Clarification of the role of water in proline-mediated aldol reactions

Article abstract of DOI:10.1021/ja0738881

A coherent mechanistic rationalization of the role of water in aldol reactions employing aromatic aldehydes shows that the intrinsic kinetic effect of water within the catalytic cycle is a suppression of reaction rate. The presence of water suppresses for

Full text of DOI:10.1021/ja0738881

Published on Web 11/15/2007
Clarification of the Role of Water in Proline-Mediated Aldol Reactions
Natalia Zotova,† Axel Franzke,‡ Alan Armstrong,*,‡ and Donna G. Blackmond*,†,‡
Department of Chemical Engineering and Chemical Technology and Department of Chemistry, Imperial College
London, London SW7 2AZ, United Kingdom
Received May 30, 2007; E-mail: d.blackmond@imperial.ac.uk
The report by List, Lerner, and Barbas1 in 2000 of an intermo-
lecular direct aldol reaction catalyzed by proline became an
unexpected watershed for the field of organocatalysis.2-4 Pihko and
co-workers4b,c were the first to observe significantly higher yields
with addition of water to intermolecular aldol reactions, even
allowing employment of stoichiometric substrate ratios in some
cases. This finding has great potential to widen the scope of proline
catalysis, which to date has not achieved practical levels of
efficiency. Pihko suggested that in the absence of water the
formation of oxazolidinones deactivates proline, concluding that
water accelerates the reaction. As pointed out recently,5 however,
Figure 1. Pseudo-first-order rate constant for the aldol reaction of eq 1 as
a function of added water. Open circles, left axis: stoichiometric conditions;
filled circles, right axis: 1.75 M excess 1. Final conversion is 88-99%
and product ee is 64-69% ee.
rate acceleration by water is counter-intuitive in the generally
accepted enamine mechanism. Seebach, Eschenmoser, and co-
workers6 have recently provided an alternative view of the role of
oxazolidinones within the aldol reaction network.
In this report, kinetic and spectroscopic studies provide a coherent
mechanistic rationalization of the role of water in the aldol reaction
shown in eq 1. Our work highlights the importance of deconvoluting
the intrinsic kinetic effect of water within the catalytic cycle from
its effects off the cycle.
Figure 2. Temporal change in species 7 and 8 in the interaction between
2 and 4 at 25 °C in DMSO-d6. Left: 1H NMR spectra, bottom to top: 10,
30, 120 min. Right: [7], green triangles; [8], blue circles; [7] + [8], open
black diamonds.
The methodology of reaction progress kinetic analysis7 was
employed using the “same excess” experimental protocol to
establish conditions of steady state in active catalyst concentration
within the cycle (see Supporting Information). Under these condi-
tions, the observed global rate reflects the intrinsic kinetics of the
catalytic cycle deconvoluted from any influence from spectator
species. Figure 1 shows that in the case of the reaction in eq 1, the
role of water within the catalytic cycle is to suppress, rather than
to accelerate, reaction rate. In agreement with Pihko, product ee
was unaffected by water in this concentration range.4b,8 We also
confirmed Pihko’s observation that addition of water allows the
reaction to proceed in quantitative yield for both stoichiometric and
excess ketone conditions. The trend in Figure 1 is consistent with
the generally accepted enamine mechanism shown in Scheme 1
for a case where the rate-determining step succeeds enamine
formation but precedes product hydrolysis, as supported by an
observed positive dependence on the aldehyde concentration (see
Supporting Information).
Scheme 1. Proposed Catalytic Cycle for Aldol Reaction of Eq 1
solution proline after 10 min. The concentration of 7 decreased to
one-third of this value concomitant with increasing [8] that
ultimately equaled that of the initial solution proline concentration
(Figure 2).
The 1H NMR shifts for species 7, representing a doublet of
doublets, are in good agreement with Seebach’s characterization
of the oxazolidinone derived from proline and pivaldehyde.9 Species
7 is therefore tentatively assigned as the two diastereomers of the
proline oxazolidinone of 2 (7a/7b ) 6:1). Although we were unable
to isolate species 7, we were able to obtain 8, identified by
spectroscopic analysis (1H, COSY, NOESY, 13C NMR, HMQC,
and HMBC; see Supporting Information) as the two diastereomers
present in a 2.5:1 ratio of 8a/8b from our data and in analogy with
1H NMR spectroscopic monitoring of the reaction of eq 1 in the
absence of water showed a species 7 forming within the first few
minutes of the reaction, which then decreased over time while a
second species 8 increased. Further experiments revealed that 7
and 8 may be attributed to species formed between aldehyde 2 and
proline 4. The concentration of 7 was roughly equal to that of
† Department of Chemical Engineering and Chemical Technology.
‡ Department of Chemistry.
9
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J. AM. CHEM. SOC. 2007, 129, 15100-15101
