Energetics of Multistep versus One-step Hydride Transfer Reactions of Reduced Nicotinamide Adenine Dinucleotide (NADH) Models with Organic Cations and p-Quinones

Article abstract of DOI:10.1021/jo9715985

Free energy changes of each elementary step involved in the formal hydride transfer (H_T^-) reactions (including the so-called "one-step" H_T^- and "multistep" H_T^- mechanisms) of the reduced ni

Full text of DOI:10.1021/jo9715985

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6108 J . Org. Chem. 1998, 63, 6108-6114
En er getics of Mu ltistep ver su s On e-step Hyd r id e Tr a n sfer
Rea ction s of Red u ced Nicotin a m id e Ad en in e Din u cleotid e (NADH)
Mod els w ith Or ga n ic Ca tion s a n d p-Qu in on es
J in-Pei Cheng,* Yun Lu, Xiaoqing Zhu, and Linjing Mu
Department of Chemistry, Nankai University, Tianjin 300071, China
Received August 27, 1997
Free energy changes of each elementary step involved in the formal hydride transfer (H-T) reactions
(including the so-called “one-step” H-T and “multistep” H-T mechanisms) of the reduced nicotinamide
adenine dinucleotide (NADH) models with various cations and quinones (17) were investigated
either by direct thermodynamic measurements or by calculations from thermochemical cycles.
Based on the energetic data thus derived, combined with kinetic observations (particularly kinetic
isotope effects), the mechanistic characteristics of the NADH-mediated reductions were systemati-
cally analyzed. Practical guidelines that resulted from these analyses suggest that a mutistep
mechanism (e--H• or e--H+-e-) would be followed if the energy gap of the initial electron transfer
[∆G(e-T)] between the NADH model compound and the reducing substrate is considerably smaller
than the empirical critical limit of 1.0 V for an endothermic e-T. In contrast, if ∆G(e-T) is much
greater than 1.0 V, a concerted one-step H- may take place. The guideline also suggests that a
T
“hybrid” mechanism is possible if the ∆G(e-T) is in an intermdiate situation.
In tr od u ction
acceptor (which may also be a good hydride acceptor6)
may initiate a one-step hydride transfer reaction as
well.1a,b,2e-g Cases also exist where distinctions between
a true one-step hydride process and a multistep process
are quite difficult to make if only conventional techniques
such as electron spin resonance (ESR), chemically re-
duced dynamic nuclear polariation (CIDNP), ultraviolet-
visible (UV-vis), isotope labeling, and product analysis
are relied upon.1-5,7-11 In these cases, knowledge about
thermodynamic driving forces of every mechanistically
feasible elementary step for each proposed mechanism
may play a valuable or sometimes even decisive role in
mechanism distinction, especially when combined with
kinetic evidence from other sources.3c However, thermo-
dynamic analysis of this kind is very sparse in the
literature largely because of the transient nature of the
intermediate species involved in NADH-mediated reduc-
tions (Scheme 1). In this paper, we report our recent
evaluations of the detailed energetics for each elementary
step shown in Scheme 1 to facilitate mechanism dif-
ferentiation. The approaches used in this work to derive
these otherwise hard-to-get energetic data are primarily
various thermochemical cycles (eqs 1-5, see Results),
which are similar to the general strategy applied fre-
quently in recent years in evaluating important quanti-
ties such as bond dissociation energy (BDE),6,12 pK(HA+•),13
hydride affinities,14 bond energies of radical ions,15 and
so on.
