Supporting Information
The Role of Benzoic Acid in Proline-Catalyzed Asymmetric Michael
Addition: A Density Functional Theory Study
Hongwei Shi, Xiangui Huang, Guixia Liu,* Kunqian Yu, Congying Xu, Weihua Li,
Bubing Zeng,* Yun Tang*
Contents
Figure S-1. The X-ray diffraction structure of asymmetric Michael addition between ketones and
nitroolefins catalyzed by L-proline. ………………………………………………………………………………………S2
Figure S-2. Energy profile (a) and optimized geometries (b) of the other reaction path of the
enamine formation and the enamine hydrolysis. The letter c represents proline.………………………S3
Figure S-3. The B3LYP/6-31G(d) optimized structures containing the p-substituted benzoic acid
derivatives. The distance unit is Å.…………………………………………………………………………………………S4
Figure S-4. The B3LYP/6-31G(d) optimized structures involving m/o-substituted benzoic acid
derivatives. The distance unit is Å.…………………………………………………………………………………………S5
Figure S-5. The B3LYP/6-31G(d) optimized structures of the other possible reaction paths with
m/o-substituted benzoic acid derivatives in the stage of enamine formation. The distance unit is
Å.…………………………………………………………………………………………………………………………………………S7
Table S-1. Total (au) and relative energies (kcal/mol) of the equilibrium geometries and the
transition states at the B3LYP/6-311+G(2df,p) level with zero-point energy corrections
(au). ……………………………………………………………………………………………………………………………………S8
Table S-2. The atom coordinates of r and p.……………………………………………………………………………S9
Synthesis method
………………………………………………………………………………………………………………S11
S1
Figure S-1. The X-ray diffraction structure of asymmetric Michael addition between ketones
and nitroolefins catalyzed by L-proline.
S2
1snts
40.5
8snts
Relative Energy (kcal/mol)
35.9
9snts
29.8
1snp
10.5
r+c 1snr
0
1.2
8snp
4.4
8snr
0.2
9snr
p+c
-3.5 9snp
-9.1
-7.2
(a)
1.340
1.241
1.900
1snr
1.600
1snts
1.166
2.354
1snp
1.581
2.562
8snr
8snts
8snp
1.360
1.587
1.231
9snr
9snts
3.096
9snp
(b)
Figure S-2. Energy profile (a) and optimized geometries (b) of the other reaction path of the
enamine formation and the enamine hydrolysis. The letter c represents proline.
S3
1.594
1.278
1.361
4pnhr
1.823
4pnhts
4pnhp
1.577
1.854
1.372
4pochr
1.266
4pochts
4pochp
1.857
1.375
1.263
1.566
4pchr
1.586
4pnoar
4pchts
1.154
1.254
4pchp
1.547
4pnoats
1.543
4pnoap
1.934
1.241
1.400
4pnobr
4pnobts
4pnobp
Figure S-3. The B3LYP/6-31G(d) optimized structures containing the p-substituted benzoic
acid derivatives. The distance unit is Å.
S4
1.464
1.629
1.239
1.178
4oar
4oats
4oap
1.819
1.467
1.243
1.403
4obr
4obts
4obp
1.623
1.193
1.218
4mar
1.500
4mats
4map
1.500
1.236
1.837
1.404
4mbr
1.572
4mbts
1.165
1.247
4moar
4mbp
1.464
4moats
S5
4moap
1.287
1.483
4mobr
1.887
1.359
4mobts
4mobp
Figure S-4. The B3LYP/6-31G(d) optimized structures involving m/o-substituted benzoic
acid derivatives. The distance unit is Å.
S6
1.836
1.591
1.277
1.364
4oantir
4oantits
1.252
1.558
4oantip
1.860
1.387
4mantir
1.671
2.484
4mantits
1.167
1.248
4moantiar
4mantip
1.463
4moantiats
2.191
4moantiap
1.887
1.527
2.450
4moantibr
1.271
1.376
4moantibts
4moantibp
Figure S-5. The B3LYP/6-31G(d) optimized structures of the other possible reaction paths
with m/o-substituted benzoic acid derivatives in the stage of enamine formation. The
distance unit is Å.
S7
Table S-1. Total (au) and relative energies (kcal/mol) of the equilibrium geometries and the
transition states at the B3LYP/6-311+G(2df,p) level with zero-point energy corrections (au).
species
ZPVE
B3LYP/6-31G(d)
TE
B3LYP/6-311+G(2df,p)
RE
4oantir
0.481234
-4195.157661
0
4oantits
0.476852
-4195.135504
13.9
4oantip
0.481592
-4195.143648
8.8
4mantir
0.48059
-4195.166216
0
4mantits
0.476374
-4195.144045
13.9
4mantip
0.481131
-4195.149861
10.3
4moantiar
0.513445
-4309.684014
0
4moantiats
0.50906
-4309.683812
0.1
4moantiap
0.512675
-4309.679266
3.0
4moantibr
0.513614
-4309.675009
5.7
4moantibts
0.509202
-4309.665374
11.7
4moantibp
0.51373
-4309.675487
5.4
S8
Table S-2. The atom coordinates of r and p.
