Study on the Catalytic Behavior of Bifunctional Hydrogen-Bonding Catalysts Guided by Free Energy Relationship Analysis of Steric Parameters

Article abstract of DOI:10.1002/chem.201605666

Free energy relationship (FER) studies to correlate steric parameters with the enantiocatalytic performance of bifunctional tertiary-amine hydrogen-bonding catalysts, including (S,S)-cyclohexane-1,2-diamine-derived thioureas, Cinchona alkaloid derived thioureas, and (S,S)-cyclohexane-1,2-diamine-derived squaramides, in Michael reactions revealed that the reactions are much favored by catalysts with less bulky N-substituents. The observed FERs are independent of the chiral scaffold and hydrogen-bond donor, and deepen the understanding of current bifunctional hydrogen-bonding catalysts. Moreover, DFT calculations were performed to interpret the observed high reactivities of thioureas with less bulky substituents. In particular, the computations demonstrated the advantage of a benzyl thiourea catalyst, in which an extra CH???π interaction between catalyst and substrate is the key factor.

Full text of DOI:10.1002/chem.201605666

A Journal of
Accepted Article
Title: Catalytic Behavior Study of Bifunctional Hydrogen-Bonding
Catalysts Guided by Free Energy Relationship Analyses of Steric
Parameters
Authors: Xin Li, Chen Yang, Jie Wang, Yang Liu, Xiang Ni, and JinPei
Cheng
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Catalytic Behavior Study of Bifunctional Hydrogen-Bonding
Catalysts Guided by Free Energy Relationship Analyses of Steric
Parameters
Chen Yang,†,[a] Jie Wang,†,[a] Yang Liu, Xiang Ni, Xin Li,*
[a]
[a]
,[a, b]
and Jin-Pei Cheng[a,b]
Abstract: Free energy relationship (FER) studies to correlate steric
parameters against enantiocatalytic performance of bifunctional
tertiary-amine hydrogen-bonding type catalysts, including (S, S)-
cyclohexane-1, 2-diamine derived thioureas, Cinchona alkaloid
derived thioureas and (S, S)-cyclohexane-1, 2-diamine derived
squaramides, for Michael reactions revealed that the Michael
reactions are much favored by catalysts with less bulky N-
substituents. The observed FERs are independent of chiral scaffold
and hydrogen-bond donors, deepening the understanding of current
bifunctional hydrogen-bonding catalysts. Moreover, DFT calculations
were performed to interpret the observed high reactivities of
thioureas with less bulky substituents. Especially, the computations
demonstrated the advantage of benzyl thiourea catalyst, in which
extra CH-π interaction of hydrogen bond between catalyst and
substrate should be the key point.
Figure 1. Relationship between catalyst structure and enantiocatalytic
performance in asymmetric reactions.
catalyst molecule. In fact, the seminal work of Jacobsen et al.,
who applied the linear FER as a probe to diagnose the
performance of catalyst in asymmetric epoxidations of cis-
alkenes,[ 6 ] much stimulated the research endeavors in this
regard. On this basis, prediction of new chemical
transformations has also started to emerge recently (Figure 2).[
Introduction
2,
Quantitative descriptions of the interrelationships between
structure and reactivity are the central issue of physical organic
chemistry.[1] Among the numerous principles established in past,
now the most frequently used is still the (linear) free energy
relationship (FER) analysis method, which has also proved its
value for better understanding of asymmetric reactions.[2]
7-9]
In this context, Sigman and co-workers have made
remarkable contributions in finding correlations between the
In principle, establishing a correlation between the catalyst
property and enantioselectivity depends on whether or not the
difference in the two transition states (TSs) free energies of the
enantiodetermining step in a specific reaction is primarily
determined by the structural features of the catalyst (Figure 1),
which are reflected by various parameters of molecules, such as
Hammett constants,[ 3 ] Charton values,[ 4 ] pK
s,[ 5 ] and so on.
a
Hence, the goal to achieve useful relationships may be realized
≠
by manipulating the mathematical function ΔΔG = F(M
1
,…,
M,…,M
i
n
), in which M represents the relevant parameter of the
i
+
+
[
a]
C. Yang, J. Wang, Y. Liu, Dr. X. Ni, Prof. Dr. X. Li, Prof. Dr. J.-P.
Cheng
State Key Laboratory of Elemento-organic Chemistry, Nankai
University, Tianjin 300071 (P. R. China ).