The mechanisms of reduced nicotinamide adenine
dinucleotide (NADH) model-mediated reductions have
long been a subject of extensive investigations in the
overlapping areas of chemistry and biology because of
their relevant importance in understanding the vital
functions of the NADH coenzyme in living bodies. Al-
though there have been many discussions in the litera-
ture regarding this issue in recent years,1-3 a working
solution to clarifying the long-debated superficial hydride
transfer mechanisms [i.e., (i) the one-step hydride trans-
fer2 and (ii) the multistep hydride transfer1b-e,3] has not
yet been reached. Investigations showed that when a
one-electron oxidant was used in the reaction, it was often
observed that the reductions followed the electron transfer-
initiated multistep sequence (e--H+-e- or e--H•).4,5 On
the other hand, it was also shown that a good electron
(1) (a) Yausi, S.; Ohno, A. Bioorg. Chem. 1986, 14, 70. (b) Fukuzumi,
S.; Koumitsu, S.; Hironaka, K.; Tanaka, T. J . Am. Chem. Soc. 1987,
109, 305 and references therein. (c) Tanner, D.; Kharrat, A. J . Org.
Chem. 1988, 53, 1646. (d) Bunting, J . W. Bioorg. Chem. 1991, 19, 456.
(e) Fukuzumi, S.; Tokuda, Y. J . Phys. Chem. 1993, 97, 3737. (f) He,
G.-X.; Blasko, A.; Bruice, T. C. Bioorg. Chem. 1993, 21, 423. (g) Ohno,
A. J . Phys. Org. Chem. 1995, 8, 567.
(2) (a) Bunting, J . W.; Sindhuatmadji, S. J . Org. Chem. 1981, 46,
4211. (b) Bunting, J . W.; Chew, V. S. F.; Chu, G. J . Org. Chem. 1982,
47, 2303. (c) Chung, S.-K.; Park, S. U. J . Org. Chem. 1982, 47, 3197.
(d) Kreevoy, M. M.; Lee, I.-S. H. J . Am. Chem. Soc. 1984, 106, 2550.
(e) Carlson, B. W.; Miller, L. L. J . Am. Chem. Soc. 1985, 107, 479. (f)
Miller, L. L.; Valentine, J . R. J . Am. Chem. Soc. 1988, 110, 3982. (g)
Coleman, C. A.; Rose, J . G.; Murray, C. J . J . Am. Chem. Soc. 1992,
114, 9755.
(3) (a) Fukuzumi, S.; Nishizawa, N.; Tanaka, T. J . Org. Chem. 1984,
49, 3571. (b) Fukuzumi, S.; Nishizawa, N.; Tanaka, T. J . Chem. Soc.,
Perkin Trans. 2 1985, 371. (c) Fukuzumi, S.; Iishikawa, M.; Tanaka,
T. J . Chem. Soc., Perkin Trans. 2 1989, 1811. (d) Tanner, D. D.;
Kharrat, A.; Oumar-Mahamat, H. Can. J . Chem. 1990, 68, 1662. (e)
Iishikawa, M.; Fukuzumi, S. J . Chem. Soc., Faraday Trans. 1990, 86,
3531. (f) Fukuzumi, S.; Chiba, M. J . Chem. Soc., Perkin Trans. 2 1991,
1393.
(5) (a) Okamoto, T.; Ohno, A.; Oka, S. Bull. Chem. Soc. J pn. 1980,
53, 330. (b) Powell, M. F.; Wu, J . C.; Bruice, T. C. J . Am. Chem. Soc.
1984, 106, 3850. (c) Sinha, A.; Burice, T. C. J . Am. Chem. Soc. 1984,
106, 7291.
(6) Klippenstein, J .; Arya, P.; Wayner, D. D. M. J . Org. Chem. 1991,
56, 6736.
(7) Yasui, S.; Nakamura, K.; Ohno, A. J . Org. Chem. 1984, 49, 878.
(8) (a) Adam, W.; Heil, M.; Hutterer, R. J . Org. Chem. 1992, 57,
4491. (b) Liu, Y. C.; Li, B.; Guo, Q. X. Tetrahedron 1995, 51, 9671.
(9) Ohnishi, Y.; Ohno, A. Chem. Lett. 1976, 697.
(10) Ohno, A.; Yamamoto, H.; Oka, S. Bull. Chem. Soc. J pn. 1981,
54, 3489.
(4) (a) Carlson, B. W.; Miller, L. L. J . Am. Chem. Soc. 1983, 105,
7453. (b) Carlson, B. W.; Miller, L. L.; Neta, P.; Grodkowsk, J . J . Am.
