The
logarithms of computed relative rates were compared with the log-
arithms of experimentally determined relative rates to give direct
comparisons of the relative free energies of activation (Fig. 2). A
strong correlation (R2 = 0.94) with a slope near unity (1.13 0.09)
was found for all substrates, excluding 2,6-dimethylbenzaldehyde
and 2,4,6-trimethylbenzaldehyde. The relative rates for the conver-
sions of these two substrates were well above what might be ex-
pected from the correlation between computed and measured
relative rates. While these data are somewhat compelling evidence
for a side reaction for substrates bearing 2,6-disubstitution, we
posited that such a side reaction should lower selectivity in the
reduction of the d-benzaldehyde analogs of these reactants, if the
side reaction is the suspected non-selective 9-BBN reduction of
the aldehydes following dehydroboration of (R)-Alpine-Borane.
Exploring the selectivity profile for the d-benzaldehyde isotopo-
logs of the substrates shown in Figure 2 can be performed in a
number of ways. In the current study, we elected to perform these
measurements by obtaining 2H NMR spectra of the resulting alco-
being well understood. Another key observation lends some in-
sight into the problem: while aralkyl and dialkyl ketones behave
unpredictably under Alpine-Borane reduction, ynones are typically
reduced faster with higher selectivities, in general, than other clas-
ses of ketones.8–10 This behavior can be understood in the context
of the relative steric presence of alkynyl substituents. The two sp-
hybridized carbon centers adjacent to the carbonyl significantly
attenuate the steric bulk of these substituents near the carbonyl.
Of course, the determinants of substrate range are not simply con-
cerned with the relative bulk of the large (RL) substituent and the
small (RS) substituent on the prochiral ketone. Excess steric bulk
in the large substituent appears to attenuate reactivity in the
reduction of ynones bearing an a-3° center. As in other Alpine-Bor-
ane reductions with attenuated selectivity, a competing non-selec-
tive reduction via 9-BBN is thought to result in low selectivities for
these substrates.10 Here, we explore a similar phenomenon in the
Alpine-Borane reductions of benzaldehydes. We utilize a very
accurate means of measuring relative reactivity in Alpine-Borane
reductions. These results are compared to the computed relative
rates obtained from density functional calculations. Finally, a very
accurate means of measuring enantiomeric excess has been em-
ployed with the objective of correlating aberrations in reactivity
profiles with a reduction in selectivity. The objectives of these
studies are to (1) provide further evidence for the suspected non-
selective 9-BBN reduction as a competing side reaction, (2) provide
an experimentally validated transition structure for the Alpine-
Borane reduction of benzaldehydes, and (3) understand the limita-
tions upon substrate range for these conversions.
We employed a new methodology to determine the relative
rates of Alpine-Borane conversion of the 11 representative alkyl-
substituted benzaldehydes identified as shown in Figure 2. This
method allows for the simultaneous competition of numerous sub-
strates. The strength of this approach lies in the inherently large
chemical shift dispersion in 13C spectra. Because the methyl groups
upon each substrate aldehyde and product alcohol are resolved at
the baseline, we can compare the relative conversions using a
quantitative 13C NMR method (see Supplementary data). This
method relies upon a simultaneous competition reaction whereby
the eleven-substituted substrates denoted in Figure 2 compete for
a limited amount of (R)-Alpine-Borane. The relative amounts of
each alkyl-substituted benzaldehyde were quantified before reac-
tion as detected by distinct methyl resonances. Following reaction,
hol products within a poly-c-benzyl-L
-glutamate matrix.16,17 This
method was chosen because all of the alternative methods have
significant drawbacks for this particular measurement: quantita-
tive measurements of the enantiomeric ratio using a chiral HPLC
stationary phase are precluded, as the stereogenic center bears
two atoms that differ only in isotopic identity. Chiral shift agents
are typically challenging because of the simultaneous shift and
broadening of the relevant peaks. Finally, the only viable alterna-
tive, the construction of Mosher’s esters of the resulting alcohols
is costly, time consuming, and can suffer from contamination via
the minor enantiomer of the Mosher’s acid chloride utilized. To en-
sure quantitative accuracy in the 2H NMR determinations of enan-
tiomeric ratio, these measurements were carried out using
calibrated 90° pulse widths and relaxation times corresponding
to greater than 5ÂT1 for the resonance of the major enantiomer.
Overnight acquisitions using a tunable broadband probe on a
400 MHz Varian Unity NMR provide signal-to-noise ratios of at
least 20:1 for the minor enantiomer. Thus, the strength of this
method resides in the tremendous dynamic range in 2H signals
that can be accessed. Table 1 shows further support for the hypoth-
esis of a non-selective side reaction, as the only substrates with
significantly less than 95% ee are the 2,6-dimethyl-d-benzaldehyde
and 2,4,6-trimethyl-d-benzaldehyde.
