C O M M U N I C A T I O N S
Table 1. Rate Constants for the Benzoin Condensationa,e
should not show general acid or general base catalysis. General
acid/ base catalysis by the buffer is also excluded by comparison
of entries 2 ([buffer] ) 0.5 M) and 4 ([buffer] ) 0.2 M.). Entry
11, without added dodecyl groups on the PEI, has ca. 50%
hydrophilic cationic residues and ca. 50% neutral ones, and was
less potent than those with added hydrophobic groups.
Imidazolium salts are poorer catalysts, so the study of dialkyl-
imidazolium ions was performed at higher catalyst loading (8 mM),
pH (10), and temperature (under reflux, 100 °C). As entries 12 to
17 show, the rates again increased as the alkyl groups were longer,
promoting better hydrophobic binding into the PEI, and perhaps
with the benzaldehyde. (By contrast, the ions with longer alkyl
groups were slower in THF solvent without PEIs, where steric
effects were not overridden by hydrophobic binding. See Supporting
Information).
The most striking contrast with the thiazolium data was the
finding that the polycationic PEI was a much better catalyst (entry
17) than was the polyamine catalyst (entry 18), all relative to the
simple dimethylimidazolium ion alone (entry 12). At pH 10 the
polyamine 11 has much less positive charge than at pH 8, and these
data show that the most important effect of PEI 13 at pH 10, besides
binding the catalysts and benzaldehydes into a hydrophobic core,
is the presence of a polycationic system that furnished electrostatic
stabilization to the anions of the reaction species.
Previously, we showed that modified PEI may act as an artificial
binding domain to provide a water-excluded core and important
general acid/base reactivity for biomimetic rate enhancement.15 This
work shows that the reversible hydrophobic binding of different
coenzyme mimics and substrates into modified PEI’s hydrophobic
core can lead to very effective true catalysis. Furthermore, PEI can
be manipulated to furnish cationic groups that promote electrostatic
stabilization of anionic reaction intermediates and transition states.
b
entry
R1
R2
X
PEI
V ( × 10-9 M/s)
krel
Thiazolium Coenzyme Mimics (14)
BnO
BnO
BnO
BnO
BnO
BnO
C12H25S
C12H25S
C12H25S
C12H25S
C12H25S
1c
2
C12H25
C12H25
C12H25
C12H25
C12H25
Bn
Br
Br
Br
Br
I
Cl
I
I
-
4
1
11
13
11
11
11
11
11
11
11
12
5040 ( 60
5136 ( 111
5167 ( 222
4944 ( 111
24 ( 2
552 ( 56
9424 ( 524
4664 ( 40
1552 ( 16
596 ( 16
1260 ( 15
1284 ( 28
1304 ( 56
1248 ( 28
6 ( 0.5
3
4d
5
6
7
8
9
10
11
Me
138 ( 14
2356 ( 131
1166 ( 10
388 ( 4
C4H9
C6H13
Bn
I
Br
I
C4H9
149 ( 4
Imidazolium Coenzyme Mimics (4)
12
13
14
15
16
17
18
Me
C4H9
I
I
I
I
I
I
I
0.36
13 ( 0.17
18.7 ( 0.33
44 ( 2
833 ( 11
1225 ( 3
83 ( 5
1
13
13
13
13
13
11
37 ( 0.5
52 ( 1
123 ( 6
2314 ( 31
3402 ( 8
230 ( 14
C6H13
C8H17
C10H21
C12H25
C12H25
a Coenzyme loading ) 10 mol % (14), 40 mol % (4); [PEI] ) 6
mM; [PhCHO]initial ) 40 mM. b Relative to entry 1 or 12, respectively.
Errors are the deviations from two runs. c One run. d Buffer
concentration ) 0.2 M Na2HPO4 (pH ≈ 8.0). e Calculated from the
initial slope of [Benzoin] vs time. Errors are the deviations from two
runs.
In another PEI 12, all alkyl groups were methyl. Some of the
laurylated PEI was also permethylated to polycation 13 with
dimethyl sulfate and cesium carbonate.
Acknowledgment. This work was supported by the NSF and
the NIH.
We examined the benzoin condensation (Table 1) catalyzed by
thiazolium salts 14 and imidazolium salts 4 in which the hydro-
phobic side chains were varied (see Supporting Information).
Thiazolium and imidazolium salts are referred to as coenzyme
mimics and the PEI derivatives as enzyme mimics, by analogy with
the biochemical species. The thiazolium reactions were run in water
with 10 volume % DMSO and 0.5 M disodium phosphate buffer
(pH 8.0) with 2 mM thiazolium salt, PEI 6 mM in nitrogen atoms,
and 40 mM initial [benzaldehyde]. The product [benzoin] was
determined by HPLC. When the reaction was carried to only 10%
loss of benzaldehyde, benzoin formed linearly with time; the
resulting rate constants are listed in Table 1, entries 1-11.
As the table shows, catalysts with two hydrophobic chains were
the most effective, with ca. 103-fold accelerations relative to the
coenzyme mimic alone. The exception was bulky N-3 benzyl
substitution (entries 6 and 10). Entry 8 with an n-butyl group was
somewhat more active than the n-hexyl group (entry 9), which was
on the edge of insolubility. Entries 2 and 3 indicate that a
permethylated PEI polycation was, if anything, slightly more
effective than was the PEI with titratable amines. This indicates
that the nitrogens of the PEIs are furnishing cations for electrostatic
stabilization of the negative charges formed in the catalytic
processes of Scheme 1, not general acid and general base catalysis
as they did in transaminations. The reversible steps of Scheme 1
Supporting Information Available: Experimental details, charac-
terization data for new compounds, and nonaqueous benzoin condensa-
tion data. This material is available free of charge via the Internet at
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