Thermodynamics and kinetics of the hydride-transfer cycles for 1-aryl-1,4-dihydronicotinamide and its 1,2-dihydroisomer

Article abstract of DOI:10.1002/chem.200304714

Five 1-(p-substituted phenyl)-1,4-dihydronicotinamides (GPNAH-1,4-H ₂) and five 1-(p-substituted phenyl)-1,2-dihydronicotinamides (GPNAH-1,2-H₂) were synthesized, which were used to mimic NAD(P)H coenzyme and its 1,2-dihydroisomer re

Full text of DOI:10.1002/chem.200304714

FULL PAPER
Thermodynamics and Kinetics of the Hydride-Transfer Cycles for
1-Aryl-1,4-dihydronicotinamide and Its 1,2-Dihydroisomer
Xiao-Qing Zhu,* Lei Cao, Yang Liu, Yuan Yang, Jin-Yong Lu, Jian-Shuang Wang,
and Jin-Pei Cheng*[a]
Abstract: Five 1-(p-substituted phenyl)-
1,4-dihydronicotinamides (GPNAH-1,4-
H2) and five 1-(p-substituted phenyl)-
1,2-dihydronicotinamides (GPNAH-1,2-
H2) were synthesized, which were used
to mimic NAD(P)H coenzyme and its
1,2-dihydroisomer reductions, respec-
tively. When the 1,4-dihydropyridine
(GPNAH-1,4-H2) and the 1,2-dihy-
droisomer (GPNAH-1,2-H2) were treat-
ed with p-trifluoromethylbenzylidene-
malononitrile (S) as a hydride acceptor,
both reactions gave the same products:
transfer from the corresponding 1,4-
dihydroisomer, but the kinetic examina-
tion displays that the former reaction is
remarkably slower than the latter reac-
tion, which is mainly due to much more
negative activation entropy for the for-
mer reaction. When the formed pyridi-
4-position on the pyridinium ring in
GPNA is much easier to accept the
‡
hydride than the 2-position, which in-
dicates that when the 1,4-dihydropyri-
dine is used the hydride donor to react
with S, the formed pyridinium derivative
‡
GPNA may return to the 1,4-dihydro-
‡
nium derivative (GPNA ) was treated
pyridine by a hydride transfer cycle; but
when the 1,2-dihydropyridine is used as
the hydride donor, the formed pyridini-
um derivative can not return to the 1,2-
dihydropyridine by the hydride reverse
with SHÀ, the major reduced product
was the corresponding 1,4-dihydropyri-
dine along with a trace ofthe 1,2-
dihydroisomer. Thermodynamic and ki-
netic analyses on the hydride transfer
‡
transfer from SHÀ to GPNA . These
‡
‡
pyridinium derivative (GPNA ) and
from SHÀ to GPNA all suggest that the
results clearly show that the hydride-
transfer cycle is favorable for the 1,4-
dihydronicotinamides, but unfavorable
for the corresponding 1,2-dihydroisom-
ers.
carbanion SHÀ by a hydride one-step
transfer. Thermodynamic analysis on
the two reactions shows that the hydride
transfer from the 1,2-dihydropyridine is
much more favorable than the hydride
Keywords:
kinetics
hydride transfer
¥ nicotinamide
¥
¥
thermodynamics
a derivative of1,4-dihydropyridine rather than a derivative of
1,2-dihydropyridine.[1, 4] From then on, various of1,4-dihydro-
pyridine derivatives such as 1-benzyl-1,4-dihydronicotinamide
(BNAH),[5] Hantzsch 1,4-dihydropyridine (HEH),[6] 10-meth-
yl-9,10-dihydroacridine (AcrH2)[7] and many other 1,4-dihy-
dropyridine derivatives[8] have been extensively used to mimic
NAD(P)H reduction; this, ofcourse, introduced an interest-
ing question as to why NAD(P)H coenzyme in its biological
evolution chooses 1,4-dihydropyridine rather than the 1,2-
dihydropyridine structure as its redox active center in its
reversible hydride transfer cycle [Eq. (1)]. The answer could
result mainly from regiochemistry control of the enzyme. But
the difference between NAD(P)H and its 1,2-dihydroisomer
in thermodynamics and kinetics caused by the different
structures in the hydride transfer cycles still is not clear up till
now; this obviously is important and necessary to understand
the biological evolution ofNAD(P)H coenzyme of r the 1,4-
dihydropyridine rather than the 1,2-dihydroisomer as the
reaction center structure.
Introduction
The reduced form of the nicotinamide-adenine dinucleotide
coenzyme [NAD(P)H] with 1,4-dihydropyridine ring plays a
vital role in many bio-reductions in living bodies by transfer a
hydride ion to the surrounding substrates [Eq. (1)].[1 3] In the
past decades studies, the structure and chemical properties of
NAD(P)H have been an interesting issue. Before the 1950s,
NAD(P)H was generally believed to be a derivative of1,2-
dihydropyridine and at that time some researchers devoted
their academic career to the study on the reaction mechanism
ofNAD(P)H by using small molecule derivatives of1,2-
dihydropyridine as NAD(P)H model compounds.[1, 4] Until
the late 1950s, NAD(P)H was unambiguously identified to be
[a] Prof. X.-Q. Zhu, Prof. J.-P. Cheng, L. Cao, Y. Liu,
Y. Yang, J.-Y. Lu, J.-S. Wang
Department ofChemistry,
State Key Laboratory ofElemento-Organic Chemistry
Nankai University, Tianjin 300071 (China)
Fax: 0086-022-23502458
In this article, we wish to elucidate the question by using a
chemical mimic method. Compounds 1-(p-substituted phe-
E-mail: xqzhu@nankai.edu.cn
Chem. Eur. J. 2003, 9, 3937 3945
DOI: 10.1002/chem.200304714
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3937

X.-Q. Zhu, J.-P. Cheng et al.
FULL PAPER
(1)
nyl)-1,4-dihydronicotinamides (GPNAH-1,4-H2) and their
1,2-dihydroisomers (GPNAH-1,2-H2) (Scheme 1) were used
as NAD(P)H and its 1,2-dihydroisomer models, p-trifluoro-
methylbenzylidenemalononitrile (S) was used as a hydride
reaction mixtures; no remarkable inhibitory effect on the two
reaction rates was observed. Redox potentials ofthe reactants
in Equations (2) and (3) were determined by cyclic voltam-
metry at 100 mVsÀ1 in acetonitrile. The results show that the
oxidation potentials ofthe dihydropyridines cover 0.281
0.400 V (vs Fc‡/0) for GPNAH-1,4-H2 and 0.199 0.302 V (vs
Fc‡/0) for GPNAH-1,2-H2 and the reduction potential of p-
trifluoromethylbenzylidene-malononitrile (S) is À1.229 V (vs
Fc‡/0). Free energy changes ofone electron transfer from the
1,4-dihydropyridines and the 1,2-dihydropyridines to S were
estimated by using Nernst equation. The detailed results are
summarized in Table 1.
