A kinetic study of the conjugate addition of benzenethiol to cyclic enones catalyzed by a nonsymmetrical uranyl-salophen complex

Article abstract of DOI:10.1021/jo070357m

(Chemical Equation Presented) The Et₃N-assisted addition of benzenethiol to enones in chloroform is catalyzed with high turnover efficiency by the phenyl-substituted uranyl-salophen compound 3. Catalytic data show a close adherence to a quaterm

Full text of DOI:10.1021/jo070357m

3
A Kinetic Study of the Conjugate Addition of
Benzenethiol to Cyclic Enones Catalyzed by a
Nonsymmetrical Uranyl-Salophen Complex
uranyl-salophen compounds as metalloreceptors and metal-
4
locatalysts.
Valeria van Axel Castelli, Antonella Dalla Cort,
Luigi Mandolini,* Valentina Pinto, and Luca Schiaffino
Dipartimento di Chimica and IMC-CNR,
UniVersit a` La Sapienza, 00185 Roma, Italy
luigi.mandolini@uniroma1.it
ReceiVed February 28, 2007
Conjugate additions of thiols to activated olefins are biologi-
5
6
cally relevant and synthetically useful reactions. We reported
that uranyl-salophen compounds 1 and 2 catalyze with high
turnover efficiency the tertiary amine assisted addition of
benzenethiol to cyclic and acyclic enones and provided a detailed
4
a-c
description of the complex kinetics.
The almost parallel pendants in 2 form a narrow cleft easily
accessible by sterically unhindered, planar donor guests.7
Attractive van der Waals interactions of the guest with the cleft
3
b
walls enhance complex formation. Association constants
The Et
3
N-assisted addition of benzenethiol to enones in
(Table 1) with a number of enones (4a-8a) and their phenylthio
chloroform is catalyzed with high turnover efficiency by the
phenyl-substituted uranyl-salophen compound 3. Catalytic
data show a close adherence to a quatermolecular mechanism
involving reaction of a base-activated thiol with a reversibly
formed complex of enone and metal catalyst, with a
complication of product inhibition due to the formation of a
product-catalyst complex. The role of the binding energy
made available by interactions with the aromatic sidearm of
the catalyst is discussed in terms of catalyst-substrate and
catalyst-transition state complementarity.
(
3) (a) Antonisse, M. M. G.; Reinhoudt, D. N. Chem. Commun. 1998,
4
43-448. (b) van Axel Castelli, V.; Dalla Cort, A.; Mandolini, L.; Pinto,
V.; Reinhoudt, D. N.; Ribaudo, F.: Sanna, C.; Schiaffino, L.; Snellink-
Ru e¨ l, B. H. M. Supramol. Chem. 2002, 14, 211-219. (c) Dalla Cort, A.;
Miranda Murua, J. I.; Pasquini, C.; Pons, M.; Schiaffino, L. Chem.sEur.
J. 2004, 10, 3301-3307. (d) Cametti, M.; Nissinen, M.; Dalla Cort, A.;
Mandolini, L.; Rissanen, K. J. Am. Chem. Soc. 2005, 127, 3831-3837. (e)
Cametti, M.; Nissinen, M.; Dalla Cort, A.; Mandolini, L.; Rissanen, K. J.
Am. Chem. Soc. 2007, 129, 3641-3648.
(4) (a) van Axel Castelli, V.; Dalla Cort, A.; Mandolini, L.; Reinhoudt,
D. N. J. Am. Chem. Soc. 1998, 120, 12688-12689. (b) van Axel Castelli,
V.; Dalla Cort, A.; Mandolini, L.; Reinhoudt, D. N.; Schiaffino, L. Chem.s
Eur. J. 2000, 6, 1193-1198. (c) van Axel Castelli, V.; Dalla Cort, A.;
Mandolini, L.; Reinhoudt, D. N.; Schiaffino, L. Eur. J. Org. Chem. 2003,
6
27-633. (d) Dalla Cort, A.; Mandolini, L.; Schiaffino, L. Chem. Commun.
2005, 3867-3869.
5) (a) Fluharty, A. L. In The Chemistry of the Thiol Group, Part 2;
Salophen ligands (salophen ) N,N′-phenylene salicylidene)
are widely studied in coordination chemistry and have found
application in supramolecular chemistry owing to the easy
(
Patai, S., Ed.; Wiley: New York, 1974; p 589. (b) Jocelyn, P. C. In
Biochemistry of the SH Group; Academic Press: London, 1972; p 98.