Chem. Soc. 1984, 106, 7233.
(11) Fukuzumi, S.; Mochizuki, S.; Tanaka, T. Inorg. Chem. 1990,
29, 653.
S0022-3263(97)01598-3 CCC: $15.00 © 1998 American Chemical Society
Published on Web 08/13/1998

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Multistep versus One-step Hydride Transfers
Sch em e 1
J . Org. Chem., Vol. 63, No. 18, 1998 6109
Ta ble 1. Red ox P oten tia ls of th e Releva n t Sp ecies
In volved in Eva lu a tion of th e En er getic Da ta Usin g
Th er m od yn a m ic Cycles for NADH Mod el Rea ction sa
compound(AH)
Eox(A-)
Eox(AH)
Erd(A+)
9-(p-GC6H4NH)FLH
G ) CH3O
G ) H
-1.817
-1.768
-1.705
-1.685
-1.531
-1.486
-1.746b
-1.784
0.214
0.438
0.506
1.135
1.215
1.415
-0.784
0.715
0.182
0.497
-1.445
-1.362
-1.352
-0.293c
-0.366c
-0.257c
0.856b
G ) Cl
XnH
9-PhXnH
Ph3CH
The substrates chosen in this work are protonated
N-arylfluorenimines (1, 9-GC6H4NHFL+), xanthylium ion
(2, Xn+), 9-phenylxanthylium ion (3, 9-PhXn+), trityl
cation (4, Ph3C+), p-benzoquinone (5, p-BQ) and its
derivatives, protonated p-benzoquinone (6, p-BQH+), and
N-methylacridinium ion (7, AcrH+). Thermodynamic
driving forces (i.e., free energy changes) for each step
involved in the one-step or multistep pathways (Scheme
1) for reductions of substrates 1-7 by the chosen NADH
models (i.e., 1-benzyl-1,4-dihydronicotinamide, BNAH, or
10-methylacridan, AcrH2) were estimated. Based on
these parameters, combined with the experimental evi-
dence from other sources, (e.g. isotope labeling and
kinetic measurements), it becomes more likely that a
clarification of possible mechanisms for an apparent
hydride transfer reaction can be better reached.
p-BQH-
p-BQH2
BNAH
-0.04d
-1.528
-0.876
AcrH2
a
Ep values in volt measured in the present work (except
otherwise specified) in DMSO at 25 °C versus ferrocenium/
ferrocene (Fc+/Fc) redox couple under the conditions as described
in Experimental Section. From ref 20. c From ref 14. From ref
2 g and 21.
b
d
reduction potentials (Erds) of BNA+, AcrH+ and substrate
cations (A+), respectively.
∆G(e-T) ) -F∆E[(A+/A•) - (NADH+•/NADH)] (1)
∆G(H+T) ) 2.303RT[pK(NADH+•) - pK(AH+•)] (2)
∆G(e-T)′ ) -F∆E[(AH+•/AH) - (NAD+/NAD•)] (3)
Reduction potentials of 9-GC6H4NHFL+ (1) were obtained
from the second oxidation wave of the 9-arylaminofluo-
renide ions (the first wave was reversible). Acid dis-
sociation constants of radical cations of the substrates
(AH ) 1H-6H), or the pK(AH+•), were obtained from the
combination of pK(AH) with oxidation potentials of the
parent molecule (Eox(AH)) and its conjugated base (Eox(A-))
using eq 4.13
pK(AH+•) ) pK(AH) + F∆E[(A•/A-) -
(AH+•/AH)]/2.303RT (4)
The redox potential data and the acidity and hydride
affinity values of the relevant species that were necessary
for calculating these energetic quantities are listed in
Tables 1 and 2, respectively.
Evaluation of the free energy changes for the follow-
up proton transfer (i.e., ∆G(H+T)) upon formation of the
NADH model radical cation requires a knowledge of their
equilibrium acidity constants [i.e., pK(BNAH+•) and
pK(AcrH2+•)]. Because these pK(AH+•) values in DMSO
(12) (a) Cheng, J .-P. Ph.D. Dissertation, Northwestern University,
Evanston, IL, 1987. (b) Bordwell, F. G.; Cheng, J .-P.; Harrelson, J . A.;
J r. J . Am. Chem. Soc. 1988, 110, 1229. (c) Bordwell, F. G. Acc. Chem.