E-mail: xin_li@nankai.edu.cn
[
[
b]
+]
Prof. Dr. X. Li, Prof. Dr. J.-P. Cheng
Collaborative Innovation Center of Chemical Science and
Engineering, Tianjin 300071 (P. R. China ).
These authors contributed equally to this work.
Figure 2. Overview of probing asymmetric reactions by virtue of physical
organic parameters.
Supporting information for this article is given via a link at the end of
the document.
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outcomes of asymmetric reactions and the two-, three-, or
multiple dimensional models by employing a set of steric,
electronic, and molecular vibrational parameters.[2,7] Increased
research attention in this area is also reflected by a number of
recent investigations.[8] However, cases focused on
organocatalysis are still limited.[7d,e,j, 8c,e-g,o]
It is well realized that the hydrogen-bonding interaction, due
to its universal existence in nature, has become a prominent
mode in exploring organocatalysis for useful transformations.[10]
Intensive efforts have been made on elucidating mechanisms in
this connection by using either experimental or computational
approaches. However, investigations to link the stereoselectivity
of reaction with the performance of the catalysts remain elusive
till present, and due to its great potential in guiding the design of
new catalysts, it warrants immediate explorations.[8e-h,o]
Especially, given the fact that 3,5-bis(trifluoromethyl)phenyl, 3,5-
bis(trifluoromethyl)benzyl, fluorinated ethyl as well as benzyl and
methyl groups come forth in lots of privileged bifunctional
hydrogen-bonding catalysts (Figure 3), the reason behind these
phenomena need more rational explanations.
bond strengthening, the acidities (pK s) of catalysts, which trend
a
is generally consistent with the electronic effect, have been
extensively studied.[8h,17,18] Indeed, we observed a linear FER
correlation between products’ enantioselectivities and cataysts’
a
pK s in the Michael addition of diethyl malonate to nitrostyrene
with catalyzed by three type meta- and/or para-substituted
aromatic tertiary-amine thioureas.[8h] However, We also noticed
that alkyl substituted thioureas did not follow the correlation in
that case. In 2014, Pápai and Soós[16f] found benzyl diamino-
cyclohexane-based squaramide catalyst without electronic
perturbation can also lead to excellent enantioinduction in the
reaction of acetylacetone and nitrostyrene.[19] Very recently, in
the Michael addition of 3-substituted benzofuranones to alkyl 2-
phthalimidoacrylates, our group found that the methyl thiourea
catalyst with the smallest alkyl substituent can induce as high
stereoselectivities as 3,5-bis(trifluoromethyl)benzyl thiourea
did.[8o] These new findings remind us to revisit the role of steric
hindrance properties of the bifunctional thioureas/squaramides
in the stereocontrol for the mode Michael addition.
Table 1. Profiles of thioureas catalyzed model reaction.[a]
pK
a
Cat
k
initial min-1[c]
Yield(%)[d]
e.r.[e]
ΔΔG (er)
≠
[f]
[
b]
4
4
4
4
a (H)
-
4.12E-5
9.07E-4
8.63E-4
1.03E-3
1.57E-3
8.95E-4
1.15E-4
8.91E-5
1.56E-4
1.45E-3
13
78
76
88
91
72
50
41
41
90
89.2:10.8
86.0:14.0
84.8:15.2
82.7:17.3
88.7:11.3
80.6:19.4
85.3:14.7
72.4:27.6
67.1:32.9
83.6:16.4
1.25
1.07
1.02
0.93
1.22
0.84
1.04
0.57
0.42
0.96
Figure 3. Representative tertiary-amine (thio)ureas/squaramide catalysts.
b (Me)
c (Et)
20.5
21.0
21.6
20.2
20.5[g]
17.0[g]
21.4
21.2
-
Herein, we evaluated three types of chiral bifunctional
catalysts, including (S, S)-cyclohexane-1,2-diamine derived
thioureas, Cinchona alkaloid derived thioureas and (S, S)-
cyclohexane-1,2-diamine derived squaramides to reveal the
effect of substituent group adhere to N-H hydrogen bonds on the
Michael reaction enantioselectivities.
