A study on the reactions of NADH models with electron-deficient alkenes. A probe for the extreme of concerted electron-hydrogen atom transfer mechanism

Article abstract of DOI:10.1016/j.tetlet.2008.10.143

The reactions of 9-fluorenylidenemalononitrile (FDCN) and 1,1-diphenyl-2,2-dicyanoethylene (DPCN) with Hantzsch ester (HEH), N-methyl Hantzsch ester (Me-HEH), and 1-benzyl-1,4-dihydronicotinamide (BNAH) in oxygen-saturated acetonitrile have been studied. The aerobic reactions with HEH give solely reduction products. However, reactions with Me-HEH and BNAH not only result in reduction products, but also give varying amounts of oxidation products. The amount of oxidation product appears to be related to the electronic character and bulkiness of reactants. We propose that all these reactions follow a general mechanism of concerted electron-hydrogen atom transfer mechanism. If the electron-transfer complex is very tight, only 'concerted hydride transfer reaction' occurs. However, if the electron-transfer complex is not so tight, oxygen can capture the radicaloid intermediate to result in oxidation products.

Full text of DOI:10.1016/j.tetlet.2008.10.143

Tetrahedron Letters 50 (2009) 312–315
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A study on the reactions of NADH models with electron-deficient
alkenes. A probe for the extreme of concerted electron-hydrogen
atom transfer mechanism
a
c,
*
Xin-Qiang Fang a, Hua-Jian Xu a, Hong Jiang a, You-Cheng Liu a,b, , Yao Fu , Yun-Dong Wu
*
a Department of Chemistry, University of Science and Technology of China, Hefei 230026, China
b College of Chemistry, Lanzhou University, Lanzhou 730000, China
c Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China
a r t i c l e i n f o
a b s t r a c t
Article history:
The reactions of 9-fluorenylidenemalononitrile (FDCN) and 1,1-diphenyl-2,2-dicyanoethylene (DPCN)
with Hantzsch ester (HEH), N-methyl Hantzsch ester (Me-HEH), and 1-benzyl-1,4-dihydronicotinamide
(BNAH) in oxygen-saturated acetonitrile have been studied. The aerobic reactions with HEH give solely
reduction products. However, reactions with Me-HEH and BNAH not only result in reduction products,
but also give varying amounts of oxidation products. The amount of oxidation product appears to be
related to the electronic character and bulkiness of reactants. We propose that all these reactions follow
a general mechanism of concerted electron-hydrogen atom transfer mechanism. If the electron-transfer
complex is very tight, only ‘concerted hydride transfer reaction’ occurs. However, if the electron-transfer
complex is not so tight, oxygen can capture the radicaloid intermediate to result in oxidation products.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 16 September 2008
Accepted 31 October 2008
Available online 5 November 2008
In recent years, the idea that hydride transfer from coenzyme
NADH models takes place through a concerted electron-hydrogen
atom transfer mechanism (concerted hydride transfer) has gained
increasing support from many investigators.1–3 Verhoeven et al.4
have applied the valence-bond configuration mixing (VBCM)
model5 to the study of mechanism and transition state structure
of hydride transfer reactions mediated by NAD(P)H models and
rationalized the results with the notion that the general occurrence
of concerted hydride transfer as the lowest energy reaction path-
way, which also explains why the activation energy of such a con-
certed pathway is often linearly related to that of a hypothetical
single electron-transfer process.
substituted phenyl ethanes, kinetic studies showed that the relative
rates of reactions bear a good linear relationship with Hammett
r
constants for the p-substituent groups.7 The same reactions carried
out in oxygen-saturated acetonitrile produced the corresponding di-
p-substituted ethanes and di-p-substituted aryl ketones in variable
ratios determined by the nature of the electronic character of the
p-substituent groups.8 The results are consistent with the concep-
tion that, due to the electronic and steric effect of the substituent
groups on the ethylenic linkage, electron transfer and hydrogen
atom transfer fromBNAH to the substrate moleculedo nottake place
synchronously, electron transfer has progressed farther than hydro-
gen atom transfer, so that the transition state possesses partial
diradical and partial covalent bonding character, which bifurcates
in the presence of oxygen into two pathways leading to the forma-
tion of the corresponding 1,1-di-p-substituted aryl-2,2-dinitroeth-
ane and di-p-substituted aryl ketone.9
Savéant et al.6 have studied the dynamics of proton transfer
from the cation radicals of NADH analogues and found that the
homolytic cleavage of the Å+C–H bond appears to be the dominant
factor governing the dynamics of proton transfer in the series of
NADH cation radicals studied and suggested that the proton trans-
fer from the cation radical is better viewed as a concerted electron-
hydrogen atom transfer rather than a stricto sensu proton transfer.