Table 1. Oxidation potentials ofthe 1,4- and 1,2-dihydropyridines (V vs
Fc‡/0) and free energy changes of one electron transfer from the 1,4- and
1,2-dihydropyridines to S [kcalmolÀ1].
Scheme 1.
‡/0 [a]
[b]
NAD(P)H models
Eox (V vs Fc
)
DGeT [kcalmolÀ1
]
acceptor. From the experimental results, it is interesting to
find that i) the 1,4-dihydronicotinamides are more stable by
about 1.5 kcalmolÀ1 than the corresponding 1,2-dihydroisom-
ers to release a hydride, but the activation free energy of the
hydride transfer from the 1,4-dihydropyridines to S is smaller
than that from the corresponding 1,2-dihydroisomer by about
2 kcalmolÀ1; ii) the 4-position on the pyridinium generated
from the 1,4- or 1,2-dihydronicotinamides is quite favorable to
accept a hydride than the corresponding 2-position in
thermodynamics and kinetics. These results show that the
active center ofNAD(P)H should be also more favorable in
thermodynamics and kinetics to choose 1,4-dihydropyridine
rather than 1,2-dihydropyridine by the hydride transfer cycle
without the steric control ofenzyme.
CH3OPNAH-1,4-H2
CH3PNAH-1,4-H2
PNAH-1,4-H2
ClPNAH-1,4-H2
BrPNAH-1,4-H2
CH3OPNAH-1,2-H2
CH3PNAH-1,2-H2
PNAH-1,2-H2
0.281
0.313
0.363
0.395
0.400
0.199
0.222
0.251
0.297
0.302
34.83
35.55
36.72
37.44
37.56
32.92
33.47
34.14
35.19
35.31
ClPNAH-1,2-H2
BrPNAH-1,2-H2
[a] Measured by CV in MeCN at 258C and reproducible to 5 mV or better.
[b] Free energy changes of one electron transfer from the NAD(P)H
models to S were obtained from the equation DGeT ꢀ À 23.06 [Ered(S) À
Eox(GPNAH)] [kcalmolÀ1], taking Ered(S) ˆ À1.229 (V vs Fc‡/0).
Kinetics ofthe two reactions [Eqs. (2) and (3)] were
conveniently monitored with UV/Vis absorption spectra by
Results
1-(p-Substituted phenyl)-1,4-dihydronicotinamides (GPNAH-
1,4-H2)[9] and their corresponding 1,2-dihydroisomers
(GPNAH-1,2-H2)[10] were synthesized according to literature
method and were treated with p-trifluoromethylbenzylidene-
malononitrile (S) in acetonitrile/methanol (9:1 v/v) at room
temperature under argon atmosphere, to give the 1-(p-
(2)
‡
substituted phenyl)nicotinamide cations (GPNA , as
‡
NAD(P) models) and 2-(p-trifluoromethylbenzyl)malononi-
trile (SH2) [Eqs. (2) and (3)]. 4,4-Dideuterated PNAH-1,4-H2
(PNAH-4,4-D2) was used as a substitute for PNAH-1,4-H2 to
react with S under the same conditions; one deuterium atom
was found to be located at the b-position to the cyano group in
the reduced product 2-(p-trifluoromethylbenzyl)malononi-
trile by 1H NMR and MS spectral data. p-Dinitrobenzene (p-
DNB), a stronger electron acceptor,[11] was added into the two
(3)
following the time dependence of the absorbance at lmax
390 nm for the 1,2-dihydropyridines (Figure 1) and at lmax
ˆ
ˆ
3938
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Chem. Eur. J. 2003, 9, 3937 3945

Hydride-Transfer Cycles
3937 3945
Table 3. Activation parameters for the reductions of S with GPNAH-1,4-
H2 and GPNAH-1,2-H2 in acetonitrile/methanol.
[a]
NA(P)H models
DEa
DH=[b]
DS=[c]
À TDS=[d]
GPNAH-1,4-H2
p-OCH3
p-CH3
p-H
p-Cl
15.7 Æ 0.9
16.0 Æ 0.9
17.2 Æ 0.7
18.0 Æ 0.7
17.8 Æ 0.9
15.1 Æ 0.9
15.4 Æ 0.9
16.6 Æ 0.7
17.4 Æ 0.7
17.2 Æ 0.9
À 14.4 Æ 2.8
À 13.7 Æ 2.9
À 10.0 Æ 2.2
À 8.1 Æ 2.2
À 8.8 Æ 2.9
4.3 Æ 0.8
4.1 Æ 0.9
3.0 Æ 0.6
2.4 Æ 0.6
2.6 Æ 0.9
p-Br
GPNAH-1,2-H2
p-OCH3
p-CH3
p-H
p-Cl
10.3 Æ 0.6
10.5 Æ 0.6
10.8 Æ 0.6
11.5 Æ 0.6
11.2 Æ 0.6
9.7 Æ 0.6
9.9 Æ 0.6
À 34.9 Æ 1.8
À 34.3 Æ 2.1
À 33.6 Æ 1.8
À 31.9 Æ 1.8
À 32.5 Æ 1.8
10.4 Æ 0.5
10.2 Æ 0.6
10.0 Æ 0.5
9.5 Æ 0.5
9.7 Æ 0.5
10.2 Æ 0.5
10.9 Æ 0.5
10.7 Æ 0.5
p-Br
Figure 1. Change in the UV/Vis absorption spectra during the reduction of
S by PNAH-1,2-H2. Conditions: 0.127mm PNAH-1,2-H2, 10.62mm S in
CH3CN/CH3OH at 258C. Spectra were recorded at 10 min intervals. Inset:
Decay curve ofPNAH-1,2-H 2 by S at lmax ˆ 390 nm.
[a] From the Arrhenius plots, the unit is [kcalmolÀ1]. [b] From the slope of
the Eyring plots, the unit is [kcalmolÀ1]. [c] From the intercept ofthe
Eyring plots, the unit is [calmolÀ1 KÀ1]. [d] The unit is [kcalmolÀ1].
‡
(AcrH ) iodide in dry acetonitrile [Eqs. (4) and (5)]. The
‡
360 nm for the 1,4-dihydropyridines under pseudo-first-order
reaction conditions with S in more than 25-fold excess. The
pseudo-first-order rate constants were calculated by Guggen-
heim×s method.[12] The second-order rate constants (k2) at
different temperature between
heat ofreaction of N-methylacridinium (AcrH ) iodide with
GPNAH-1,4-H2, GPNAH-1,2-H2 and SHÀ can be directly
determined by titration calorimetry, respectively (Figure 2).
The detailed experimental results are listed in Table 4.
25 and 458C are given in Ta-
ble 2, which were derived from
(4)
the slopes ofthe plots ofthe
pseudo-first-order rate con-
stants versus the concentrations
of S. Arrhenius activation energy (DEa) and Eyring activation
parameters: activation enthalpy (DH=) and activation entropy
(DS=) for the two reactions [Eqs. (2) and (3)] were summar-
ized in Table 3, which were derived from Arrhenius plots of
lnk2 and Eyring plots ofln( k2/T) versus the reciprocal ofthe
absolute temperature (1/T), respectively.