Res. 1988, 21, 456. (d) Bordwell, F. G.; Cheng, J .-P.; J i, G.-Z.; Satish,
A. V.; Zhang, X.-M. J . Am. Chem. Soc. 1991, 113, 9790. (e) Bordwell,
F. G.; Zhang, X.-M. Acc. Chem. Res. 1993, 26, 510. (f) Cheng, J .-P.;
Zhao, Y. Tetrahedron, 1993, 49, 5287. (g) Cheng, J .-P.; Zhao, Y.; Huan,
Z. Sicience in China (series B) 1995, 38, 1417.
(13) (a) Nicholas, A. M. P.; Arnold, O. Can. J . Chem. 1982, 60, 2165.
(b) Bordwell, F. G.; Bausch, M. J . J . Am. Chem. Soc. 1986, 108, 2473.
(c) Bordwell, F. G.; Cheng, J .-P.; Bausch, M. J . J . Am. Chem. Soc. 1988,
110, 2867. (d) Bordwell, F. G.; Cheng, J .-P.; Bausch, M. J . J . Am. Chem.
Soc. 1988, 110, 2872. (e) Bordwell, F. G.; Cheng, J .-P. J . Am. Chem.
Soc. 1989, 111, 1792.
(14) (a) Cheng, J .-P.; Handoo, K. L.; Parker, V. D. J . Am. Chem.
Soc. 1993, 115, 2655. (b) Handoo, K. L.; Cheng, J .-P.; Parker, V. D. J .
Am. Chem. Soc. 1993, 115, 5067.
(15) (a) Bordwell, F. G.; Zhang, X.-M.; Cheng, J .-P. J . Org. Chem.
1993, 58, 6410. (b) Zhang, X.-M.; Bordwell, F. G. J . Am. Chem. Soc.
1994, 116, 904.
Resu lts
All the thermodynamic data required in this study
were obtained at 25 °C in dimethyl sulfoxide (DMSO).
Free energy changes (∆G) for each elementary step of
the e--H+-e- mechanism in Scheme 1 were either directly
measured (i.e., for electron transfers) or calculated using
eqs 1-3 (here NADH represents its models BNAH or
AcrH2, NAD+ represents their oxidized forms), where
E(NADH+•/NADH) and E(AH+•/AH) are the oxidation
potentials (Eoxs) of BNAH, AcrH2, and substrates (AH),
respectively; and E(NAD+/NAD•) and E(A+/A•) are the

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6110 J . Org. Chem., Vol. 63, No. 18, 1998
Cheng et al.