The investigations of our laboratory on the reactions of NADH
models with activated ethylenic compounds also provided
evidence for concerted electron-hydrogen atom transfer mecha-
nism for equivalent hydride transfer. Thus, in the reactions of
1,1-di-p-substituted phenyl-2,2-dinitroethylenes with 1-benzyl-
1,4-dihydronicotinamide (BNAH) to give the corresponding di-p-
Recently, Hantzsch ester (HEH) has been widely used as reduc-
ing agent for organocatalytic hydrogenation of
aldehydes,10a–e ,b-unsaturated ketones,10f,g and imines.10h–j We
also found that N-methyl Hantzsch ester (Me-HEH) can convert
,b-epoxy ketones to b-hydroxy ketones.10k The reaction mediated
a,b-unsaturated
a
a
by Me-HEH appears to be electron-transfer mechanism,10k while
the reaction mediated by HEH is generally considered as direct
hydride transfer.11 It appears, therefore, the mechanism may differ
with different substrates and more investigation is needed.
Recently, we studied the reactions of HEH and Me-HEH with
FDCN and DPCN in deaerated acetonitrile and oxygen-saturated
acetonitrile, respectively. The objective of the research is twofold:
* Corresponding authors. Tel./fax: +86 551 3603254 (Y.-C.L.).
E-mail addresses: ycliu@ustc.edu.cn (Y.-C. Liu), chydwu@ust.hk (Y.-D. Wu).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.10.143

X.-Q. Fang et al. / Tetrahedron Letters 50 (2009) 312–315
313
firstly, to find the extreme case of concerted electron-hydrogen
H
H
EtO2C
Me
CO2Et
Me
CN
9
CN
H
atom transfer, which is equivalent to direct hydride transfer, and
secondly, to elucidate the substituent effect upon the mechanism.
For comparison, the reaction of BNAH with FDCN and DPCN is also
studied to ascertain the scope and generality of the reaction mech-
anism (Fig. 1).
NC
NC
a
N
D
proton
transfer
formal hydride transfer
FDCN reacted with HEH in dry deaerated acetonitrile at 30 °C
under Argon in the dark for 6 h to give 9-fluorenylmalononitrile
(FDCNH) in 91% yield (Table 1, entry 1). In this reaction no quench-
ing agent such as hydrochloric acid is added because the interme-
diate Hantzsch ester radical cation is a strong acid,12 which
provides the proton for quenching the reaction. The addition of
m-dinitrobenzene to the reaction showed no inhibiting effect upon
the reaction.
CN
H
CN
H
NC
H
NC
D
Column chromatography
on SiO2
Scheme 1. Isotope tracing experiment.
Isotope tracing experiment using N-deuterated Hantzsch ester
shows that deuterium goes to the a-position of FDCNH and the re-
oxidation product was obtained. However, in the reaction of FDCN
with Me-HEH in oxygen-saturated acetonitrile, the products ob-
tained consisted of not only FDCNH (78%) but also small amounts
of 9-fluorenone (FDO, 8.3%) (Table 2, entry 2). TLC tests indicated
that FDO was formed gradually in the progress of the reaction
and reached the maximum and then ceased to increase. When
BNAH was used in the reaction with FDCN in oxygen-saturated
acetonitrile, FDCNH was surprisingly the minor product (6%) and
sult is in consistence with the mechanism depicted in Scheme 1.
The reactions of FDCN with Me-HEH and BNAH were carried out
in dry deaerated acetonitrile under argon for appropriate time
and then quenched with acetic acid (Table 1, entries 2 and 3). Addi-
tion of m-dinitrobenzene showed no appreciable effect upon the
reaction of FDCN with Me-HEH but showed remarkable baffling
effect to the reaction of FDCN with BNAH.
The reactions of DPCN with the three models needed higher
reaction temperatures, longer reaction time and the yields were
relatively lower than that of the reactions of FDCN (Table 1, entries
4–6).