(5)
À
Heterolytic dissociation energies ofC H bond for the 1,4-
4
dihydropyridines (GPNAH-1,4-H2) and C2-H bond for the
1,2-dihydropyridines (GPNAH-1,2-H2) as well as Cb-H bond
for SHÀ to release a hydride were obtained from their
corresponding heat ofreaction with N-methylacridinium
Table 2. Second-order
rate
]
constants
for the reductions of
k2(GPNAH-1,4-H2)
and
k2(GPNAH-1,2-H2) [mÀ1sÀ1
S
in acetonitrile/
methanol at different temperatures between 25 and 458C.[a]
T[8C]
k2(GPNAH-1,4-H2) Â 102
p-OMe
p-CH3
p-H
p-Cl
p-Br
25
30
35
40
45
4.19 Æ 0.02 3.52 Æ 0.01 2.64 Æ 0.02 1.89 Æ 0.02 1.95 Æ 0.02
5.74 Æ 0.02 5.19 Æ 0.02 4.02 Æ 0.02 2.95 Æ 0.02 2.86 Æ 0.01
9.73 Æ 0.03 8.43 Æ 0.02 6.97 Æ 0.02 5.21 Æ 0.02 5.19 Æ 0.02
14.49 Æ 0.03 12.02 Æ 0.02 10.69 Æ 0.03 8.15 Æ 0.03 8.07 Æ 0.09
23.23 Æ 0.22 21.18 Æ 0.18 17.62 Æ 0.15 13.74 Æ 0.12 13.68 Æ 0.11
‡
Figure 2. Titrated calibration graph: AcrH in acetonitrile was titrated
into p-trifluoromethylbenzyl- malononitrile-2-yl carbanion (SHÀ) in ace-
tonitrile solution ([SHÀ] ꢀ0.011m, [AcrH ] ˆ 0.0105m). DHrxn
ˆ
‡
18.0 kcalmolÀ1
.
T[8C]
k2(GPNAH-1,2-H2) Â 102
25
30
35
40
45
1.23 Æ 0.01
1.54 Æ 0.01
2.20 Æ 0.02
2.77 Æ 0.04
3.81 Æ 0.04
1.12 Æ 0.02 0.96 Æ 0.02 0.76 Æ 0.02 0.77 Æ 0.02
1.40 Æ 0.02 1.22 Æ 0.02 1.00 Æ 0.02 1.01 Æ 0.02
2.04 Æ 0.02 1.77 Æ 0.03 1.48 Æ 0.03 1.49 Æ 0.02
2.56 Æ 0.03 2.27 Æ 0.02 1.91 Æ 0.03 1.91 Æ 0.04
3.55 Æ 0.04 3.14 Æ 0.04 2.69 Æ 0.04 2.66 Æ 0.04
Discussion
Mechanisms of the two reactions [Eqs. (2) and (3)]: Accord-
ing to the product analysis and the isotope deuterium atom
tracing experiment mentioned above, it is conceived that the
reactions ofGPNAH-1,4-H 2 and GPNAH-1,2-H2 with S were
[a] Second-order rate constants k2 were obtained from the corresponding
pseudo-first-order rate constants by the linear correlation against the
concentration of S.
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X.-Q. Zhu, J.-P. Cheng et al.
FULL PAPER
‡
Table 4. Heat ofreaction ofAcrH
with the 1,4-dihydropyridines, 1,2-
dihydropyridines and SHÀ in dry acetonitrile and the heterolytic C4-H, C2-H
and Cb-H bond dissociation energies in the 1,4-dihydropyridines, 1,2-
dihydropyridines and SHÀ in acetonitrile [kcalmolÀ1].
[a]
[b]
À
Compounds
DHrxn
DHhet(C H)
CH3OPNAH-1,4-H2
CH3PNAH-1,4-H2
PNAH-1,4-H2
ClPNAH-1,4-H2
BrPNAH-1,4-H2
14.7
13.6
12.0
10.5
10.8
68.3
69.4
71.0
72.5
72.2
CH3OPNAH-1,2-H2
CH3PNAH-1,2-H2
PNAH-1,2-H2
ClPNAH-1,2-H2
BrPNAH-1,2-H2
16.2
15.1
13.5
11.7
12.2
66.8
67.9
69.5
71.3
70.9
Figure 3. Correlation oflog k2 (at 258C) versus s constants for the
&
*
reactions ofGPNAH-1,4-H 2 ( ) and GPNAH-1,2-H2 ( ) with S.
SHÀ
18.0
65.0
‡
[a] The reaction heats ofAcrH with the 1,4-dihydropyridines (GPNAH-
1,4-H2), 1,2-dihydropyridines (GPNAH-1,2-H2) and SHÀ measured by
titration calorimetry in dry CH3CN at 258C. The data obtained were
average values ofat least two independent runs, each ofwhich was again an
average value of 10 consecutive titrations except for the first. The
reproducibility is 0.5 Æ 0.2 kcalmolÀ1. [b] Obtained from the equation
states.[17] Due to the significant dependence of the logk2 on the
remote substituent G and the negative 1 values for the two
reactions, the rate-limiting step should be the initial hydride
transfer rather than the second step protonation of SHÀ; this
indicates that the reaction rates of S with the dihydropyridines
obtained by following the disappearance of the dihydropyr-
idines (Table 2) should be controlled by the initial hydride
transfer rather than the second step protonation of SHÀ.
DHhet(C H) ˆ DHhet(AcrH2) À DHrxn, taking DHhet(AcrH2) ˆ 83 kcalmolÀ1
À
in acetonitrile from ref. [13]. Standard deviation was estimated to be
smaller than 1 kcalmolÀ1
.
carried out first by a formal hydride transfer from the
dihydropyridines (GPNAH-1,4-H2 and GPNAH-1,2-H2) to
the b-position to cyano group in the substrate S. No
remarkable inhibitory effect of p-dinitrobenzene on the two
reaction rates[14] and the estimation oflarge positive rfee
energy changes for one electron transfer from the dihydro-
pyridines to S (see Table 1) suggest that the formal hydride
transfer from the dihydropyridines to S could not be initiated
by single electron transfer.[15] A tentative reduction mecha-
nism of S by GPNAH may be proposed as shown in Scheme 2:
a hydride departs from the dihydropyridines first attached the
b-carbon of S to form a carbanion intermediate SHÀ, which
then attracts a proton from methanol to form the final
reduction product SH2.
Thermodynamics and kinetics of the initial hydride transfer
and the hydride reverse transfer: In order to elucidate the
difference of the redox reactivity between NAD(P)H and its
1,2-dihydroisomer caused by the different center structures in
the hydride transfer cycles, thermodynamics and kinetics of
the hydride transfer from the two types of dihydropyridines to
S and the hydride reverse transfer in Scheme 2 were
examined. The standard state energy change and the activa-
tion free energy for the initial hydride forward transfer were
obtained from the heterolytic dissociation energies of the
[18]
À
related C H bonds (Table 4)
and from the relationship
DG=ˆ DH=À TDS=, respectively. The detailed results are
summarized in Table 5.