d (iPr)
4e (Bn)
4f (cHex)
4
4
4
g (Ph)
Results and Discussion
h (tBu)
Among the hydrogen-bonding organocatalyst family,[10] many
bifunctional chiral (thio)ureas, such as Jacobsen catalysts,[ 11]
Takemoto catalyst,[ 12 ] cinchona-type catalyst[ 13 ] and BINOL
3
i (Et C)
2
4j (CHPh )
derived catalyst,[ 14 ] have been explored to achieve various
asymmetric transformations.[15] Subsequently, Rawal[16a-e] found
[a] The reaction was conducted with 1a (0.1 mmol), 2a (0.15 mmol) and 20
mol% catalyst in 0.4 mL toluene at room temperature for 48h. [b] pK values
a
that squaramides can also serve as excellent hydrogen-bonding
catalysts.[ 16 ] If we look back to inspect the process of the
catalyst’s designing and/or optimization, one will find electronic-
tuning strategy is widely used and proved to be very effective.
Since the proton-donating ability is associated with hydrogen-
of catalysts were determined in DMSO via UV spectrophotometric
[20]
titrations. [c] Isolated yield. [d] Initial rates were determined in C
6
D
6
≠
according to ref. 8h. [e] Determined by HPLC analysis. [f] ΔΔG =RTln(e.r.),
R= 0.001986 kcal/K/mol, T=298.15K. [g] Taken from ref. 8h.
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Firstly, nine (S, S)-cyclohexane-1,2-diamine based tertiary-
amine thiourea catalysts (4a-4i) with different size substituents
were evaluated in the model reaction (Table 1). The robust
should be noted that, the lower reaction rate of 4a was attributed
to its very low concentration in the reaction. Additionally, we also
noticed there is no correlation between the catalyst acidities and
the enantioselectivities, if the aryl and alkyl substituted catalysts
were considered together (Figure S3). Less acidic alkyl catalysts,
such as 4b, 4c and 4e can induce good enantioselectivities as
good as more acidic phenyl catalysts, indicating acidity may not
be the key factor in control of catalytic performance for alkyl
catalysts.
1 5
multifaceted Sterimol parameters (B , B , L) were chosen to
[
21 ]
perform the following correlative steric analyses.
By
performing a stepwise regression,[ 22 ] the dependence of the
enantioselectivity (∆∆G ) on substituents was determined as
∆G = -0.49*B +0.04*B +1.7 with a confidence level of 95%
1 5
≠
≠
∆
(determined by an f-test, similarly hereinafter). As shown in
Figure 4, a very good linear plot between predicted and
≠
Table 2. DFT calculation results for catalysts 4b, 4e and 4g.[a]
experimentally measured ∆∆G
positive correlation between substituents and catalytic
enantioselective results. The negative coefficient of B reflects
values indicated a strong
∆G≠
kcal/mol)
p
i
Cat.
TS
e.r. (calc.)
e.r. (exptl.)
86.0:14.0
(
(%)
92.5
6.8
1
4
b-B-S
4b-B-R
4b-A-S
18.2
19.8
21.2
26.2
16.4
18.6
17.9
20.5
22.6
20.7
24.4
24.3
19.3
20.4
20.2
27.1
the present reaction requests a catalyst with a minimum width
substituent to induce high enantioselectivity, while the width of
4b
93.2:6.8
(Me)
substituent (B
5
) impacts the enantioselectivity a little. This
0.7
outcome is somewhat non-intuitive, because a general ligand
and catalyst design practice is to use a component of larger size
in order to achieve better stereoselective outcome.[7a, 8o] The
nature of the correlation between steric parameters and
observed enantioselectivities was also maintained for the
Michael reaction of ortho-chloro nitrostyrene (Figure S1) and the
reaction of dibenzoylmethane to alkyl nitrostyrene (Figure S2).
The simplest catalyst 4a can induce highest enantioselectivity,
but its poor solubility in apolar solvents precludes the practical
application. Benzyl, followed by methyl, ethyl and phenyl, all
exhibited good ability of stereoselective induction. The further
electronical optimizations on phenyl and benzyl groups have led
4b-A-R
0.0
4
4
4
4
e-B-S
1
2
90.2
2.3
e-B-S
e-B-R
1
2
1
2
7.3
e-B-R
0.1
4e
Bn)
92.6:7.4
88.7:11.3
(
4e-A-S
4e-A-S
0.0
0.1
4e-A-R1
e-A-R
0.0
4
2
0.0
4g-B-S
73.9
11.0
15.1
0.0
4g-B-R
[
12]
4g
Ph)
to the discovery of Takemoto catalyst
and Li & Cheng
89.0:11.0
85.3:14.7
(
catalyst[
8o]
4g-A-S
4g-A-R
respectively. The fluorinated ethyl catalyst has been
successfully used in several asymmetric reactions.[ 23 ] Very
recently, we also proved that methyl catalyst can induce
excellent stereoselectivities in our recent report.[8o] These
findings indicated the power of FER analyses in understanding
of catalytic behavior.