For recent examples, see: (c) Lutolf, M.P.; Tirelli, N.; Cerritelli, S.;
Colussi, L.; Hubbell, J. Bioconjugate Chem. 2001, 12, 1051-1056. (d)
Schmidt, T. J.; Ak, M.; Mrowietz, U. Bioorg. Med. Chem. 2007, 15, 333-
1
synthetic accessibility of a large variety of different structures.
2
+
In their robust complexes with the uranyl dication UO2
,
the N2O2 donor atoms occupy four of the five coordination sites
of the uranium, while leaving the fifth position available
for labile coordination of a monodentate ligand. Such
342.
(6) For selected examples, see: (a) Adam, W.; Nava-Salgado, V. O. J.
2
Org. Chem. 1995, 60, 578-584. (b) Michael, K.; Kessler, H. Tetrahedron
Lett. 1996, 37, 3453-3456. (c) Sreekumar, R.; Rugmini, P.; Padma Kumar,
R. Tetrahedron Lett. 1997, 38, 6557-6560. (d) Rohrig, S.; Hennig, L.;
Findesein, M.; Welzel, P.; Frischmuth, K.; Marx, A.; Petronisch, T.; Koll,
P.; M u¨ ller, D.; Mayer-Figge, H.; Sheldrich, W. S. Tetrahedron 1998, 54,
3413-3438. (e) Cheng, S.; Comer, D. D. Tetrahedron Lett. 2002, 43, 1179-
1181. (f) Heggli, M.; Tirelli, N.; Zisch, A.; Hubbell, J. A. Bioconjugate
Chem. 2003, 14, 967-973. (g) McDaid, P.; Chen, Y.; Deng, L. Angew.
Chem., Int. Ed. 2002, 41, 338-340.
Lewis acid-base interaction provides the basis for the use of
*
To whom correspondence should be addressed. Tel: +39 0649913624.
Fax: +39 06490421.
(
1) Vigato, P. A.; Tamburini, S. Coord. Chem. ReV. 2004, 248, 1717-
2
128.
(
2) (a) Sessler, J. L.; Melfi, P. J.; Pantos, G. D. Coord. Chem. ReV.
2
2
006, 250, 816-843. (b) Ephritikhine, M. Dalton Trans. 2006, 2501-
516.
(7) Van Doorn, A. R.; Bos, M.; Harkema, S.; Van Eerden, J.; Verboom,
W.; Reinhoudt, D. N. J. Org. Chem. 1991, 56, 2371-2380.
1
0.1021/jo070357m CCC: $37.00 © 2007 American Chemical Society
Published on Web 06/09/2007
J. Org. Chem. 2007, 72, 5383-5386
5383

TABLE 1. Association Constants for Complexes between
SCHEME 1. Mechanism of the Conjugate Addition of
Benzenethiol to Enones in Nonpolar Solvents
Salophen-Uranyl Receptors 1-3 and Carbonyl Compounds 4-8 in
a
CHCl3 at 25.0 °C
1
2
3
4
4
5
5
6
6
7
7
8
8
a
b
a
b
a
b
a
b
a
b
14 ( 1
<3
7.6 ( 0.6
<3
17 ( 2
<3
3.7 ( 1.2
<3
460 ( 40
68 ( 6
870 ( 120
140 ( 20
320 ( 50
90 ( 20
900 ( 200
100 ( 20
820 ( 150
240 ( 20
130 ( 20
70 ( 7
530 ( 80
90 ( 10b
330 ( 40
110 ( 10b
90 ( 8
3.2 ( 0.4
<3
6.4 ( 1.4
<3
which does not necessarily imply a three-body collision, but
can instead be accomplished by the reaction of the enone with
a weak complex of thiol and base. In the mechanism depicted
in Scheme 1, a proton is first transferred from sulfur to nitrogen,
and then from nitrogen to the R-carbon atom of the enolate
intermediate. The kinetics reveal the composition of the rate-
limiting transition state as that of a ternary complex of base,
thiol, and enone in a 1:1:1 ratio, but is uncertain whether it is
b
<3
a
Data from refs 3b and 4a, unless otherwise stated. b This work, from
UV-vis titrations.
derivatives (4b-8b) exceed those obtained with the parent
compound 1 by 1-2 orders of magnitude, with the notable
exception of the 6,6-dimethyl derivatives 8a and 8b, in which
the bulky gem-dimethyl group apparently hinders effective
insertion of the guest into the narrow cleft.
+
the formation or disruption of the BH -paired enolate that is
rate determining. The rate constants k for the Et N-catalyzed
o
3
addition of benzenethiol to enones 4a-8a listed in the first
column in Table 2 show that, within the cyclohexenone series,
the reaction is quite sensitive to the presence of the bulky gem-
dimethyl group and to its distance from the site of nucleophilic
4
b
attack.