In order to determine the rate-limiting step in the reaction
route (Scheme 2), Hammett-type free energy analyses of the
two reactions were made, which provide two excellent straight
lines oflog k2 against the s constant ofthe substituents G with
reaction constant 1 values of À0.672 and À0.413 for the 1,4-
dihydropyridines and for the 1,2-dihydropyridines as the
hydride donors, respectively (Figure 3). The negative 1 values
indicate the developing positive charge on the pyridine ring in
the rate-limiting step.[16] The magnitude ofthe 1 values is a
measure ofthe increase ofthe efective positive charge at the
1-position nitrogen atom on the pyridine ring in going from
the dihydropyridines to their corresponding transition
The standard state energy change and the corresponding
activation free energy for the hydride transfer from SHÀ to
GPNA (the hydride reverse transfer) were obtained accord-
ing to the principle of microscopic reversibility,[19] that is under
the same conditions, the mechanism for the hydride forward
transfer is the same as that for the hydride reverse transfer
(see Figure 4) and the detailed thermodynamic and kinetic
data were listed in Table 6.[20]
The most eye-catching feature in the second column of
Table 5 is that the standard state energy changes ofthe initial
hydride transfer from the 1,4-dihydropyridines and from the
1,2-dihydropyridines to S are all positive values, which
‡
Scheme 2.
3940
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Chem. Eur. J. 2003, 9, 3937 3945

Hydride-Transfer Cycles
3937 3945
Table 5. Standard state energy change and activation free energies of the
hydride transfer from the 1,4-dihydripyridines and the 1,2-dihydropyridines
to S (hydride forward transfer) in acetonitrile solution [kcalmolÀ1].
indicates that the initial hydride transfer from the 1,4- or 1,2-
dihydropyridines are not spontaneous in thermodynamics.[21]
Evidently, the initial hydride transfer requires some energies
which can easily be compensated from the follow-up proto-
nation of SHÀ. The experimental results that no reactions of
the dihydropyridines with S were observed in dry acetonitrile
without methanol may be used to support this. From the
comparison ofthe changes in energy ofthe hydride of rward
transfer from the 1,4-dihydropyridines and from the 1,2-
dihydropyridines to S, it is clear that the energy required for
the hydride transfer from the 1,4-dihydropyridines to S is
larger than the energy required for the hydride transfer from
the corresponding 1,2-dihydropyridines to S; the reason is that
the heterolytic dissociation energy ofthe C 4-H bond in the 1,4-
NAD(P)H models
DH(HÀT) (forward)[a]
DG= (forward)[b]
GPNAH-1,4-H2
CH3O
CH3
H
Cl
3.3
4.4
6.0
7.5
7.2
19.4
19.5
19.6
19.8
19.8
Br
GPNAH-1,2-H2
CH3O
CH3
H
Cl
Br
1.8
2.9
4.5
6.3
5.9
20.1
20.1
20.2
20.4
20.4
À
dihydropyridines is larger than that ofthe C H bond in the
[a] DH(HÀT) ˆ DHhet(GPNAH) À DHhet(SHÀ). [b] Obtained from the
equation of DG=(forward) ˆ DH=(forward) À TDS=(forward). The values
of DH= and DS= can be obtained from Table 3.
2
corresponding 1,2-dihydropyridines, which appears to indi-
cate that the hydride transfer from the 1,2-hydropyridines to S
should be faster than the hydride
transfer from the 1,4-hydropyridines
to S, but the experimental results
show that the cases are just reverse
(see Table 2),[18] the reason is that the
activation free energies of the hydride
transfer from the 1,2-dihydropyridnes
(20.1 20.4 kcalmolÀ1) are generally
larger than that ofthe hydride trans-
fer from the corresponding 1,4-dihy-
dropyridnes (19.4 19.8 kcalmolÀ1).
Detailed comparison ofthe values of
DH= and the values of ÀTDS= in
Table 3 for the two reactions shows
that for the hydride transfer from the
1,4-dihydropyridines to S, the DH= is
larger (in an absolute sense) than the
corresponding ÀTDS= by 10.7
14.6 kcalmolÀ1
; this indicates that
the hydride transfer from the 1,4-
dihydropyridines to S is mainly con-
trolled by activation enthalpy, but for
the reaction with the 1,2-dihydropyr-
idines, the DH= is not larger than the
Figure 4. Reaction coordinate diagram for the hydride transfer from 1-phenyl-1,2-dihydronicotinamide
(PNAH-1,2-H2) and from 1-phenyl-1,4-dihydronicotinamide (PNAH-1,4-H2) to S and for the hydride
reverse transfers.
Table 6. Standard state energy change and activation free energies of the
corresponding ÀTDS=, which indicates that the hydride
transfer from the 1,2-dihydropyridines to S is not only
controlled by activation enthalpy but also quite more
controlled by activation entropy. Obviously the latter is a
main factor which makes the activation free energy of the
hydride transfer from the 1,2-dihydropyridines to S larger
than that of the hydride transfer from the 1,4-dihydropyr-
idines to S. According to the structures ofthe 1,4-dihydropyr-
idines and 1,2-dihydropyridines, it is clear that in the 1,4-
dihydropyridines only one substituent resides proximate to
the reaction center to repulse the substrate in the transition
state, whereas in the 1,2-dihydropyridines there are two
substituents located at the ortho-positions to repulse the
approach ofthe substrate in the transition state (see
Scheme 4); this can be used to explain why the activation
entropy (DS=) for the hydride transfer from the 1,2-dihydro-
pyridines to S (À31.9 À 34.9 calmolÀ1 KÀ1) is much more
negative than that for the hydride transfer from the
‡
hydride transfer to the 4-position and to the 2-position in GPNA from SHÀ
(hydride reverse transfer) in acetonitrile solution [kcalmolÀ1].
‡
NAD(P) models
DH(HÀT) (reverse)[a]
DG= (reverse)[b]
attack to the 4-position
‡
CH3OPNA
À 3.3
À 4.4
À 6.0
À 7.5
À 7.2
16.1
15.1
13.6
12.3
12.6
‡
CH3PNA
‡
PNA
‡
ClPNA
‡
BrPNA
attack to the 2-position
‡
CH3OPNA
À 1.8
À 2.9
À 4.5
À 6.3
À 5.9
18.3
17.2
15.7
14.1
14.5
‡
CH3PNA
‡
PNA
ClPNA
‡
‡
BrPNA
[a] Obtained from the equation of DH(HÀT)(reverse) ˆ ÀDH(HÀT)(for-
ward), the unit is kcalmolÀ1. The related data were listed in Table 4.
[b] Calculated according to the equation of DG=(reverse) ˆ
DG=(forward) À DH(HÀT)(forward), the unit is kcalmolÀ1. The related
data were listed in Table 3.
