Rapid quantification of the activating effects of hydrogen-bonding catalysts with a colorimetric sensor

Article abstract of DOI:10.1021/ja3050663

A sensor has been developed to quickly and simply assess the relative reactivity of different hydrogen-bonding catalysts. Specifically, blue-shifts seen upon treatment of H-bonding catalysts with the colorimetric compound 7-methyl-2-phenylimidazo[1,2-a]pyrazin-3(7H)-one correlate well to the K _eq of binding to the sensor. The blue-shifts also show a high degree of correlation with relative rates in Diels-Alder reactions of methyl vinyl ketone and cyclopentadiene employing the H-bonding catalysts. The relevance of the sensor blue-shifts to the LUMO-lowering abilities of the H-bonding catalysts is discussed.

Full text of DOI:10.1021/ja3050663

Communication
pubs.acs.org/JACS
Rapid Quantification of the Activating Effects of Hydrogen-Bonding
Catalysts with a Colorimetric Sensor
Phuong N. H. Huynh, Ryan R. Walvoord, and Marisa C. Kozlowski*
Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6323,
United States
S
* Supporting Information
number of Lewis acids,10−12 was discovered to give a readily
discernible signal upon coordination (eq 1) with a range of H-
ABSTRACT: A sensor has been developed to quickly and
simply assess the relative reactivity of different hydrogen-
bonding catalysts. Specifically, blue-shifts seen upon
treatment of H-bonding catalysts with the colorimetric
compound 7-methyl-2-phenylimidazo[1,2-a]pyrazin-
3(7H)-one correlate well to the Keq of binding to the
sensor. The blue-shifts also show a high degree of
correlation with relative rates in Diels−Alder reactions of
methyl vinyl ketone and cyclopentadiene employing the
H-bonding catalysts. The relevance of the sensor blue-
shifts to the LUMO-lowering abilities of the H-bonding
catalysts is discussed.
bond donors (Chart 1). Figure 1 illustrates the simplicity of the
method, with changes in color that are readily visible to the
naked eye upon saturation with different H-bonding catalysts.
Chart 1. Hydrogen-Bonding Catalysts
lectrophile activation by small-molecule hydrogen-bond
Edonors has emerged as an important paradigm for
enantioselective catalysis.1 Nonetheless, a thorough under-
standing of the principles and features that govern the reactivity
and selectivity of these catalysts remains incomplete. A number
of physical organic measurements have provided scales that can
be used to estimate the reactivity, such as pKa tables,2
nucleophilicity and electrophilicity parameters,3 Irving−Wil-
liams order,4,5 etc., but no scales have been made for all
categories of hydrogen-bonding catalysts. Contributing to this
problem is the large range of H-bond strengths, from 0.2 to 40
kcal/mol.6 While the strength of a H-bonding interaction can
be inferred from ΔpKa,7,8 such a measurement gives an
incomplete account with respect to catalysis since a water
molecule poorly mimics a substrate. As a result, secondary
interactions, such as sterics, dual H-bonding,9 and H-bonding
directionality, between a H-bond donor and an electrophilic
substrate are not fully incorporated. Here, we present a simple
spectroscopic measurement using a colorimetric sensor to
determine the effectiveness of H-bonding catalysts in electro-
philic activation of a monodentate substrate. The measurement
is effective for a range of catalysts encompassing a pKa window
of ∼7−20.
We assessed a number of methods to judge the ability of
different H-bond donors to activate a carbonyl (LUMO-
lowering) but found that methods effective for strong Lewis
acids, such as changes in IR or NMR signals, provided
insufficient signal or were technically challenging. In search of a
simple, easily applied measurement, we elected to use a
colorimetric sensor molecule. 7-Methyl-2-phenylimidazo[1,2-
a]pyrazin-3(7H)-one (1), which gives good correlations
between λmax-shifts and the Fukuzumi parameters for a small
Figure 1. Change in color upon addition of hydrogen-bonding
catalysts (see Chart 1) to the pyrazinone sensor 1 in dichloromethane.
Received: May 24, 2012
© XXXX American Chemical Society
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dx.doi.org/10.1021/ja3050663 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
added until no further blue-shift is seen. At this point, any water
has been displaced, and the sensor is saturated. The λmax
obtained at this juncture is then used in the correlations to