The effects of alkyl substitution upon the aryl ring can be rea-
soned to be largely steric in nature. Electronically, 2,4-dimethyl-
benzaldehyde and 2,6-dimethylbenzaldehyde should be similarly
reactive. However, the 2,6-disubstituted analog is found, both
Figure 2. Relationship between experimental and computed relative rates for the
(R)-Alpine-Borane reduction of alkyl-substituted benzaldehydes using 2,3-dimeth-
ylbenzaldehyde (1) as a reference substrate.

H. Zhu et al. / Tetrahedron Letters 50 (2009) 6803–6806
6805
Table 1
BBN moiety. In fact, it can be observed that increasing the steric
bulk of a para-substituent has negligible effects upon the com-
puted and experimentally determined relative rates (Fig. 2). Upon
the addition of a 2-CH3 substituent, the transition structure must
accommodate the methyl group such that it interacts with the car-
bocyclic portion of the 9-BBN moiety (not shown) or with the prox-
imal axial methyl substituent on the isopinocampheyl group. As is
shown in Figure 3A, the transition structure has an energetic pref-
erence for the latter, where the C–C separation between these two
methyl groups is 4.119 Å. The transition structure for the similarly
positioned reduction of 2,6-dimethylbenzaldehyde shows that the
addition of another o-methyl substituent forces a compromise be-
tween the interaction of the substrate with the 9-BBN and isopino-
campheyl groups. The result of this compromise is that the
occluded methyl group on the isopinocampheyl moiety is closer
(3.914 Å) to the 2-CH3 substituent of the substrate (Fig. 3B).
The structures shown in Figure 3 offer a satisfactory explanation
of the variances in predicted and measured relative rates for
substrates bearing 2,6-substitution patterns. The simultaneous
interaction of the 2- and 6-methyl groups in 2,6-dimethylbenzal-
dehyde and 2,4,6-trimethylbenzaldehyde with the isopinocamp-
Enantiomeric excess and enantiomeric ratios measured for the reduction of variably
substituted d-benzaldehydes using 2H NMR
Substitution
% eea
era
4-CH3
4-C2H5
4-i-C3H7
96.96% 0.11%
94.59% 0.19%
96.80% 0.17%
97.84% 0.18%
97.45% 0.77%
95.14% 0.09%
95.67% 0.24%
75.40% 1.14%
96.00% 0.15%
97.21% 0.18%
88.27% 0.22%
64.7 2.6
35.9 1.8
61.5 4.0
91.7 7.0
77.6 9.5
40.2 0.7
45.2 1.2
7.1 0.3
4-t-C4H9
2,3-(CH3)2
2,4-(CH3)2
2,5-(CH3)2
2,6-(CH3)2
3,4-(CH3)2
3,5-(CH3)2
2,4,6-(CH3)3
48.9 2.8
70.6 5.1
16.0 0.3
a
Errors in % ee and er measurements were computed from signal-to-noise ratios
in the spectra.
computationally and experimentally, to be less reactive. Steric
occlusion of the 2,6-disubstituted analog is most likely the cause
of this effect. In fact, this hypothesis is supported, to some degree,
in the transition structures shown in Figure 3. The transition struc-
ture for the reduction of 4-methylbenzaldehyde (Fig. 3C) by (R)-Al-
pine-Borane serves as something of a negative control. In this
structure, the substituent is well removed from interactions with
the isopinocampheyl group and the carbocyclic portion of the 9-
heyl group enforce
a later transition state. The actively
participating atoms in the transition state form a six-membered ar-
ray of atoms. Table 2 contains a summary of the structural param-
eters from computed transition structures for the (R)-Alpine-
Borane reduction of the 11 alkyl-substituted benzaldehydes inves-
tigated here. The simplest observation that can be drawn from the
transition structures and frequency calculations are that, in terms
of the evanescent CIpc–H and nascent B–O bonds, the transition
states for the two 2,6-disubstituted benzaldehyde substrates are
later than those for all other substrates. These observations are
reinforced by the magnitude of the imaginary frequency (
ciated with the reaction coordinate at the saddle point. For these
two substrates,
à is larger than those for the other substrates. This
m
à) asso-
m
observation implies that steric frustration at the transition state
enforces a greater participation of hydride motion in the transition
state. This supposition is borne out to some degree by observing
the reduced mass associated with m
à for various substrates. The re-
duced mass associated with mà for 4-methylbenzaldehyde is
2.18 amu; whereas, the corresponding reduced mass for 2,6-benz-
aldehyde is 1.96 amu. In summary, the principal parameters
describing computed transition structures indicate a later transi-
tion state for 2,6-disubstituted substrates. By Hammond’s postu-
late, it may be assumed that the later transition states for these
substrates leads to a higher associated free energy of activation,
thus allowing for a successfully competing background reaction.
Upon further investigation of Table 2, it may be possible to di-
vide the substrates into three classes. Experimentally, alkyl-substi-
tuted benzaldehydes bearing only one ortho-substituent are found
to be more reactive than other substrates. As one might expect
Figure 3. Computed transition structures [B3LYP/6-31+G(d,p)] for the favored re
attack upon (A) 2,4-dimethylbenzaldehyde, (B) 2,6-dimethylbenzaldehyde, and (C)
4-methylbenzaldehyde. The carbocyclic portion of the 9-BBN moiety has been
eliminated for clarity. In each transition structure, the isopinocampheyl group
resides on the left, and the substrate resides on the right. The transferred hydrogen
atom is represented by an unbonded white sphere near the center of each structure.