Addition of catalytic amounts of metal catalyst 3 strongly
enhances rates of addition of benzenethiol to enones 4a-8a.
1
Typical time-concentration data from H NMR analysis of the
reaction mixtures are plotted in Figure 1. In all cases, the
disappearance of the enone reactant was complete and was
accompanied by the equivalent formation of the addition
product. No extra peaks due to reaction intermediate and/or side
products were observed.
Our interest in nonsymmetrically substituted uranyl-salophen
derivatives8 led us to the discovery that van der Waals
interactions of the bound substrates with the single aromatic
sidearm in 3 are strong enough to ensure binding affinities
comparable to those of the complexes with 2 (Table 1). Again
the 6,6-dimethyl derivative 8a is an exception, in that its binding
affinity to 3 is much higher than to 2. It was felt therefore that
the “half-cleft” receptor 3 could act as a catalyst of the conjugate
thiol addition to enones, capable of combining the advantages
of compounds 1 and 2, because it binds to the enone substrate
with affinities comparable or even greater than those of 2, while
leaving one of the two faces of the activated double bond more
accessible to nucleophile addition. With this idea in mind, we
have carried out a careful kinetic study of the conjugate addition
of benzenethiol to enones 4a-8a in chloroform solution,
catalyzed by a combination of triethylamine and compound 3.
As shown in a previous study,4 the rate law for the tertiary
amine (B) catalyzed addition of benzenethiol (T) to enones (E)
is that of a clean third-order process (eq 1).
c
rate ) k [B][T][E]
(1)
o
Since the concentration of the base catalyst is constant in a given
run, second-order time dependence was actually observed, with
kobs ) ko[B]. Consistent with the kinetics, the reaction mech-
anism is depicted as a termolecular process (Scheme 1),
FIGURE 1. Time-concentration profile for the Michael type addition
3
of 0.05 M benzenethiol to 0.02 M 5a in the presence of 1 mM Et N
1
and 0.1 mM 3. The points are obtained from H NMR analysis, and
the solid line is calculated from eq 3. The dotted line is the time-
concentration profile for the same reaction in the absence of metal
(8) For a review article, see: Dalla Cort, A.; Pasquini, C.; Schiaffino,
o
catalyst calculated from the k value in Table 2.
L. Supramol. Chem. 2007, 19, 79-87.
5
384 J. Org. Chem., Vol. 72, No. 14, 2007

TABLE 2. Kinetic Data for the Addition of Benzenethiol to Enones 4a-8a in the Presence of Et3N and in the Absence (ko) and Presence (kcat)
a
of Metallocatalysts 1-3 in CHCl3 at 25.0 °C
1
2
3
ko
kcat
kcat/ko
kcatKE
KTq
kcat
kcat/ko
kcatKE
KTq
kcatb
kcat/ko
kcatKE
KTq
4
4
4
4
3
4
4
5
5
5
5
4
5
6
5
5
6
5
5
4
4
5
6
7
8
1.6
0.66
0.024
0.080
0.14
1400
1600
10
320
480
880
2400
420
4000
3400
2.0 × 10
1.2 × 10
170
1200
1500
1.2 × 10
1.8 × 10
7.0 × 10
1.5 × 10
1.1 × 10
630
710
1.8
100
2.6
390
1100
75
1200
19
2.9 × 10
6.4 × 10
1500
1.8 × 10
9.7 × 10
6.2 × 10
1.6 × 10
120
1300
2700
11
90
40
810
4100
460
1100
290
1.1 × 10
8.6 × 10
5800
7.1 × 10
1.3 × 10
2.4 × 10
3.6 × 10
2.6 × 10
4
4
1.3 × 10
2.9 × 10
17
3600
a
All quantities are defined in eqs 1 and 2. Rate constants ko and kcat have units of M s-1; equilibrium constants KE and KTq [KT * (kcat/ko)‚KE] have
-2
-
1
units of M . Rate constants ko and catalytic constants kcat for reactions catalyzed by 1 and 2 from refs 4a-c. Equilibrium constants KE from Table 1.
b
Experimental errors calculated as ( 2σ (95% confidence limit) are in the order of ( 5%.