Ta ble 2. Acid Dissocia tion Con sta n ts of Neu tr a l
Su bstr a tes [p K(AH)] a n d Ra d ica l Ca tion s p K(AH+•) a n d
Hyd r id e Affin ities of th e Cor r esp on d in g Ca tion s
[∆GH-(A+)] in DMSO a t 25 °C
this value is assured on the part of the redox potential
measurement of this work (reproducible to 10 mV) if
confidence in the accurary of the two literature values
used in the evaluation is assumed. Unfortunately, the
pK(BNAH+•) cannot be directly calculated in the same
simple manner because of the lack of the ∆GBDE value of
the 4-C-H bond in BNAH. The missing quantity can
be estimated from eq 6, however. For this purpose, a
calorimetric measurement of the heat of hydride transfer
between BNAH and AcrH+ in DMSO was carried out (see
Experimental Section) and a value of -17.4 ( 0.3 kcal/
mol was obtained. This value is assumed to be equal to
the corresponding free energy because the entropy con-
tribution to this quite symmetrical reaction in acetonitrile
was shown to be negligible as judged by the close match
of the heat of hydride transfer in MeCN measured in this
work (∆H(H-T) ) -12.3 kcal/mol) with the free energy
of hydride transfer (∆G(H-T) ) -11.2 kcal/mol) deter-
d
compound(AH)
pK(AH)a
pK(AH+•
)
-∆GH-(A+)g
9-(p-GC6H4NH)FLH
G ) CH3O
G ) H
19.9
19.3
19.0
-14.3
-17.8
-18.2
-18e
-18e
-18e
10
46.8
49.1
50.3
G ) Cl
XnH
30.0b
27.9b
30.6b
26.2c
19.76b
90.3h
89.3h
96.5h
70.7i
102.9i
9-PhXnH
Ph3CH
p-BQH-
p-BQH2
BNAH
-5.5
f
j
-3.3
59.0
f
AcrH2
-6.9
76.5k
a
Determined in the present work (except the ones specified)
by the double standard acid (SA) method (see Experimental
Section): SA1 ) dibenzyl sulfone [pK(SA1) ) 23.9]; SA2 )
m-cyanobenzylphenyl sulfone [pK(SA2) ) 20.6] or SA2 ) p-
b
c
mined from an equilibrium study.6,19 The pK(BNAH+•
)
cyanobenzylphenyl sulfone [pK(SA2) ) 18.52]. From ref 12c.
d
From ref 20. Calculated from eq 4. e From Cheng, J .-P., Ph.D.
evaluated from eq 5 using a ∆GBDE thus estimated from
eq 6 is -3.3. Accumulation of all the experimental errors
from this rather lengthy evaluation gave an uncertainty
of ∼1.3 pK units, which is acceptable for the purpose of
this study and is comparable to or better than the
uncertainty of 2 pK units generally found for the pKa
quantities of radical cations in the literature.13
Dissertation, Northwestern University, Evanston, IL, 1987.
g
f Derived using eq 5 (see text for details). In kcal/mol, calculated
h
i
from eq 10 or 11. Quoted from ref 14a. From refs 15 and 16.
Calculated from eq 11, where ∆GBDE for BNAH, E(BNA+/BNA•),
j
and E(H•/H-) were taken as 69.2 kcal/mol (see text), -0.991 V
(value from Table 1 adjusted to versus NHE by adding 0.537 V),
and -0.55 V (vs NHE),14a respectively. From ref 16.
k
Free energy changes of the hydrogen atom transfer
Sch em e 2
step in the e--H• mechanism [∆G(H• )] and of the direct
T
BDE
hydride transfer step in the one-step mechanism [∆G(H-T)]
were evaluated from eqs 7 and 8, respectively, based on
the thermodynamic cycles shown in Scheme 1.
∆G(H• ) ) ∆G(H+T) + ∆G(e-T)′
(7)
T
∆G(H-T) ) ∆G(e-T) + ∆G(H+T) + ∆G(e-T)′ (8)
Sch em e 3
Alternatively, ∆G(H-T) may also be evaluated from the
difference between the hydride affinities of substrate
+
-
[-∆GH (A )] and of the oxidized form of model compound
BDE
+
-
[-∆GH (NAD )] (eq 9) according to Scheme 1. Calcula-
tion of hydride affinities for the individual cationic species
are not yet reported, eqs 5 and 6, which are based
respectively on the thermodynamic cycles shown in
Schemes 2 and 3,6 were used jointly to derive these data.
can be easily made using eq 1014 or eq 11.16 The ∆G(H-
)
T
values of the overall reactions thus evaluated are in fact
identical to those from eq 9.
pK(NADH+•) ) [∆GBDE - FE(NADH+•/NADH) +
FE(H+/H•)]/2.303RT (5)
∆G(H-T) ) -∆GH-(NAD+) - [-∆G -(A+)] (9)
H
-∆GH-(A+) ) 2.303RTpK(AH) + F∆E[(A•/A-) +
∆∆GBDE[(BNAH) - (AcrH2)] ) ∆G(H-T) +
F∆E[(AcrH+/AcrH•) - (BNA+/BNA•)] (6)
(A+/A•)]
-F∆E[(H•/H-) + (H+/H•)]
-∆GH-(A+) ) ∆G
(10)
Bond dissociation free energy of the 9-C-H bond in
AcrH2 was evaluated previously by Parker and co-
workers as 71.6 kcal/mol16,17 by modeling with the
structurally similar xanthene. Combination of this value
+ FE(A+/A•) - FE(H•/H-)
BDE
(11)
•
with E(H+/H•) of -2.48 V18 and E(AcrH2+/AcrH2 ) of 1.034
The energetic data derived in this work for each
processes of interest (Scheme 1) are summarized in Table
3.