[
a] Active energies of transition states are calculated according to
≠
solution-phase (Toluene) Gibbs free energies: ΔG =GTS-Gacetylacetone
-
G
nitrostyrene-Gcat..The distribution of product is calculated using Maxwell-
≠
≠
Boltzmann statistics: p
ΔG
i
=100*exp(-ΔG
i
/RT)/∑
i
(exp(-ΔG
i
/RT)), where
≠
i
represents the activation energy of corresponding transition state.
Subsequently, DFT calculations[25-28]were performed to
rationalize the difference of rates between alkyl and aryl
substituents as well as to figure out the reason why benzyl
catalyst shared a most fast rate and highest enantioselectivity
(Table 2, Figure 5-7). Two popular dual activation paths have
been proposed in the Michael addition reaction of diethyl
malonate to nitrostyrene.[16f, 26] Path A involves the activation of
the nucleophile and electrophile by tertiary amine and thiourea,
respectively. In Path B, the protonated amine interacts with the
electrophile, while the thiourea stabilizes the deprotonated
nucleophile. Taking 4b, 4e and 4g as model catalysts,
corresponding transition states of the model reaction (Figure 5-7)
were calculated according to the above mentioned two activation
models. The calculated results were outlined in Table 2. It was
found that path B may be the most possible reaction route for
catalyst 4b, 4e and 4g. However, path A cannot be excluded in
the case of 4g, which shares a 15% portion.[26] The calculated
stereoselectivities reproduced the experimental observations
very well, indicating the calculations are applicable for the
current system (Table 2). The active energies of TSs for 4b, 4e
and 4g leading to main product were predicted as 18.2, 16.4 and
and 19.3 kcal/mol respectively, which agreed well with the
1
1
1
0
0
0
.4
.2
.0
.8
.6
.4

1
5
G (er) = -0.49*B + 0.04*B +1.7

H
y = 0.98x+0.018
2
Bn
R =0.98
Et
Me
Ph
cHex
iPr
tBu
Et C
3
0.4
0.6
0.8
1.0
1.2
1.4

Experimental G (er) Kcal/mol
Figure 4. FER analysis of Cyclohexane-1, 2-diamine derived thioureas.
The determination of initial rates[24] indicated that the steric
effect had negative influence on the activity, albeit no linear
correlation was observed. Interestingly, the reaction catalyzed
by alkyl catalysts (e.g. 4b, 4d, 4e) shared faster rates than that
catalyzed by phenyl catalyst 4g, especially the benzyl catalyst
4
e shared a most fast rate among studied catalyst (Table 1). It
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determined rates for 4b (9.07E-4), 4e (1.57E-3) and 4g (1.15E-
4). Compared to phenyl catalyst, the model reaction catalyzed
by alkyl catalysts possesses a lower energetic barrier, which
should be responsible for the fast reaction rates.
4
e-B-S
1
0
2
4e-B-S 2.2
4
4b-B-S 0
4b-B-R 1.5
4
e-B-R
1
1.5
2
4e-B-R 4.1
4b-A-S 2.9
4b-A-R 8.0
Figure 5. Relative energies and optimized transition-state geometries in the
model reaction catalyzed by 4b (units: kcal/mol).
We then turned our attention to make sense of the peculiar
action of catalyst 4e, which showed both the fastest reaction rate
and the highest enantiomeric ratio. The key feature of benzyl
group can be reflected by its flexibility[ 29 ] and aromatic ring,
which should be the origin of the observed good performance.
Thus, two typical conformation of benzyl group in TSs were
calculated (Figure 6). In the two typical transition states leading
4e-A-S1 6.2
4e-A-S2 4.3
to major (S) enantiomer, TS 4e-B-S
stable than TS 4e-B-S by 2.2 kcal/mol (Figure 6). Similarly, in
the transition states leading to minor (R) enantiomer, TS 4e-B-R
is predicted to be more stable than TS 4e-B-R by 2.6 kcal/mol.