Chem. Eur. J. 2003, 9, 3937 3945
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3941

X.-Q. Zhu, J.-P. Cheng et al.
FULL PAPER
[22]
corresponding
1,4-dihydropyridines
to
S
(À8.8
product (the yield ofmore than 90%)
with a trace ofthe
1,2-dihydroisomer,[23] which is well consistent with the as-
sumptions made according to the thermodynamic and kinetic
analyses above mentioned.
À 14.4 calmolÀ1 KÀ1).
For the hydride transfer from SHÀ to GPNA (the hydride
reverse transfer), the standard state energy changes and the
activation free energies are not only dependent on the nature
ofthe two reactants but also on the sites ofthe reaction center
on the pyridinium ring where the hydride from SHÀ attacks.
From Table 6, it is clear that when the hydride from SHÀ
attacks the 4-position on the pyridinium ring, not only the
thermodynamic driving force (À3.3 À 7.5 kcalmolÀ1) is larg-
er than that when the hydride attacks to the 2-position (À1.8
À 6.3 kcalmolÀ1), but the activation free energy (16.1
12.6 kcalmolÀ1) is also smaller than that when the hydride
attacks the 2-position (18.3 14.5 kcalmolÀ1); this indicates
‡
Nature of the transition state in the hydride forward transfer
and the hydride reverse transfer: In order to further support
the proposal that the 1,4-dihydropyridine is much more easy
to form than the corresponding 1,2-dihydropyridine from
GPNA by hydride transfer from SHÀ, the nature ofthe
‡
transition states in the hydride transfer from the 1,4- and 1,2-
dihydropyridines to S was examined. When the standard state
enthalpy changes [DH(HÀT)] and the activation enthalpies
(DH=) for the two reactions [Eqs. (2) and (3)] were plotted
against the Hammett substituent constant s, four excellent
straight lines were observed (see Figure 5) with slope values
that when GPNA reacts with SHÀ, it is much easier for t
4-position in GPNA to accept the hydride ion than for the
‡
‡
2-position to accept the hydride ion. This result means that the
pyridinium derivatives formed from the 1,2-dihydropyridines
cannot return to the original reduced form, 1,2-dihydropyr-
idines by accepting a hydride from SHÀ. The oxidation re-
duction cycles ofthe 1,4-dihydropyridines and the 1,2-
dihydroisomers in the reactions with S are shown in Scheme 3.
=
=
Figure 5. Hammett plots of DH (1,4-) ( ) and DH (1,2-) ( ), DH1,4(HÀ
)
T
~
!
( ), DH1,2(HÀT) ( ) vs s. The values of DH (1,4-), DH (1,2-), DH1,4(HÀT),
and DH1,2(HÀT) are listed in Tables 3 and 5, respectively.
=
=
Scheme 3. Hydride-transfer cycles of the 1,4-dihydropyridines and the 1,2-
dihydroisomers in the reactions with S.
&
*
In the hydride transfer cycle of the 1,4-dihydropyridines in
the reaction with S, a hydride from the 1,4-dihydropyridines
of4.51 Æ 0.46 (equivalent to Hammett reaction constant 1 of
À0.79)[24] for the activation enthalpy of the reaction with the
1,4-dihydropyridines [DH=(1,4-)], 2.22 Æ 0.21 (equivalent to 1
of À0.39) for the activation enthalpy of the reaction with the
1,2-dihydropyridines [DH=(1,2-)], 8.93 Æ 0.58 (equivalent to 1
of À1.57) for the standard state enthalpy changes of the
reaction with the 1,2-dihydropyridines [DH1,2(HÀT)] and
7.84 Æ 0.65 (equivalent to 1 of À1.38) for the standard state
enthalpy changes ofthe reaction with the 1,4-dihydropyr-
idines [DH1,4(HÀT)]. The positive slope values reflect that
positive charge increases on the nitrogen atom at the
1-position in going from the GPNAH to the transition state
‡
transfers to the substrate S to produce GPNA and SHÀ
(hydride forward transfer). In reverse order, the pyridinium
‡
GPNA formed may return to the initial reduced form, 1,4-
dihydropyridines, by the hydride reverse transfer from SHÀ to
the 4-position on the pyridinium ring. Whereas in the
oxidation reduction cycle ofthe 1,2-dihydropyridines in the
reaction with S, the hydride transfers from the 1,2-dihydro-
‡
pyridines to the substrate S to produce GPNA and SHÀ
(hydride forward transfer). In the reverse order, however, the
‡
GPNA formed can not return to the initial reduced form, 1,2-
dihydropyridines, by the hydride reverse transfer from SHÀ to
the 2-position on the pyridinium ring, because it is much more
favorable for the hydride to attack the 4-position than to
attack the 2-position in both thermodynamic and kinetic
terms, which makes the oxidation reduction cycle ofthe 1,2-
dihydropyridines in the reactions with S break in the reverse
process.
‡
or to GPNA and the magnitude ofthe slope values is a
indicator for the relative change of the effective charge at the
1-position nitrogen atom.[25] In order to quantitatively eval-
uate the effective charge on the 1-position nitrogen atom in
the 1,4-dihydropyridines and the 1,2-dihydropyridines in the
transition states, we defined the effective charge on the
1-position nitrogen atom in GPNAH-1,4-H2 and GPNAH-1,2-
H2 as zero, and the effective charge on the 1-position nitrogen
In order to support the above proposal, the reaction of
‡
‡
GPNA with SHÀ was examined. When GPNA (G ˆ H) was
treated with SHÀ in dry acetonitrile under argon atmosphere,
the 1,4-dihydropyridine was obtained as the major reduced
‡
atom in GPNA as the positive, one unit from our basic
knowledge ofthe electronic structures ofthe neutral
3942
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Chem. Eur. J. 2003, 9, 3937 3945

Hydride-Transfer Cycles
3937 3945
GPNAH-1,4-H2 and GPNAH-1,2-H2 as well as their corre-
sponding production quaternary ammonium salts;[26] this
indicates that the slope value of 7.84 for the hydride transfer
from the 1,4-dihydropyridines to S [DH1,4(HÀT)] is equivalent
to a positive charge increase of one unit on the 1-position
much more close to the side ofthe initial reactants ( SHÀ
‡
‡
GPNA ) than that ofthe hydride transef r to the 2-position;
this indicates that the transition state ofthe hydride transfer
from SHÀ to the 4-position is formed easier and earlier than
the other transition state, since the two reactions were
‡
‡
nitrogen in going from GPNAH-1,4-H2 to GPNA , and from
initiated from the same reactants (SHÀ ‡ GPNA ).[28] This
which it is easily available that the slope value of4.51 ofr
[DH=(1,4-)] is equivalent to positive charge increase of0.58 on
the 1-position nitrogen atom in going from GPNAH-1,4-H2 to
the transition state. Since the effective charge on the
1-position nitrogen in GPNAH-1,4-H2 has been defined as
zero, the effective charge on the 1-position nitrogen in the
transition state ofthe 1.4-dihydropyridines should be ‡0.58
(Scheme 4). Similarly, according to the slope value of8.93 for
the hydride transfer from the 1,2-dihydropyridines to S
[DH1,2(HÀT)] equivalent to positive charge increase of one
unit on the 1-position nitrogen in going from GPNAH-1,2-H2
result again supports that the 1,4-dihydropyridines have
precedence over the corresponding 1,2-dihydropyridines to
form from the reduction of the corresponding pyridinium
‡
cation GPNA by hydride donor SHÀ.