Table 2 summarizes the results of reactions of FDCN and DPCN
with NADH models in oxygen-saturated acetonitrile. The reaction
of FDCN with HEH in oxygen-saturated acetonitrile gave the same
products as that in deaerated acetonitrile (Table 2, entry 1). No
Table 2
Reaction of FDCN and DPCN with NADH models in oxygen-saturated acetonitrilea
CN
O
NC
FDCNH
DPCNH
+
(FDO)
NADH models
O2, CH3CN
O
NC
CN
CN
NC
CN
NC
+
(BPO)
Entry
Reaction
T (°C)
Time (h)
Product/yieldb (%)
DPCN
FDCN
1
2
3
4
5
6
FDCN + HEH
30
12
12
12
24
24
24
FDCNH (90), FDO (0)
FDCNH (78), FDO (8.3)
FDCNH (6), FDO (76)
FDCNH (30), BPO (0)
DPCNH (46), BPO (2)
DPCNH (15), BPO (11)
H
H
FDCN + Me-HEH
FDCN + BNAH
DPCN + HEH
DPCN + Me-HEH
DPCN + BNAH
30
30
40
60
40
H
H
H
H
CONH2
EtO2C
Me
CO2Et
Me
EtO2C
Me
CO2Et
Me
N
N
H
N
CH2Ph
BNAH
Me
Me-HEH
a
General conditions: FDCN or DPCN (0.1 mmol), NADH models (0.15 mmol),
HEH
CH3CN (15 mL).
b
Isolated yield based on ethylenic substrates.
Figure 1.
Table 1
Reactions of FDCN and DPCN with NADH models in deaerated acetonitrilea
CN
H
CN
H
NC
H
NC
H
CN
NC
CN
NC
NADH
or
or
models
Ar,
CH3CN
DPCNH
FDCNH
Entry
Reaction
T (°C)
Time (h)
Product/yieldb (%)
1
2
3
4
5
6
FDCN + HEH
30
30
30
40
60
40
6
12
6
24
24
24
FDCNH (91)
FDCNH (80)
FDCNH (85)
DPCNH (30)
DPCNH (40)
DPCNH (35)
FDCN + Me-HEH
FDCN + BNAH
DPCN + HEH
DPCN + Me-HEH
DPCN + BNAH
a
General conditions: FDCN or DPCN (0.1 mmol), NADH models (0.15 mmol), CH3CN (15 mL).
Isolated yield based on ethylenic substrates.
b

314
X.-Q. Fang et al. / Tetrahedron Letters 50 (2009) 312–315
obtained consist of FDCNH (6%) and FDO (76%) with the latter as
the predominant product.
CN
CN
OO
NC
NC
NC
From the above analysis, it is seen that there is a mechanistic
extreme in the concerted electron-hydrogen atom transfer mecha-
nism, which is equivalent to direct hydride transfer.
O2
+
FDCN
Me-HEH
Fukuzumi and co-workers18 have recently reported the detailed
investigation on the borderline between one-step hydride transfer
and multistep electron transfer–proton transfer or electron–pro-
ton–electron transfer of NADH analogues in some specific reaction
systems.
CN
O
O
_
O
e
In the reaction of DPCN with Me-HEH in oxygen-saturated ace-
tonitrile, owing to the fact that the two phenyl groups are not
coplanar with C–C double bond and there is a methyl group on
the NADH model, the steric effect renders the reaction of oxygen
with the transition state feasible and BPO is obtained as the oxida-
tion product in addition to the reduction product.
Supporting evidence for concerted electron-hydrogen atom
transfer is also provided by the fact that the reaction of 1,1-di-p-
methoxyphenyl-2,2-dinitroethylene with BNAH to give high yield
(>90%) of 1,1-di-p-methoxyphenyl-2,2-dinitroethane, whereas
1,1-di-o-methoxyphenyl-2,2-dinitroethylene does not react with
BNAH even in the presence of magnesium perchlorate or upon irra-
diation with light, although it can be readily reduced to the corre-
sponding substituted ethane with sodium borohydride.19 This
retardation effect of the ortho substituent clearly indicates con-
certed electron-hydrogen atom transfer mechanism.20
In summary, by comparison of the reactions of HEH, Me-HEH,
and BNAH with FDCN and DPCN in deaerated acetonitrile21 and
oxygen-saturated acetonitrile22, it is reasonable to conclude that
all these reactions take place via an electron-hydrogen atom trans-
fer mechanism and the difference exists only in the degree of con-
certedness. The reaction of FDCN with HEH appears to represent
the extreme case of concerted hydride transfer.
Scheme 2. Mechanism of the formation of FDO.
FDO became the major product (76%) (Table 2, entry 3). The reac-
tion of DPCN with HEH still gave only the reduction product (Table
2, entry 4). Benzophenone (BPO) was isolated in the reactions of
DPCN with Me-HEH and BNAH in oxygen-saturated acetonitrile
with the yields of 2% and 11%, respectively (Table 2, entries 4
and 5). The ratios of BPO versus DPCNH decreased when compared
with that of FDO versus FDCNH.
With reference to the literature13 and our previous report,14 the
formation of FDO and BPO is attributed to the reactions of oxygen
with the anionic radicaloid species in the transition states formed
via electron transfer from the NADH models to FDCN and DPCN
(Scheme 2).