As previously found for the reactions catalyzed by 1 and 2,4b
in the presence of 3, the reactions no longer exhibited second-
order time dependence because the metal catalyst 3 binds
significantly to the enone reactant and, in the majority of cases,
also to the reaction product. The bound enone plays a key role
in the catalysis, as interaction with the Lewis acidic uranyl center
strongly stabilizes the negative charge transferred from the sulfur
nucleophile to the carbonyl oxygen. The proposed mechanism
k K [B][T][E][cat]
cat E tot
rate ) k [B][T][E] +
(2)
o
1 + K [E] + K [P]
E
P
Numerical values of the quantities ko (Table 2), KE, and KP
Table 1) are known from independent measurements, and the
composition of the reaction mixtures as a function of time is
(
1
known from H NMR data. Hence the only unknown quantity
is kcat. For each catalytic run, a value of kcat was chosen in such
a way that the left side of eq 3 plots against time as a straight
line through the origin with slope 1. An example of such plots
is shown in Figure 2, based on the time-concentration data in
Figure 1. In all cases, time-concentration profiles were
reproduced to a good precision upon introduction of the
optimized kcat value into eq 3. It is significant that a good
adherence of data points to eq 3 was obtained using KE and KP
values from independent measurements and not merely by a
fitting procedure in which such quantities are treated as
adjustable parameters.
(Scheme 2) is an extended complexation catalysis scheme,
SCHEME 2. Complexation Catalysis with Product
Inhibition in the Conjugate Addition of Benzenethiol to
Enones in Nonpolar Solvent in the Presence of
Uranyl-Salophen Catalyst (cat)
involving a combination of Brønsted base (B) and Lewis acid
(
cat) catalysts and product inhibition caused by the formation
1
+ K [E]
o
[E]o
of a product-catalyst complex (P-cat). The highest energy
transition state has the composition of a quatermolecular
complex (9) arising from the addition of a base-activated thiol
to an enone-catalyst complex.
P
ln
m([T] - [E] ) [E]
+
o
o
E
K - KP
1 + K [E]
o
P
[T]o
-
ln
+
(
)
m - n
(m - n)([T] - [E] )
[T]
o
o
(
K - K )k K [B][cat]
E
P
cat
E
tot
m(m - n)
(
K - K )k ([E] - [E])
E P o o
ln 1 -
) t (3)
(
)
k + k K [cat] + k K [E]
o
cat
E
tot
o
E
o
m ) k [B](1 + K [E] ) + k K [B][cat]
(4)
(5)
o
P
o
cat
E
tot
n ) k [B]([T] - [E] )(K - K )
o
o
o
P
E
The kinetic parameters for the reactions catalyzed by 3 are
summarized in Table 2, where the corresponding data for the
reactions catalyzed by 1 and 2 are also reported for comparison.
Like in the simple Michaelis-Menten mechanism of enzyme
Whenever the rate of the reaction catalyzed by the base alone
is significant compared with the rate of the reaction catalyzed
by a combination of base and metal catalyst, the overall reaction
rate is given by eq 2, where the second term on the right is a
direct consequence of Scheme 2 and holds whenever [E‚cat]
9
kinetics, the relevant parameters are kcat and kcat‚KE. The
meaning of kcat is that of the rate constant for the transformation
of the catalyst-bound enone into the catalyst-bound product, with
the obvious difference that here kcat is a third-order rate constant
not first order as in the Michaelis-Menten kinetics. The quantity
kcat‚KE is an apparent fourth-order rate constant that refers to
the properties and reaction of the free catalyst and free substrate
,
[E]. Analytical integration of eq 2 has been reported
4b,c
previously.
The form that the integrated equation takes for
the case of unequal reactant concentrations is that of eq 3, where
the quantities m and n are defined in eqs 4 and 5, respectively.
This is an unpleasantly complicated equation, but its practical
application is straightforward.
(9) Fersht, A. In Enzyme Structure and Mechanism, 2nd ed.; W.H.
Freeman: New York, 1985; Chapter 3.
J. Org. Chem, Vol. 72, No. 14, 2007 5385

effect on catalyst-transition state complementarity. Markedly
different behaviors, however, are observed in the reactions of
enone 8. Here the gem-dimethyl group in position 6 reduces
dramatically the catalyst-transition state complementarity in
the case of 2, but much less so in the case of 3. The net result
1
is that kcat for the reaction of 3 is still /12 that of 1, but well
1
5-fold higher than that of 2. The single sidearm in 3 shows a
better transition state complementarity than the two sidearms
in 2 because the former can accommodate sterically hindered
transition states.
To sum up, like its congeners 1 and 2, uranyl-salophen
complex 3 binds reversibly to enones 4a-8a and promotes
reactions of the bound substrates. The higher stability of the
catalyst complexes of the enone reactants compared with those
of the addition products ensures effective turnover catalysis with
low product inhibition. A major driving force for catalysis, the
only one in the case of 1, is provided by interaction of the uranyl
center with the carbonyl oxygen of the altered enone in the
transition state (dynamic binding). The passive binding due
to van der Waals interactions with the aromatic sidearm in 3 is
realized both in the transition state and in the reactant state.