10.1021/ja0738881 CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. Reactions of Aromatic Aldehydes with Proline
Oxazolidinone formation from proline 4 and acetone 1, which
is less favored for the ketone than for the aldehyde, is also observed
under reaction conditions in the absence of water (see Supporting
Information). We have been unable to observe enamine formation
from acetone, although a recent ESI-MS study claims evidence for
this species.13 Our studies cannot directly address the question6 of
the role of oxazolidinones as active intermediates in the aldol
catalytic reaction network, but the proposed rate acceleration by
H2O via activation of the electrophile does not appear to operate
in our case.6,14
Addition of water to the proline-mediated aldol reaction is shown
to suppress the intrinsic kinetic rate for the reaction of aromatic
aldehydes, where the rate-limiting step succeeds enamine formation
but precedes product hydrolysis. This work clarifies and highlights
the complex and often opposing roles that water may play both on
and off the catalytic cycle. Deconvoluting these effects will allow
observations of the role of additives such as water to serve as
mechanistic probes and will aid in obtaining true mechanistic
understanding in these reactions. A full kinetic and mechanistic
study of the proline-mediated aldol reaction will be reported
separately.
Orsini.10 When the mixing of 2 and 4 was carried out in the presence
of 0.6 M water in DMSO, the solution concentration of proline
remained fairly constant over time while formation of both 7 and
8 was suppressed by more than 75%.
Acknowledgment. NMR support from Mr. Peter Haycock is
gratefully acknowledged. D.G.B. and A.A. acknowledge a grant
from the EPSRC. A.F. acknowledges a grant from the Swiss
National Science Foundation and Novartis. D.G.B. acknowledges
research support from AstraZeneca. D.G.B. holds a Royal Society
Wolfson Research Merit Award.
These results agree with previous studies suggesting that ir-
reversible deactivation of proline in the presence of aromatic
aldehydes and in the absence of added water occurs as shown in
Scheme 2. Oxazolidinones are reversibly formed as has previously
been shown for electron-rich aldehydes. In the case of electron-
deficient aromatic aldehydes such as 2 or p-nitrobenzaldehyde, the
iminium species 9 may undergo decarboxylation to form the
azomethine ylide 10 which may then react with a further aldehyde
molecule to form the stable 1-oxapyrrolizidine 8.10-12 The first
report of intermolecular aldol reactions mediated by proline alluded
to such deactivation, although experimental observations were not
reported in that work.1
Note added After ASAP Publication. Reference numbering was
corrected in paragraphs 6 and 10 on November 26, 2007.
Supporting Information Available: Experimental procedures and
NMR spectra. This material is available free of charge via the Internet
at http://pubs.acs.org.
Oxazolidinone formation serves as a parasitic off-cycle equilib-
rium for nonaromatic aldehydes that do not undergo the further
reactions shown in Scheme 2.4b,c Addition of water has implications
for the catalytic cycle shown in Scheme 1 for both irreversible and
reversible off-cycle reactions. Addition of water suppresses forma-
tion of both on- and off-cycle iminium ions 5 and 9 by Le
Chatelier’s principle, concomitantly suppressing on-cycle species
6 and off-cycle species 7, 8, and 10.
Thus two conflicting roles are delineated for water: increasing
water increases the total catalyst concentration within the cycle
due to suppression of spectator species, and water decreases the
relative concentration of key intermediates in the cycle by shifting
the equilibrium from 5 back toward proline 4. The net effect of
added water on the globally observed rate will depend on the relative
concentrations of iminium ions 5 and 9, which may be different
for different aldehydes and can be a complicated function of
substrate concentrations and the various rate and equilibrium
constants for the steps shown in Schemes 1 and 2. The mechanistic
point revealed by our kinetic studies is that for substrate combina-
tions of acetone and aromatic aldehydes, the intrinsic rate per actiVe
catalyst species within the cycle is suppressed, not accelerated, by
added water.
In the absence of water, irreversible deactivation due to formation
of 8 from one molecule of 4 and two molecules of 2 causes the
reaction rate and maximum achieveable yield to be lower than that
expected for the given initial concentrations of 2 and 4. By contrast,
reversibly formed oxazolidinones such as those formed from
aliphatic aldehydes may be converted back through aldehyde to
product at late stages in the reaction.4b Such a case may ultimately
provide high yields but will still exhibit less than optimal efficiency
by siphoning off proline 4 as a spectator oxazolidinone for a
significant part of the reaction.
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