1
is predicted to be more
2
1
2
These data suggested extra interactions between benzyl group
and substrate stabilized corresponding transition states. The
following noncovalent interaction analysis[ 30 ] of TS 4e-B-S
1
confirmed the existence of extra CH-π and CH-O interactions[31]
(
(
Figure 6 and 8a). It can be deduced that CH–π interactions
C68-H73–π & C61-H78–π, see TS 4e-B-S in Figure 6)
4
e-A-R
1
8.0
2
4e-A-R 7.8
1
between benzyl catalyst and electrophile contributed more in the
stabilization of the transition state than CH-O interaction
between benzylic hydrogen and nucleophile. As a result, the
active energy further lowered down to 16.4 kcal/mol. The
mentioned CH–π interactions can be clearly seen from the
representation of transition state in Van der Waals radii form
Figure 6. Transition-state geometries in the model reaction catalyzed by 4e
and their relative energies (units: kcal/mol).
1
the energy of R transition state (4e-B-R ) is 1.5 kcal/mol higher
than the S transition state. This calculation is in good agreement
with the observed e.r. value of 88.7:11.3 (Table 1). The peculiar
performance of 4e in the Michael reaction of dibenzoylmethane
to alkyl nitrostyrene (Figure S2) can also be attributed to the
(Figure 8b). In fact, Houk and Schafmeister et al. have observed
that the CH-π interaction can boost reaction rate in an aldol
reaction, where reactions catalyzed by N-Bn proline derivative
reacted faster than that catalyzed by N-Et derivative.[32] Due to
the different strength of CH-π hydrogen bond in transition states,
existence of CH-π hydrogen bond between benzylic aromatic
[ 33 ]
ring and vinylic hydrogen in nitrostyrene (Figure S4).
To
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Chemistry - A European Journal
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further validate theadvantage of CH-π interaction, we decided to
ethyl, benzyl and phenyl substituents are still optimal candidates,
the relationship maintains the same form regardless of the
alternation of chiral scaffold. Holding the (S, S)-cyclohexane-1,2-
diamine scaffold still, the relationship are expected to be kindred
when changing the hydrogen-bonding section from thioureas to
test a “new” catalyst according to the steric analysis. The CHPh
2
substituted thiourea 4j should show a better performance than
the iPr substituted catalyst 4d for existence of CH-π interaction,
although 4j possesses a slightly bigger steric effect than 4d. As
expected, 4j exhibited a better enantioselective inducement and
a faster reaction rate (1.45E-3) than 4d. This phenomenon
reminds us a “butterfly” substituent like CHPh2 may be a better
choice in some reactions. Indeed, a recent report from the Soós
group achieved an asymmetric Robinson annulation reaction
with a CHNaph2 derived bifunctional organocatalyst.[34]
squaramides. Thus,
a set of squaramides (6a-6f) were
evaluated (Table 4). It should be noted that 1,3-
diphenylpropane-1,3-dione was used to replace diethyl malonate
for the Michael addition of diethyl malonate to nitrostyrene
catalyzed by 6 didn’t work under our conditions. Meanwhile, 4
mol% catalysts were used for their poor solubility. The best-fit
Table 3. Cinchona alkaloid derived thioureas catalyzed Michael reaction.[a]
4g-B-S 0
4g-B-R 1.1
Yield(%)[b]
e.r.[c]
ΔΔG (er)
≠
[d]
Cat
5
a (Me)
81
75
52
90
56
62
49
87.1:12.9
86.1:13.9
85.5:14.5
88.5:11.5
84.0:16.0
90.5:9.5
1.133
1.079
1.049
1.209
1.084
1.336
0.586
5
b (Et)
5
c (iPr)
5
d (Bn)
e (cHex)
f (Ph)
g (tBu)
4g-A-S 0.9
4g-A-R 7.8
Figure 7. Relative energies and optimized transition-state geometries in the
model reaction catalyzed by 4g (units: kcal/mol).
5
5
5
72.9:27.1
[
a] The reaction was conducted with 1a (0.1 mmol), 2a (0.15 mmol) and 20
mol% catalyst in 0.4 mL toluene at room temperature for 48h. [b] Isolated yield.
≠
[
c] Determined by HPLC analysis. [d] ΔΔG =RTln(e.r.), R= 0.001986 kcal/K/mol,
T=298.15K.