According to the thermodynamic and kinetic examination
‡
for the hydride reverse transfer from SHÀ to GPNA above
mentioned, we know that there are two main factors which
make the activation energy potential ofthe transition state to
yield the 1,4-dihydropyridines much lower than that ofthe
transition state to yield the 1,2-dihydropyridines: one is that
À
the heterolytic dissociation energy ofC H bond in the 1,4-
4
‡
À
to GPNA , it is clear that the effective charge on the
dihydropyridines is larger than that ofC H bond in the
2
1-position nitrogen in the transition state ofthe 1.2-dihydro-
pyridine is ‡0.25 (Scheme 4).[27] Comparing the effective
charges on the 1-position nitrogen atom in the two transition
states shows that the effective charge on the 1-position
nitrogen atom in the transition state of1,2-hydropyridines
(‡0.25) is quite smaller than the effective charge in the
corresponding in the transition state of1,4-hydropyridines
(‡0.58); this indicates that the location ofthe transition state
of1,2-dihydropyridines is close to the side ofreactants
GPNAH-1,2-H2 (early reagent-like), but the transition state
of1,4-dihydropyridines is in the middle or slight close to the
corresponding 1,2-dihydropyridines; the other is that hin-
drance at the 2-position on the pyridinium ring in GPNA is
‡
larger than that at the 4-position.
Conclusion
According to the thermodynamic and kinetic examination of
the two reactions ofifve 1-( p-substituted phenyl)-1,4-dihy-
dronicotinamides (GPNAH-1,4-H2) and five 1-(p-substituted
phenyl)-1,2-dihydro- nicotinamides (GPNAH-1,2-H2) with p-
trifluoromethylbenzylidenemalononitrile (S), following con-
clusions can be drawn:
‡
side ofproducts GPNA (see Scheme 4 and Figure 4).
As shown from the hydride reverse transfer from SHÀ to
‡
GPNA in Figure 4 and Scheme 4, it is clear that the position
1) The oxidation potential ofthe 1,4-dihydropyridines is
generally larger than that ofthe corresponding 1,2-
dihydroisomers by 0.082 0.112 V and the heterolytic
À
ofthe transition state in the reaction coordination ofr the
‡
hydride transfer from SHÀ to the 4-position ofGPNA is
dissociation energy ofC
H
4
bond in the 1,4-dihydropyri-
dines is also larger than that
À
ofC H bond in the corre-
2
sponding 1,2-dihydroisomers
by 1.2 1.5 kcalmolÀ1, which
indicates that to the same
substrate, the thermodynam-
ic driving force of the 1,4-
dihydropyridines offers an
electron or a hydride is small-
er than that ofthe corre-
sponding 1,2-dihydroisomers.
2) When the two types ofthe
dihydropyridines were treat-
ed with the same substrate
(S), though the thermody-
namic driving force of the
hydride transfer from the
1,4-dihydropyridines is quite
smaller than that ofthe cor-
responding 1,2-dihydroisom-
ers, the activation free energy
ofthe latter reactions is larg-
er than that ofthe ofrmer
Scheme 4. Effective charge maps on the rate-determining transition states in the reactions of S with 1,4-
dihydronicotinamide and with 1,2-dihydronicotinamide.
Chem. Eur. J. 2003, 9, 3937 3945
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3943

X.-Q. Zhu, J.-P. Cheng et al.
FULL PAPER
injections from
a
250 mL injection syringe (containing 0.0105m 10-
reactions, which is due to the more negative activation
entropy for the latter reactions.
methylacridinium iodide) into the reaction cell (1.00 mL) containing
0.011m NAD(P)H models or SHÀK . Injection volumes (10 mL) were
delivered 0.5 s time interval with 500 s between every two injections. The
reaction heat was obtained by area integration ofeach peak except for the
first.
‡
3) When the hydride reverse transfers from SHÀ to the
‡
pyridinium GPNA , the hydride transfer to the 4-position
on the pyridinium ring to form the 1,4-dihydropyridines is
much more favorable than the hydride transfer to the
2-position on the pyridinium ring to form the 1,2-dihydro-
pyridines in both ofthermodynamics and kinetics, which
Electrochemical experiments: All electrochemical experiments were
carried out by CV (sweep rate, 100 mVsÀ1) using a BAS-100B electro-
chemical apparatus in acetonitrile under an argon atmosphere as described
previously.[34] Bu4NPF6 (0.1m) was employed as the supporting electrolyte.
A standard three-electrode assembly consisted ofa glassy carbon disk as
the working electronic, a platinum wire as counter electrode, and 0.1m
‡
indicates that the pyridinium derivatives GPNA [as
‡
NAD(P) models] can return to the 1,4-dihydropyridines
AgNO3/Ag as reference. All sample solution was 1.0mm. The ferrocenium/
rather than the 1,2-dihydropyridines by abstracting a
hydride.
These results indicate that the active center ofNAD(P)H is
also more favorable to choose the 1,4-dihydropyridine rather
than 1,2-dihydropyridine in the hydride transfer cycle without
the steric control ofenzyme.
‡/0
ferrocene redox couple (Fc
) was taken as an internal standard.
Reproducibility is generally smaller than 5 mV.
Acknowledgement
These studies were supported by grants from the Natural Science
Foundation ofChina (NSFC) for Outstanding Youth (No. 20125206), the
NSFC (No. 20272027) and the Doctorate Program Foundation of
Institutions ofHigher Education administrated by the Ministry of
Education of China. We also thank the referees for their highly valuable
suggestions regarding the revision.