binding (Keq) and rate (krel, see below). For example, a
measurement can be made using 10 μg of the sensor and ≤10
mg of the catalyst without special precautions to exclude
moisture.
Diels−Alder reactions of α,β-unsaturated carbonyl dieno-
philes are well established to undergo rate acceleration with
Lewis acids by LUMO-lowering of the dienophile,17−20 and a
similar activation is believed to operate for H-bonding
catalysts.21 To limit the number of different interactions
between the substrates and the H-bonding catalyst, the
monodentate substrate methyl vinyl ketone was selected
along with a nonbonding diene, cyclopentadiene (eq 2). Rate
measurements by NMR22,23 showed a range of activities for
different H-bonding catalysts (Table 1).
Figure 2. Response of sensor 1 at 2.22 × 10−5 M to increasing
amounts of N,N′-di(3,5-bis(trifluoromethyl)phenyl)thiourea (4) in
dichloromethane.
Table 1. Hydrogen-Bonding Catalyst Saturated λmax and Keq
Values for Binding to 1, along with kcat Values for the
Reaction in Eq 2 at 1 mol% Catalyst Loading in Benzene
A plot of ln(krel) (krel = kcat/kuncat) vs the inverse of the λmax
-
shift (Figure 4) showed a strong correlation, indicating that the
binding to the sensor provides a reasonable account of the
LUMO-lowering ability of different H-bonding catalysts. In
contrast, the pKa values do not track well with the reactivity
(Table 1, pKa vs kcat).
H-bond
catalyst
λmax
(nm)
pKa (in DMSO)
Keq (M−1
)
kcat (s−1
)
a
none
499
490
487
477
473
465
−
2
3
4
5
6
13.4 (ref 7)
1.67 × 10
3.23 × 10
1.77 × 103
3.34 × 103
3.47 × 105
1.26 × 10−6
1.80 × 10−6
2.09 × 10−5
4.90 × 10−5
1.79 × 10−4
b
17.1 (ref 15)
8.5 (ref 7)
12.8−13.6 (ref 16)
12.8−13.6 (ref 16)
c
a
b
c
kuncat = 7.50 × 10−5 s−1. For 2-naphthol. First pKa may be 1−2 units
lower due to dicationic nature of 6.
Figure 4. Correlation of Diels−Alder krel values from different
hydrogen-bonding catalysts with the wavelength-shifts of sensor 1.
In conclusion, pyrazinone sensor 1 was found to rapidly
provide a read-out of the relative reactivity of hydrogen-
bonding catalysts in the Diels−Alder reaction of methyl vinyl
ketone and cyclopentadiene. Namely, catalysts that cause a
greater blue-shift at saturation of the sensor are more reactive.
Thus, it appears that the interaction between hydrogen-bond
donors and the carbonyl of the sensor provides a good
approximation of the LUMO-lowering potential available via H-
bonding. These preliminary results support the use of sensor 1
as a tool to gauge the relatively reactivity of new H-bonding
catalysts and to further the understanding of why some H-
bonding catalysts are more effective than others. Exploration of
additional H-bonding donors and Lewis acids with the
pyrazinone sensor and with other reactions is underway.
Figure 3. Correlation between wavelength-shift and Keq.
Figure 2 further illustrates the blue-shift in the λmax of the
sensor when combined with increasing amounts of a H-
bonding catalyst, in this case N,N′-di(3,5-bis(trifluoromethyl)-
phenyl)thiourea (4). With these data, Keq values (Table 1) for
the sensor−H-bond donor association13 could be readily
obtained from the corresponding titration curves as illustrated
for 4.14 The inverse of the λmax-shift obtained upon saturation
with 2−6 showed a strong correlation with the Keq value
(Figure 3), indicating that this λmax-shift could be used as a
reliable indicator of the association between the sensor and a
prospective H-bonding catalyst.
ASSOCIATED CONTENT
■
S
* Supporting Information
Importantly, this sensor coordinates very weakly to water
(Δλmax at saturation = 3.4 nm), which is easily displaced by
catalyst. Thus, implementation is simple: sufficient catalyst is
Experimental procedures, kinetics results, and spectral data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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Journal of the American Chemical Society
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(23) Wittkopp, A.; Schreiner, P. R. Chem.Eur. J. 2003, 9, 407−414.
AUTHOR INFORMATION
Corresponding Author
marisa@sas.upenn.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support was provided by the NIH (RO1GM087605).
Partial instrumentation support was provided by the NIH for
NMR (1S10RR022442). P.N.H.H. gratefully acknowledges the
Vietnam Education Foundation for a fellowship.
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