(a)
(b)
≠
equation was determined as ∆∆G = -0.72*B -0.19*L+3.2. The
1
≠
plot of the predicted and experimentally measured ∆∆G values
shows a good linear correlation with a slope of 0.93 and a y
intercept of 0.077 (Figure 10). The correlation pointed out that
methyl, ethyl and benzyl substituents are still optimal candidates.
Interestingly, phenyl was not a suitable substituent for the
Michael addition studied here. It could be anticipated that
electronic perturbation of benzyl rather than phenyl may further
promote the enantioselectivity for this Michael reaction. This
finding is in line with the results reported by the Rawal group,
who firstly introduced 3,5-bis(trifluoromethyl)benzyl squaramide
to organocatalysis in 2008.[19] Though one could think that the
methyl group is too small to affect the enantioselectivities, the
good performance of methyl squaramide confirmed its value and
may make itself applicable in some transformations in future.[
Attractive
Repulsive
Figure 8. (a) Local nonovalent interactions in TS 4e-B-S
1
; (b) Representation
of 4e-B-S in Van der Waals radii.
1
We speculated the above mentioned FER relationship may
be universal in similar tertiary-amine (thio)ureas/squaramide
systems. Thus, two set of catalytic systems were next inspected
(
Table 3-4, Figure 9-10). For Cinchona alkaloid derived
≠
thioureas (5a-5g), the equation was determined as ∆∆G = -
.54*B +0.079*L+1.7. The slope of the plot is 0.91 and the
0
1
intercept is 0.067, which indicated the enantioselectivities
correlated well with the substituents (Figure 9). Since the methyl,
8o]
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Chemistry - A European Journal
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FULL PAPER


G (er) = -0.72*B
1
- 0.19*L+3.2
1
1
1
1
0
0
0
0
.3
.2
.1
.0
.9
.8
.7
.6
G (er) = -0.54*B
1
+ 0.079*L+1.7
Ph
1.6
1.4
Bn
y = 0.93x+0.077
y = 0.91x+0.096
Me
2
Et
R =0.93
2
R =0.91
cHex
Me
Et
Bn
1.2
1.0
0.8
iPr
iPr
Ph
tBu
0.6
0.4
tBu
0
.5
0.6
0.7
0.8
0.9
1.0
1.1
1.2
1.3
1.4
0.6
0.8
1.0
1.2
1.4
1.6


Experimental G (er) Kcal/mol
Experimental G (er) Kcal/mol
Figure 9. FER analysis of Cinchona alkaloid derived thioureas.
Figure 10. FER analysis of cyclohexane-1, 2-diamine derived squaramides.
Overall, we observed kindred FERs in the three classic
bifunctional hydrogen-bonding organocatalyst families, which
confirmed the steric effects on enantioselectivities at least in
Michael reactions. All FERs pointed out the Michael reactions
catalyzed under catalysts with less hindrance substituents would
be favorable. The observed FERs are independent of chiral
scaffold and hydrogen-bond donors, toning up our
Conclusions
In summary, we have conducted FER analyses of enantiomeric
ratios against the steric parameters for three type bifunctional
tertiary-amine thioureas/squaramides, including (S, S)-
cyclohexane-1, 2-diamine derived thioureas, Cinchona alkaloid
derived thioureas and (S, S)-cyclohexane-1, 2-diamine derived
squaramides, in Michael reactions. Kindred FERs revealed that
tertiary-amine hydrogen-bonding catalysts bearing an N-
substituent of smaller size should be promising catalyst
candidates, which are applicable for further electronic
modulations. DFT calculations were performed to investigate
high reactivity of alkyl thioureas as well as the peculiar
performance of a benzyl catalyst. The CH-π interaction was
proposed to interpret the high reactivity of benzyl catalyst.
Nevertheless, a complete mechanistic picture that accounts for
the observed correlation between steric parameters and
enantioselectivities is yet to emerge. More calculations are
underway in our laboratory.
understanding
thio)ureas/squaramides (Figure 3). The FER tactic may also
lend us much help to design new catalysts.
of
current
bifunctional
tertiary-amine
(
Table 4. Cyclohexane-1, 2-diamine derived squaramides catalyzed Michael
[
a]
reaction.