Experimental Section
Materials: 1-(p-Substituted phenyl)-1,4-dihydronicotinamides (GPNAH-
1,4-H2) were prepared according to the following general methods: the
appropriate aniline (1 mmol) dissolved in dry methanol (10 mL) was added
into
a
solution of1-(2,4-dinitrophenyl)nicotinomide chloride
(1 mmol),[29, 30] a so-called Zincke salt, in dry methanol (100 mL). The
resulting red solution was then heated gently overnight or until the red
color fated to yellow, indicating the formation of 2,4-dinitroaniline. The
solution was cooled, and the precipitated side product was removed by
filtration. The filtrate was then evaporated in vacuum, and the residue was
dissolved in H2O (100 mL). The aqueous phase was then exhaustively
washed with diethyl ether. The water layer was then evaporated under
reduced pressure to give a crude product, which was recrystallized from
methanol/Et2O. Reduction ofthe pyridinium salt was perofrmed in
aqueous basic sodium dithionite to give the corresponding 1,4-dihydropyr-
idine derivatives. 4,4-Dideuterated PNAH-1,4-H2 was synthesized accord-
ing to the literature,[9] the deuterium content was larger than 95% (1H NMR
method). 1-(p-Substituted phenyl)-1,2-dihydronicotinamides (GPNAH-
1,2-H2) were obtained from reductions of the corresponding pyridinium
salt by NaBH4 according to the literature method.[10] p-Trifluoromethyl-
benzylidenemalononitrile was prepared by Knoevenagel condensation of
p-trifluoromethylbenzaldehyde with malononitrile in the presence of a
base.[31] SHÀ was obtained from the reaction of p-trifluoromethylbenzyl-
malononitrile with KH in dry acetonitrile. p-Trifluoromethylbenzylmalo-
nonitrile was available from the reduction of p-trifluoromethyl-benzylide-
nemalonotrile by 1-phenyl-1,4-dihydronicotinamide in acetonitrile/meth-
[1] J. Rydstrom, J. Hoeck, L. Ernster, Nicotinamide Nucleotide Trans-
hydrogenases in ™The Enzymes, Vol. XIII∫ (Ed.: P. D. Boyer),
Academic Press, New York, 1976.
[2] F. H. Westhermer, Ad. Enzymol. 1962, 24, 469.
[3] S. Chaykin, Annu. Rev. Biochem. 1967, 36, 149.
[4] a) U. Eisner, J. Kuthan, Chem. Rev. 1972, 72, 1 and references therein;
b) Pyridine and its Derivatives, Part 1 (Ed.: E. Klingsberg), Wiley, New
York, 1960.
[5] a) S. Fukuzumi, S. Koumitsu, K. Hironaka, T. Tanaka, J. Am. Chem.
Soc. 1987, 109, 305; b) M. F. Powell, J. C. Wu, T. C. Bruice, J. Am.
Chem. Soc. 1984, 106, 3850; c) O. Almarsson, T. C. Bruice, J. Am.
Chem. Soc. 1993, 115, 2125;. d) A. Ohno, H. Yamamoto, S. Oka, J.
Am. Chem. Soc. 1981, 103, 2041; e) L. L. Miller, J. R. Valentine, J. Am.
Chem. Soc. 1988, 110, 3982; f) H. C. Lo, O. Buriez, J. B. Kerr, R. H.
Fish, Angew. Chem. 1999, 111, 1524; Angew. Chem. Int. Ed. 1999, 38,
1429; g) B. W. Carlson, L. L. Miller, J. Am. Chem. Soc. 1983, 105, 7454;
h) N. Kanomata, M. Suzuki, M. Yoshida, T. Nakata, Angew. Chem.
1998, 110, 1506; Angew. Chem. Int. Ed. 1998, 37, 1410; i) X.-Q. Zhu, Y.
Liu, B. J. Zhao, J.-P. Cheng, J. Org. Chem. 2001, 66, 370; j) J.-P. Cheng,
Y. Lu, X.-Q. Zhu, L. Mu, J. Org. Chem. 1998, 63, 6108; k) X.-Q. Zhu,
Y. Liu, B.-J. Zhao, J.-P. Cheng, J. Org. Chem. 2001, 66, 370.
[6] a) A. I. Kruppa, M. B. Taraban, N. E. Polyakov, T. V. Leshina, J.
Photochem. Photobiol. AChem. 1993, 73, 159; b) X.-Q. Zhu, B.-J.
Zhao, J.-P. Cheng, J. Org. Chem. 2000, 65, 8158; c) X.-Q. Zhu, Y.-C.
Liu, J.-P. Cheng, J. Org. Chem. 1999, 64, 8980; d) X.-Q. Zhu, H.-L.
Zou, P.-W. Yuan, L. Cao, J.-P. Cheng, J. Chem. Soc. Perkin Trans. 2
2000, 1857; e) B.-J. Zhao, X.-Q. Zhu, J.-Q. He, Z.-Z. Xia, J.-P. Cheng,
Tetrahedron Lett. 2000, 41, 257.
[7] a) ÷. Almarsso, A. Sinha, E. Gopinath, T. Bruice, J. Am. Chem. Soc.
1993, 115, 7093; b) C. A. Coleman, J. G. Rose, C. J. Murray, J. Am.
Chem. Soc. 1992, 114, 9755; c) S. Fukuzumi, S. Mochizuki, T. Tanaka,
Inorg. Chem. 1990, 29, 653; d) P. Hapiot, J. Moiroux, J.-M. Saveant, J.
Am. Chem. Soc. 1990, 112, 1337.
[8] a) M. F. Powell, T. C. Bruice, J. Am. Chem. Soc. 1982, 104, 5834;
b) J. W. Bunting, S. Sindhuatmadja, J. Org. Chem. 1980, 45, 5411; c) A.
Anne, S. Fraoua, J. Moiroux, J.-M. Saveant, J. Am. Chem. Soc. 1996,
118, 3938; d) A. Marcinek, J. Adamus, J. Gebicki, J. Phys. Chem. A
2000, 104, 724.
‡
anol. 10-Methylacridinium iodide (AcrH IÀ) was obtained from the
treatment ofacridine by methyl iodide following the literature. [32] Reagent
grade acetonitrile was distilled from P2O5 being passed through a column of
active neutral alumina to remove water and protic impurities.
Kinetic measurements: Kinetic measurements were carried out in acetoni-
trile/methanol (9:1 v/v) using
a Hitachi U-3000 spectrophotometer
connected to a super-thermostat circulating bath to regulate the temper-
ature ofcell compartments. The oxidation rate ofthe 1,4-dihydropyridines
and the 1,2-dihydropyridines by
S were measured at 25 458C by
monitoring the changes ofabsorption ofGPNAH ([GPNAH]
ˆ
0.127 mm) at lmax ˆ 360 nm for GPNAH-1,4-H2 and at lmax ˆ 390 nm for
GPNAH-1,2-H2 under pseudo-first-order conditions (S in over 25-fold
excess). The pseudo-first-order rate constants were then converted to k2 by
linear correlation ofpseudo-first-order rate constants against the concen-
trations of S. The activation parameters were derived from Arrhenius plots
and from Eyring plots.
Titrated calibration experiments: The titration experiments were per-
formed on a CSC4200 isothermal titration calorimeter in acetonitrile at
258C. Prior to use, the instrument was calibrated against an internal heat
pulse, and the functional response was verified by determination of the heat
ofdilution ofa concentrated sucrose solution. [33] Data points were collected
every 2 s. The heat ofreaction was determined ofllowing 10 automatic
[9] M. E. Brewster, J. J. Kaminski, Z. Gabanyi, K. Czako, A. Simay, N.
Bodor, Tetrahedron 1989, 45, 4395.
[10] a) R. M. Acheson, G. Paglietti, J. Chem. Soc. Perkin 1 1976, 45; b) G.
Paglietti, P. Sanna, A. Nuvole, J. Chem. Res. (S) 1983, 245; G. Paglietti,
P. Sanna, A. Nuvole, J. Chem. Res. (M) 1983, 2326.
3944
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Chem. Eur. J. 2003, 9, 3937 3945

Hydride-Transfer Cycles
3937 3945
[11] N. Kornblum, Angew. Chem. 1975, 87, 797; Angew. Chem. Int. Ed.