r (B3LYP/6-311+G(2df,p)//B3LYP/6-31G(d), HF=-3335.2668628 a.u., frequencies are all
positive)
01
C
C
C
C
C
H
H
H
N
Br
C
H
C
C
H
C
H
C
C
H
H
N
O
O
O
H
H
H
-2.93988600
-1.53046100
-0.38513100
-0.60599900
-1.90037800
-1.42478200
0.21541400
-2.10052700
-2.78054400
-4.73929000
0.90985800
0.87372100
2.13403800
2.54478500
3.26409000
3.17444300
2.50314500
3.52738100
4.26261000
3.73317100
5.25771300
3.24619700
3.01285700
4.38060700
3.23408900
4.08203400
1.67451800
4.36909700
-0.06773400
-1.84354900
-1.03769700
0.34574600
0.84685900
-2.92353300
1.02925800
1.90539400
-1.37411300
0.59058200
-1.71239400
-2.76774100
-1.22757400
0.12718100
0.00268600
1.02348700
1.14651800
2.41044700
3.32606300
3.39643700
2.91612100
-2.19711800
-3.35080400
-1.78522600
2.75809600
0.55719500
0.62434700
4.32002100
-0.04105400
0.03069500
-0.11509000
-0.26412700
-0.22629600
0.12194700
-0.44337000
-0.34639200
0.07865700
0.02795100
-0.13481000
-0.39132900
0.15449200
0.64796200
1.46199200
-0.43149600
-1.29463500
0.09295600
-0.86487700
-1.82260500
-1.08052800
0.01712400
-0.35062700
0.28047400
1.22435500
-0.83475700
1.08265200
-0.42547000
p (B3LYP/6-311+G(2df,p)//B3LYP/6-31G(d), HF=-3335.2853509 a.u., frequencies are all
positive)
01
C
C
C
2.58788000
0.54801900
-0.12915700
-0.25164500
-0.51276900
-0.28524300
0.04174700
-0.92443700
0.27922800
S9
C
C
H
H
H
N
Br
C
C
C
H
C
H
C
H
H
C
H
H
H
H
N
O
O
O
0.65849700
2.04612900
0.00170600
0.18789700
2.68052300
1.88387300
4.50353700
-1.64595300
-2.32052900
-2.23535800
-1.92032400
-3.84378400
-2.05647500
-3.75836900
-1.93780500
-1.84477300
-4.45050800
-4.28752300
-4.06359100
-5.51961300
-4.33420700
-1.77190600
-1.86206200
-1.27351700
-4.37124400
-0.02338300
-0.00557200
-0.71971100
0.16635800
0.19147600
-0.49654300
-0.23921600
-0.31043300
0.80926300
-1.67993300
-0.13874400
0.81824200
0.74530100
-1.70565200
-1.90487600
-2.47770600
-0.53352800
1.62643100
1.01879000
-0.56967700
-0.66351900
2.15287400
2.43819400
2.87708100
-2.61676800
1.40796700
1.30287300
-1.84330800
2.36937500
2.15937900
-1.04688000
-0.15226800
0.37343300
-0.45184200
-0.05439500
1.42145600
-0.25999100
-1.51123700
-0.00373900
-1.08930300
0.58345700
-0.68058200
-0.85201500
0.79514100
-0.45466600
-1.76732200
-0.00885100
1.18447700
-0.86539200
0.52178700
S10
Synthesis method
General information
Unless otherwise stated, all reagents and solvents were obtained from commercial sources
without purification. Column chromatography was carried out on silica gel (300 ~ 400 µm).
Melting points were determined using a digital melting-point apparatus and were uncorrected. 1H
NMR and
13
C NMR spectra were recorded on a spectrometer (400 MHz and 100 MHz,
respectively) using TMS as internal standard. HRMS data were determined by ESI ionization.
Enantiomeric excesses were determined by chiral HPLC.
3-(6-Bromopyridin-3-yl)-4-nitrocyclohexanone
A solution of (E)-6-(6-bromopyridin-3-yl)-5-nitrohex-5-en-2-one (60 mg, 0.2 mmol),
L-proline (4.6 mg, 0.04 mmol) and benzoic acid derivatives (0.2 mmol) in DMSO (5.0 mL) was
stirred at room temperature for appropriate time. After the completion of the reaction indicated by
TLC, the reaction was quenched with saturated NaHCO3 (10 mL), and extracted with EtOAc (2
x15 mL). The extract was washed with water, brine and dried over anhydrous Na2SO4. The
solvent was evaporated in vacuo, and the residue was purified by column chromatography on
silica gel to afford the desired product as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.29 (d, J =
2.0 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.44 (dd, J1 = 2.4 Hz, J2 = 8.4 Hz, 1H), 5.05 - 5.00 (m, 1H),
3.74 - 3.67 (m, 1H), 2.73 - 2.46 (m, 6H);
13C
NMR (100 MHz, CDCl3) δ 204.0, 149.1, 142.1,
137.0, 133.0, 128.6, 87.3, 44.9, 43.9, 37.9, 29.6; MS(ESI): m/z = 296.9 [M - H]-; HRMS (ESI):
m/z [M + H]+ calcd for C11H12BrN2O3: 299.0031; found: 299.0029.
S11