Yield(%)[b]
e.r.[c]
ΔΔG (er)
≠
[d]
Cat
Experimental Section
6
a (Me)
48
40
46
62
54
40
92.4:7.6
91.4:8.6
1.476
1.399
1.240
1.296
0.738
0.539
Catalysts 4b-4j were synthesized according to our previous report.[8o]
Synthesis of 4a.[35] Benzoyl isothiocyanate (6.0 mmol) was dissolved in
CH Cl (10 mL) and cooled to 0 °C. (S, S)-N,N-dimethylcyclohexane-1,2-
2 2
diamine (6.6 mmol) was added dropwise. The resulting mixture was
warmed to room temperature and stirred for 2h. Then, the mixture was
2 4
washed with water (5 mL), dried over Na SO . Concentration under
vaccum gave the N-((1S,2S)-2-(dimethylamino)cyclohexyl)benzamide as
a white solid in 83% yield. The obtained compound was dissolved in
ethanol (10 mL). Then aqueous potassium carbonate (0.76 g) was added.
The mixture was stirred at reflux temperature for 4h. When the reaction is
completed, the mixture was concentrated to a small volume and filtrated.
The product was washed with petroleum ether and dried in vacuo to give
6
b (Et)
6
c (iPr)
89.0:11.0
89.9:10.1
77.7:23.3
71.3:28.7
6
6
6
d (Bn)
e (Ph)
f (tBu)
[
a] The reaction was conducted with 1a (0.1 mmol), 2a (0.15 mmol) and 4 mol%
catalyst in 0.4 mL toluene at room temperature for 48h. [b] Isolated yield. [c]
Determined by HPLC analysis. [d] ΔΔG =RTln(e.r.), R= 0.001986 kcal/K/mol,
4
a as a white solid (0.3 g).
≠
T=298.15K.
General Procedure
quinidine (2.0 mmol) and corresponding isocyanate (2.1 mmol) were
stirred overnight in 5.0 ml dry CH Cl under argon atmosphere. Then the
A
for Synthesis of Catalysts 5.[13a] 9-amino
2
2
reaction mixture was concentrated in vacuo. The residue was subjected
to column chromatography on silica gel to afford the desired catalysts 5.
This article is protected by copyright. All rights reserved.

Chemistry - A European Journal
10.1002/chem.201605666
FULL PAPER
General Procedure B for Synthesis of Catalysts 6.[16a] Substituted
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2 2
amine (2.1 mmol) was added to a CH Cl solution of dimethylsquatate
(2.0 mmol) under argon atmosphere. The mixture was stirred for 24h.
Then it was filtered and the filtrate was washed with 1M HCl. The organic
layer was dried, filtered and concentrated to afford a mono-amino-
substituted squarate. The obtained squarate (1.0 mmol) was dissolved in
1
0mL MeOH under argon atmosphere. Then (S, S)-N,N-
dimethylcyclohexane-1,2-diamine (1.1 mmol) was added. After it was
stirred for 24h, the mixture was filtered. The precipitate was washed with
cold MeOH for three times to afford squaramide 6.
General procedure for Michael addition reactions. Nitrostyrene 1 (0.1
mmol) and diethyl malonate 2 (0.15 mmol) were stirred in 0.4 ml toluene
at room temperature in the presence of 20 mol % catalyst for 48h. The
reaction mixture was directly subjected to column chromatography on
silica gel (EtOAc: Petroleum ether 1:10) to afford the desired products 3.
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We are grateful to the Natural Science Foundation (Grant Nos.
1390400 and 21421062) for financial support.
2
Keywords: bifunctional hydrogen-bonding catalysis • free
energy relationship • density functional calculations • steric
analyses
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Chemistry - A European Journal
10.1002/chem.201605666
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http://www.ks.uiuc.edu/Research/vmd/.
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Chemistry - A European Journal
10.1002/chem.201605666
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Free energy relationship studies to
correlate steric parameters against
enantiocatalytic performance of
Chen Yang, Jie Wang, Yang Liu, Xiang
Ni, Xin Li,* and Jin-Pei Cheng
bifunctional tertiary-amine hydrogen-
bonding type catalysts, including (S,
S)-cyclohexane-1, 2-diamine derived
thioureas, Cinchona alkaloid derived
thioureas and (S, S)-cyclohexane-1,
Page No. – Page No.
Catalytic Behavior Study of
Bifunctional Hydrogen-Bonding
Catalysts Guided by Free Energy
Relationship Analyses of Steric
Parameters
2
-diamine derived squaramides, for
Michael reactions revealed that the
Michael reactions are much favored
by catalysts with less bulky N-
substituents.
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