Engl. 1975, 14, 734.
entropy changes for the two reactions, there should not be remarkable
difference between them, since the two reactions give the same
products and formation entropies for the two dihydropyridines are
close to each other.
[12] a) S. R. Logan, Fundamentals of Chemical Kinetics, Addison Wesley
Longman, London, 1996, Chapter 2, p. 35; b) Techniques of Chemistry,
Volume VI Investigations of rates and mechanisms of reactions (Ed.:
G. G. Hammes), 3rd ed., Parts I and II, New York, Wiley.
[13] K. L. Handoo, J.-P. Cheng, V. D. Parker, J. Am. Chem. Soc. 1993, 115,
5067.
[21] Here we used reaction enthalpy to take place ofGibbs free energy to
predict the spontaneity ofthe reactions, since standard ground
entropy change for the hydride transfer is generally quite small.
[22] Some other reduction characters ofpyridinium derivatives to yield the
corresponding 1,4-dihydropyridines as the major product by hydride
transfer have been demonstrated by Kreevoy and co-workers: a) I.-S.
H Lee, E. H. Jeoung, M. M. Kreevoy, J. Am. Chem. Soc. 2001, 123,
7492; b) I.-S. H. Lee, K.-H. Chow, M. M. Kreevoy, J. Am. Chem. Soc.
2002, 124, 7755; c) I.-S. H. Lee, E. H. Jeoung, M. M. Kreevoy, J. Am.
Chem. Soc. 1997, 119, 2722.
[23] The 1,4-hydropyridine should be directly derived from the hydride
transfer from SHÀ to the pyridinium rather than from the isomer-
ization ofthe 1,2-dihydropyridine or rfom the reaction ofthe excess
pyridinium with the formed 1,2-dihydropyridine, since experiments
showed that the reaction ofthe pyridinium with the 1,2-dihydropyr-
idine and the isomerization of1,2-dihydropyridine all are very slow,
but the reaction ofthe pyridinium with SHÀ to yield the 1,4-
dihydropyridines is very fast.
[24] According to Hammett equation logK ˆ 1s and DH ꢀ ÀRTlogK, the
line slope of DH against s should be approximately equal to À5.71.
[25] X.-Q. Zhu, Q. Li, W.-F. Hao, J.-P. Cheng, J. Am. Chem. Soc. 2002, 124,
9887.
[26] J. W. Buting, S. Sindhuatmadja, J. Org. Chem. 1980, 45, 5411.
[27] In fact, similar evaluations of effective charge distribution on an active
atom in a transition-state structure by using Hammett linear free-
energy relationship were extensively reported in literature: a) M.
Page, A. Williams, Organic and Bio-organic Mechanism, Addison
Wesley Longman, 1997, Chapter 3, pp. 52 79; b) A. Williams, Acc.
Chem. Res. 1984, 17, 425; c) A. Williams, Acc. Chem. Res. 1989, 22,
387; d) A. Williams, Adv. Phys. Org. Chem. 1991, 27, 1; e) A. Williams,
J. Am. Chem. Soc. 1985, 107, 6335.
[14] Since the reduction potential of p-dinitrobenzene in acetonitrile
‡/0
(Ered ˆ À0.837 V vs Fc
from literature: J. Q. Chambers, R. N.
Adams, J. Electroanal. Chem. 1965, 9, 400) is larger than that ofthe
substrate p-trifluoromethylbenzylidenemalononitrile in acetonitrile
(Ered ˆ À1.229 V vs Fc‡/0), if the hydride transfer from the 1,4- or 1,2-
dihydropyridnes to p-trifluoromethyl-benzylidenemalononitrile were
initiated by single electron transfer, remarkable inhibitory effect on
the two reaction rates would had been observed, when p-dinitroben-
zene was added into the reaction mixtures.
[15] If the hydride transfer were initiated by single electron transfer, the
free energy change for this process could be estimated to be 34.83
37.56 kcalmolÀ1 for the 1,4-dihydropyridines as the electron donor and
32.92 35.31 kcalmolÀ1 for the 1,2-dihydropyridines as the electron
donor according to Nernst equation (see Table 1), which, obviously, is
quite larger than the corresponding activation free energy change of
the two reactions (DG=: 19.4 19.8 kcalmolÀ1 for the reactions with
the 1,4-dihydropyridines and 20.1 20.4 kcalmolÀ1 for the reactions
with the 1,2-dihydropyridines see Table 5). Thus it is impossible that
the hydride transfer from the dihydropyridines to S was initiated by
single electron transfer.
[16] N. S. Isaacs, Physical Organic Chemistry, 1st ed., Wiley, New York,
1987, Chapter 4.
[17] J. W. Bunting, S. Sindhatmadja, J. Org. Chem. 1981, 46, 4211.
[18] The values of DH= and DS= for the hydride transfer can be obtained
from Table 3, since the initial hydride transfer is in rate-limiting
process, the kinetic parameters for the reaction of S with the
dihydropyridines may be due to the initial hydride transfer.
[19] M. Page, A. Williams, Organic and Bio-organic Mechanism, Addison
Wesley Longman, 1997, Chapter 2, p. 42.
[28] N. S. Isaacs, Physical Organic Chemistry, 1st ed., Wiley, New York,
1987, Chapter 2.
[20] Here we made an assumption that the ground entropy changes for the
two reactions [Eqs. (2) and (3)] are equal. This assumption is
reasonable. As well known, the ground entropy change is different
from the activation entropy change, activation entropy change is
defined as the difference of entropy between reactants and the
activation complex, but the ground entropy change is defined as the
difference of entropy between reactants and products. It is evident
that the activation entropy change for the reaction of the 1,2-
dihydronicotinamide with the substrate should be quite larger than
that for the reaction of the 1,4-dihydronicotinamide with the
substrate; the reason is that there is a larger steric barriers in the
activation complex for the former reaction. But as to the ground
[29] M. Atkinson, R. Marton, R. Naylor, J. Chem. Soc. 1965, 610.
[30] T. Zincke, Ann. 1903, 330, 361.
[31] a) J. Zablicky, J. Chem. Soc. 1961, 686; b) P. Kolsaker, P. O. Ellingsen,
Acta Chem. Scand. B 1979, 33, 138.
[32] R. M. G. Robers, D. Ostovic, M. M. Kreevoy, Faraday Diss. Chem.
Soc. 1982, 74, 257.
[33] F. T. Gucker, H. B. Pickard, R. W. Planck, J. Am. Chem. Soc. 1939, 61,
459.
[34] X.-Q. Zhu, J.-Q. He, Q. Li, M. Xian, J. Lu, J.-P. Cheng, J. Org. Chem.
2000, 65, 6729.
Received: January 3, 2003 [F4714]
Chem. Eur. J. 2003, 9, 3937 3945
www.chemeurj.org
¹ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3945