Published on Web 09/26/2003
Hydrophobically Directed Selective Reduction of Ketones
Mark R. Biscoe and Ronald Breslow*
Department of Chemistry, Columbia UniVersity, New York, New York 10027
Received August 18, 2003; E-mail: rb33@columbia.edu
Table 1. Ratios of Products (3:4) Formed in the Competition
The hydrophobic effect, the tendency of nonpolar surfaces to
aggregate in water, is an intrinsic property of water that may be
exploited to obtain reactivity unique to the aqueous medium.1,2 We
have previously shown that the Diels-Alder reaction3 and the
benzoin condensation4 are dramatically accelerated when conducted
in water. The rate acceleration of these reactions results in part
from the packing of hydrophobic surfaces in the transition state,
which lowers the transition state energy by minimizing the
interfacial hydrocarbon-water contact. Building on these observa-
tions, we have developed a method to detect the packing of phenyl
rings and other hydrophobic units in the transition states of reactions
in water solutions, reactions such as displacement reactions by
anilines and phenoxide ions on benzylic halides.5 These are all
coupling reactions of two reactants.
However, it seems likely that the phenomenon is general and
that such atom-transfer reactions as hydride reductions and oxy-
genations would also be promoted and directed in water solution
by the packing geometry that minimizes the water-hydrocarbon
interface. Thus, we have now developed reducing agents that bear
a discrete hydrophobic region, to effect the selective reduction of
ketones that likewise have a hydrophobic environment. We wish
to report the development of these hydrophobic reducing agents
and the first examples of hydrophobically directed atom-transfer
hydride reactions in water with substrate selectivity and regiose-
lectivity.
We conducted the initial tests for hydrophobically directed
reductions by performing aqueous competition reactions of levulinic
acid (1) and 3-benzoylpropionic acid (2a) or 3-â-naphthoylpropionic
acid (2b) with hydrophobic borohydride reducing agents (Table
1).6 We synthesized the hydrophobic borohydrides through the
LiAlH4 reduction of commercially available substituted boronic
acids.7 We anticipated that the ratio of reduced levulinic acid to
reduced substituted propionic acid in water would change when
the reducing agent was changed from LiBH4 to a more hydrophobic
reducing agent, and indeed a change in reactivity was observed.
Reactions were performed in D2O and carried to ca. 5%
conversion, so as to measure the initial selectivities. Consistent with
hydrophobic direction, the selectivity for the reduction of the
hydrophic substrate was greater with lithium â-naphthaleneboro-
hydride than with the phenylborohydride. Likewise, the selectivity
was greater when we employed 3-â-naphthoylpropionic acid in the
competition reactions instead of 3-benzoylpropionic acid. In this
system, the percent reduction of the hydrophobic substrate varies
from a low of 37% when 3-benzoylpropionic acid is reduced by
LiBH4 in D2O to a high of 68% when 3-â-naphthoylpropionic acid
is reduced by novel LiNaphBH3 in D2O. Although only a modest
selective rate increase was involved, these results suggested that
hydrophobically directed atom-transfer was a source of the observed
selectivity.
Reactions of 3-Ketopropanoic Acids with Substituted Borohydrides
under Different Reaction Conditionsa,b
4:1
4M
4M
R
D O
2
D O:CD OD
NaCl/D O
NaClO /D O
2
3
2
4
2
2a + 1
2a + 1
2a + 1
2b + 1c
H
Ph
Naph
Naph
37:63
50:50
56:44
68:32
39:61
47:53
50:50
53:47
37:63
54:46
61:39
71:29
38:62
46:54
49:51
54:46
a Reactions conducted with a substrate concentration between 100 and
200 mM. b All ratios are within an error of (1 in at least duplicate runs.
c Substrate concentration of 4 mM.
electrostriction, “salting out” the hydrocarbon surfaces dissolved
in water. When NaCl was added to the reaction medium, a modest
increase in selectivity for the reduction of the hydrophobic substrate
was observed (Table 1). Conversely, salts such as NaClO4 and
guanidinium chloride have been shown to decrease hydrophobic
interactions by solvating the hydrocarbon surfaces dissolved in
water.4,5 When NaClO4 was added, we observed a decrease in
selectivity for the reduction of the hydrophobic substrate. The
addition of methanol to the reaction medium also (Table 1)
decreased the selectivity for reduction of the hydrophobic substrate
by hydrophobic reagents, but no effect was seen with LiBH4. These
salt and alcohol effects strongly implicate the hydrophobic effect
as a driving force in the reductions where two hydrophobic surfaces
are involved.
The potential for hydrophobically induced selectivity having been
established, we created and studied a new group of ketones based
upon quaternized â-keto amines (5 + 6) such that the selectivity
obtained with ketones on separate molecules could be compared
with the selectivity obtained when the hydrophobic and nonhydro-
phobic ketones were within the same molecule (9a, 9b, and 9c). In
this group of ketones, we also tested lithium pentafluorophenyl
borohydride (LiC6F5BH3) as a reducing agent. We expected the
perfluorinated reducing agent to be superior because of the elevated
hydrophobicity that results from fluorination.8 Because of its
electron deficiency, novel LiC6F5BH3 would also be a weaker
hydride donor than its nonfluorinated analogue and would possibly
exhibit a favorable quadrupolar interaction with a nonfluorinated
aryl group.9,10
LiC6F5BH3 did indeed prove to be the most selective reducing
agent (Table 2). In competition reactions of 5b and 6, the naphthyl
ketone was reduced preferentially over the methyl ketone in a 91:9
ratio. When salted out with LiCl, the selectivity increased to 95:5,
whereas when LiBH4 was employed, the product ratio was
approximately 50:50. When the competition reactions of 5b and 6
were performed in methanol using LiBH4 and LiPhBH3 separately,
ratios of 36:64 and 38:62 were obtained, respectively. The ap-
Additives such as salts or alcohols can be employed to either
intensify or weaken hydrophobic effects.1,4,5 Salts such as LiCl and
NaCl have been shown to increase hydrophobic interactions by
9
12718
J. AM. CHEM. SOC. 2003, 125, 12718-12719
10.1021/ja0379924 CCC: $25.00 © 2003 American Chemical Society