Table 2
Key structural parameters and imaginary frequencies associated with transition structures [B3LYP/6-31+G(d,p)] computed for favored re attack of R-Alpine-Borane upon variably
substituted benzaldehydes
(O@)CÁÁÁH (Å)
C@O (Å)
CIpcÁÁÁH (Å)
BÁÁÁO (Å)
CIpcÁÁÁB (Å)
\Ar–C–H
mà (cmÀ1
)
4-CH3
4-C2H5
4-i-C3H7
1.295
1.296
1.295
1.296
1.307
1.305
1.309
1.295
1.298
1.301
1.298
1.325
1.324
1.325
1.324
1.324
1.325
1.324
1.325
1.324
1.327
1.329
1.378
1.377
1.377
1.376
1.373
1.382
1.378
1.378
1.374
1.408
1.413
1.492
1.492
1.492
1.491
1.493
1.489
1.491
1.490
1.492
1.484
1.483
1.855
1.854
1.856
1.857
1.847
1.854
1.857
1.860
1.856
1.863
1.866
113.5°
113.6
113.5
113.5
115.0
114.6
114.4
113.7
113.5
113.1
113.1
745i
742i
739i
744i
771i
794i
797i
739i
743i
830i
840i
4-t-C4H9
2,3-(CH3)2
2,4-(CH3)2
2,5-(CH3)2
3,4-(CH3)2
3,5-(CH3)2
2,6-(CH3)2
2,4,6-(CH3)3

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H. Zhu et al. / Tetrahedron Letters 50 (2009) 6803–6806
from Hammond’s postulate, the computed transition structures
corresponding to these substrates have earlier transition states
with respect to the angle about the carbonyl carbon being reduced
and the nascent C–H bond. The imaginary frequencies associated
with the reaction coordinate motion at the saddle point also fall
roughly into three classes. For substrates bearing no ortho-substit-
uents, the imaginary frequencies average to 742i cmÀ1 with little
variation in their values. For the second class of reactants, those
bearing a single ortho-substituent, the imaginary frequencies are
all of a significantly larger magnitude, averaging to 787 cmÀ1. Fi-
nally, benzaldehydes bearing two ortho-substituents have imagi-
nary frequencies averaging to 835 cmÀ1. This suggests that the
reduced mass of the reaction coordinate motion at the transition
state is dropping as one progresses from class to class. The associ-
ated reduced masses from representative members of each class
support this hypothesis, as the imaginary frequencies have associ-
ated reduced masses of 2.18 amu for 4-methylbenzaldehyde,
2.04 amu for 2,4-dimethylbenzaldehyde, and 1.96 amu for 2,6-
dimethylbenzaldehyde. Structurally, these differences can be
understood in terms of the most important bond lengths in the
transition structures, those corresponding to the forming and
breaking C–H bonds. Substrates bearing two ortho-substituents
have markedly longer CIpc–H bonds, while those bearing a single
ortho-substituent have longer (O@)C–H bonds.
The transition structures characterized in Table 2 are qualita-
tively similar to semi-empirical transition structures reported in
earlier studies.18–20 Both density functional theory and AM1 tran-
sition structures differ from the qualitative structures shown in
Figure 1 in one important respect: the six-membered scaffold of
atoms that are primarily involved in the reaction coordinate at
the transition state form more of a half-chair structure instead of
a boat-like arrangement. Even with this important difference, the
structures shown in Figure 3 exhibit similar non-bonding interac-
tions as those that might be expected from the qualitative struc-
tures in Figure 1. Primarily, the axial methyl group upon the
isopinocampheyl group appears to be a principal director of
stereoselection.
two ortho-substituents. These exceptions have been explained
using a structure-selectivity experiment, whereby the variably
substituted d-benzaldehyde isotopologs were investigated as sub-
strates in (R)-Alpine-Borane reduction. The d-benzaldehyde sub-
strates that contained 2,6-disubstitution were found to be react
with significantly impaired selectivity, implying the role of a
non-selective side reaction. These results, in conjunction with pre-
vious findings, implicate 9-BBN as the non-selective reductant in
this side reaction. Computational models of the transition struc-
tures for favored re attack of (R)-Alpine-Borane upon the eleven
substrates tested here suggest that the eleven variably substituted
benzaldehydes may be parsed into three classes.
Acknowledgments
We thank the Graduate Research Committee (UC Merced) for
funding and Mike Colvin (UC Merced) for the use of his Linux
cluster.
Supplementary data
Supplementary data (experimental procedures, NMR integra-
tion results, computational procedures, and energies and geome-
tries of all calculated structures) associated with this article can
be found, in the online version, at doi:10.1016/j.tetlet.2009.09.109.
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In this Letter, we have presented the results of an empirical and
computational structure–reactivity study that displays a high de-
gree of correlation, excepting substrate benzaldehydes bearing