Table 3 gives the redox potentials of the reactants. A simple cal-
culation of the energy for an electron transfer would be prohibitive
for the reaction since the easiest one would be between BNAH and
FDCN, endothermic by about 30.2 kcal/mol
(
D
E = 23.02(Ered
À
Eox) kcal/mol). However, such an electron transfer would be
possible in a radical cation/radical anion complex. Charge transfer
complexes between NADH models and alkenes have been well
realized both in enzyme active site15 and in solution.16
Acknowledgments
The tightness of the electron-transfer complex is dependent
upon the redox potentials of the reactants as well as steric effect.
Large endothermicity of the electron-transfer reaction and smaller
steric effect should result in a tighter complex while smaller endo-
thermicity of the electron-transfer reaction and larger steric effect
should be associated with a looser complex. Thus, HEH, which is
planar and has the highest oxidation potential, should correspond
to a very tight complex. In addition, the bond dissociation energy
for C4–H bond of HEH is supposed to be of a relatively low value,17
the H-atom transfer should be easier to take place. It appears,
therefore, the reaction takes place via a completely concerted elec-
tron-hydrogen atom transfer mechanism and there is no feasibility
for oxygen to react with the transition state and no FDO is formed.
On the other hand, in the case of Me-HEH, because of the steric ef-
fect of the N-Me group, the transition state complex between Me-
HEH and FDCN is not so ‘tight’ as that between HEH and FDCN so
that it is feasible for oxygen molecule to approach and react with
the anionic radicaloid center to form a peroxidic intermediate,
which eventually transforms to FDO (Scheme 2).
We are grateful to National Natural Science Foundation of China
(Grant Nos. 20772115, 20802015, 20832004) and Specialized Re-
search Fund for the Doctoral Program of Higher Education of China
(20070358018) for support.
References and notes
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BNAH has the lowest oxidation potential. It should form loose
electron-transfer complex. It is thus not surprising that when FDCN
reacts with BNAH in oxygen-saturated acetonitrile, the products
Table 3
Electrode potentials (V, vs Ag/AgCl) of NADH models, FDCN, and DPCN
FDCN
DPCN
HEH
1.01
Me-HEH
0.93
BNAH
0.63
Eox
11. (a) Merjer, H. P.; Van Niel, J. C. G.; Pandit, U. K. Tetrahedron 1984, 40, 5185; (b)
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Ered
À0.68
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21. General procedure for the reduction of activated alkenes by NADH models: A
mixture of FDCN (0.1 mmol) and HEH (0.15 mmol) in 15 ml deaerated
acetonitrile was left in the dark at 30 °C for 6 h. The reaction mixture was
evaporated under reduced pressure to dryness and the residue was subjected
to column chromatography on silica gel with petroleum ether–ethyl acetate
(10:1, v:v) as eluant to give FDCNH as a white solid. Yield: 21 mg (91%). Mp
164–166 °C. 1H NMR (300 MHz, CDCl3) d 7.81 (2H, d, J = 7.5 Hz), 7.76 (2H, d,
J = 7.5 Hz), 7.51 (2H, t, J = 7.5 Hz), 7.41 (2H, t, J = 7.5 Hz), 4.42 (1H, d, J = 5.3 Hz),
4.23 (1H, d, J = 5.3 Hz). 13C NMR (75 MHz, CDCl3) d 141.47, 139.75, 129.76,
128.16, 124.73, 120.83, 111.65, 46.02, 27.72. EIMS: m/z (rel. intensity) 230 (M+,
19), 165 (100).
22. General procedure for the reaction of activated alkenes with NADH models in
oxygen-saturated acetonitrile: Acetonitrile (15 ml) was bubbled with dry
oxygen for 10 min. FDCN (0.1 mmol) and Me-HEH (0.15 mmol) were added
and the reaction vessel was sealed. After reaction at 30 °C for 12 h in the dark
under positive pressure of oxygen, the reaction mixture was quenched with
acetic acid (1 M, 0.5 ml). The solvent was evaporated under reduced pressure
and the residue was worked up by column chromatography on silica gel with
petroleum ether–ethyl acetate (10:1, v:v) as eluant to give the products FDO
(1.5 mg, 8.3%) and FDCNH (17.9 mg, 78%). FDO: yellow solid. Mp 82–83 °C. 1H
NMR (400 MHz, CDCl3) d 7.66 (2H, d, J = 7.3 Hz), 7.52 (2H, d, J = 7.3 Hz), 7.48
(2H, t, J = 7.3 Hz), 7.30 (2H, t, J = 7.3 Hz). EIMS: m/z (rel. intensity) 180 (M+,
100), 165 (68).