V [from this work, adjusted to versus normal hydrogen
electrode (NHE)] gave a pK value of -6.9 for the
10-methylacridan radical cation (AcrH2+•). Precision of
Discu ssion
(16) Cheng, J .-P.; Handoo, K. L.; Xue, J .; Parker, V. D. J . Org. Chem.
1993, 58, 5050.
(17) This value should be considered the upper limit of this bond
scission because N-methylanilino is a stronger radical stabilizing group
than phenoxy, which implies that the pK(AH+•) derived using this
number would also be a maximum value.
It is well recognized that thermodynamic driving forces
(i.e., energetics of a reaction) can usually serve as a good
guide (though may not always be in an exclusive sense)
(18) Parker, V. D. J . Am. Chem. Soc. 1992, 114, 7458 and 1993,
115, 1201 (erratum).
(19) Anne, A.; Moiroux, J . J . Org. Chem. 1990, 55, 4608.

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Multistep versus One-step Hydride Transfers
J . Org. Chem., Vol. 63, No. 18, 1998 6111
Ta ble 3. F r ee En er gy Ch a n ges (k ca l/m ol) of Ea ch Mech a n istic Step for Va r iou s Hyd r id e Tr a n sfer Mech a n ism s Sh ow n
in Sch em e 1a
mechanisms
e- - H•
e- -H+ -e-
∆G(H+
H-
model/subst
∆G(e-
)
∆G(H•
)
∆G(e-
)
)
∆G(e-T)′
∆G(H-
)
T
T
T
T
T
Group I
BNAH/Xn+
11.0
12.6
10.1
12.4
-41.3
-43.1
-47.8
-38.6
11.0
12.6
10.1
12.4
20.1
20.1
20.1
-1.9
-61.4
-63.2
-67.9
-36.7
-30.3
-30.5
-37.7
-26.2
BNAH/9-PhXn+
BNAH/Ph3C+
AcrH2/p-BQH+
Group II
BNAH/9-GC6H4NHFL+
G)CH3O
37.5
35.6
35.4
31.2
-25.1
-25.4
-26.5
-25.2
37.5
35.6
35.4
31.2
15.1
19.9
20.4
-40.2
-45.3
-46.9
-2.1
12.4
10.2
8.9
G)H
G)Cl
AcrH2/p-BQ
-23.1
6.0
Group III
BNAH/p-BQ
23.9
24.4
19.9
-35.4
-41.8
-26.4
23.9
24.4
19.9
-18.2
-17.2
-46.7
-6.5
-11.5
-17.4
BNAH/AcrH+
AcrH2/p-chloronilb
4.9
a
b
Values measured in DMSO at 25 °C or derived using eqs 1-3 and 7-9. Data evaluated similarly, using reported values from ref 16.
for analyzing various possibilities of reaction mecha-
nisms. Because general agreement on assigning reaction
mechanism from the ones proposed previously for NADH-
mediated reductions has not been reached, the detailed
thermodynamic parameters derived in this work may be
of value in providing hints for differentiating the true
paths for at least certain types of NADH model reactions.
The reactions chosen for this purpose are those listed in
Table 3 and are grouped into three categories (Groups
I-III) according to the similarities of their energetic
behaviors.
found for this group of reactions23 suggest that this
should be the case.