Consequently, 3 is a far superior catalyst to 1 only under
subsaturating conditions, but shows either comparable or lower
catalytic activity under conditions approaching saturation. In
line with expectations, the more open structure of the half-cleft
catalyst 3 compared with that of metallocleft 2 makes the
reactions catalyzed by the former much less sensitive to the
adverse influence of steric effects.
FIGURE 2. Plot of the left side of eq 3 against time for the addition
of benzenethiol to 2-cyclohexen-1-one 5a in the presence of Et
3
N and
12
12
-
2
-1
3
, with kcat ) 2700 M
s
. The straight line has a slope of 1.
(subsaturating conditions), and that determines the selectivity
for competing substrates at any substrate concentration. The
dimensionless quantity kcat/ko is a quantitative measure of the
increase of substrate reactivity upon complexation with the
uranyl catalyst, whereas the product (kcat/ko)‚KE defines the
equilibrium constant KTq for the transformation of the transition
q
q 10
state T into the catalyst-transition state complex cat‚T .
In line with expectations, the aromatic sidearm in 3 contrib-
utes significantly to the binding of the transition states in all
cases, as shown by the fact that the KTq values are the highest
for the reactions catalyzed by 3 (Table 2). In the reactions of
enones 4a-6a, catalysts 1 and 3 show very similar kcat values,
in spite of the much higher affinity of catalyst 3 toward the
transition states of the given reactions. This is a consequence
of the fact that the additional binding energy rendered available
by the van der Waals interactions with the aromatic pendant in
Experimental Section
1
Instruments and Methods. H NMR spectra were recorded in
3
CDCl with either a 200 or 300 MHz spectrometer. Association
constants of 6b-8b with 3 were determined spectrophotometrically
3
b
at 430 nm according to standard titration procedures.
Materials. Benzenethiol was distilled under reduced pressure
prior to use. Triethylamine was distilled over p-toluenesulfonyl
chloride and then over sodium. Spectrophotometric grade chloro-
1
form and chloroform-d were dried over 4 Å molecular sieves for
3
is realized equally well in the catalyst-enone complex and
at least 24 h prior to use. Enones 4a, 5a, and 6a were used as
received. Compounds 7a, 8a, 6b, 7b, 8b, and uranyl-salophen
complex 3 were available from previous works.3
in the catalyst-transition state complex, so that the free energies
are lowered by very nearly the same amounts. In the language
of Fersht, there is both catalyst-substrate and catalyst-transition
state complementarity.11 Only in dilute substrate solutions (i.e.,
KE‚[E] , 1) will catalyst 3 perform much more effectively than
b,4b
Rate Measurements. NMR tubes were dried in an oven at 130
°
C for at least 24 h and then stored in a desiccator. All sample
manipulations were carried out under an argon atmosphere.
Calculated amounts of triphenylmethane (internal standard) and of
all of the reactants except triethylamine were introduced into an
NMR tube, and a spectrum (either at 200 or 300 MHz, T ) 25.0
1
because the sole factor at work is stabilization of the transition
state and not the differential stabilization of transition and
reactant states.
°
C) was recorded at time zero. Then a known amount of triethy-
Interestingly, in the reactions of enones 4a-6a, the kcat values
measured in the presence of 3 are larger than those measured
in the presence of 2, which indicates that the binding energy
made available by the cleft walls in 2 is realized more effectively
in the reactant state than in the transition state. In the reaction
of enone 7a, catalysts 2 and 3 perform much in the same way,
about 3 times less effectively than catalyst 1, showing that a
gem-dimethyl group in position 5 has only a moderately adverse
lamine was added, and spectra were recorded at selected time
intervals. The integral of the signal of the R proton of the double
bond of the enone was compared with that of the internal standard.
Time-concentration data were fitted to eq 3. Because of the
mathematical form of this equation, the enone concentration was
taken as the independent variable in the curve-fitting procedure.
Acknowledgment. We acknowledge MIUR, COFIN 2003,
Progetto Dispositivi Supramolecolari for financial contribution.
(
10) Kurz, J. L. J. Am. Chem. Soc. 1963, 85, 987-991.
JO070357M
(11) Fersht, A. In Enzyme Structure and Mechanism, 2nd ed.; W.H.
Freeman: New York, 1985; Chapter 12.
(12) Kirby, A. J. Angew. Chem., Int. Ed. Engl. 1996, 35, 706-724.
5
386 J. Org. Chem., Vol. 72, No. 14, 2007