One may have noted from Table 1 that although AcrH2
is actually not as good an electron donor as BNAH (Eoxs
are 0.182 and 0.497 V, respectively), the electron transfer
energetics (i.e., ∆G(e-T)) of the AcrH2/p-BQH+ donor-
acceptor pair, and of the other three combinations of
Group I in Table 3 (11.0, 12.6, 10.1, and 12.4 kcal/mol,
respectively), however, all fall into the favorable range
(<23.1 kcal/mol) proposed for an electron transfer reac-
tion, indicating that the initial electron transfer is
nevertheless an energetically feasible path for these
reactions to choose. Furthermore, it is conceivable that
the small energy required for initiating an electron
transfer process can certainly be fully compensated
because both the driving forces of the overall reaction
(-30.3, -30.5, -37.7, and -26.2 kcal/mol, respectively)
and of the immediate follow-up hydrogen atom transfer
(-41.3, -43.1, -47.8, and -38.6 kcal/mol, respectively)
are highly exothermic. The experimentally observed
negligible kinetic isotope effect (kH/kD ) 1.4) and the
small enthalpy of activation for reaction of Xn+(2) with
BNAH (∆Hq ) 7.6 kcal/mol) described in our earlier
report23 provide further evidence for ruling out the
involvement of a direct C-H bond cleavage of BNAH in
the rate-limiting step, though the overall reaction does
at first sight look like a one-step hydride process. The
fact that the BNAH/Ph3C+(4) reaction was indeed ob-
served to follow the multistep pathway24 also supports
this driving force-based argument.
Th er m odyn am ics of th e Mu ltistep Hydr ide Tr an s-
fer Mech a n ism . As already mentioned, there are two
distinct cases for the so-called multistep mechanism: (i)
an electron transfer followed by a proton transfer and
then a second electron transfer (i.e., e--H+-e- pathway);
and (ii) an electron transfer followed by a hydrogen atom
transfer (i.e., e--H• pathway). Thus, in either case,
transfer of an electron is required to initiate the multistep
reaction. According to what has been extensively studied
and suggested in the literature,22 for the best result of
an electron-transfer-initiated process, the energy gap
between the donor and acceptor should not exceed the
1.0 V (i.e., 23.1 kcal/mol) limit. This empirical criterion
for a conventional electron transfer to occur would require
that the NADH model used in the reduction not be too
poor an electron donor and that the substrate not be too
poor an electron acceptor. Previous studies have shown
that reductions of some good electron acceptors, such as
substituted ferrocenium series,2e,4 ferricynide ion,5 and
some radical cations,4b by certain NADH models did
proceed via the multistep mechanism (i.e., initiated by
an electron transfer). As shown by the data in Table 1,
the reduction potential of the protonated quinone (6, Erd
of -0.04 V) is very close to that of ferrocenium (0.00 V,
serving as the internal reference) and those of 2-4 are
not too much more negative. Therefore, the situation for
the Group I reductions are expected to be similar (i.e.,
The kinetic isotope effect of the BNAH/DDQ reaction
(DDQ: 2,3-dichloro-5,6-dicyanoquinone) was reported in
the literature to be 1.5 in MeCN,3a again indicative of
the absence of a C-H bond cleaving process in the rate-
limiting step. The electron transfer energetics are easily
evaluated in this work from their respective redox
potentials16 to be 2.2 kcal/mol, a value well below the 1.0
V criterion. It is therefore reasonable to conclude that
this reaction also proceeded by an electron-transfer-
initiated multistep mechanism, even though the free
via electron transfer). In fact, the very low e- barriers
T
(20) Parker, V. D.; Cheng, J .-P., Handoo, K. L. Acta Chem. Scand.
1993, 47, 1144.
(21) Murray, C. J .; Webb, T. J . Am. Chem. Soc. 1991, 113, 7426.
(22) Eberson, L. Electron-Transfer Reactions in Organic Chemistry;
Springer-Verlag: New York, 1987.
(23) Cheng, J .-P.; Lu, Y. J . Phys. Org. Chem. 1997, 10, 577.
(24) Ishikawa, M.; Fukuzumi, S.; Goto, T.; Tanaka, T. Bull. Chem.
Soc. J pn. 1989, 62, 3754.