Metal ion-catalyzed cycloaddition vs hydride transfer reactions of NADH analogues with p-benzoquinones

Article abstract of DOI:10.1021/ja016370k

1-Benzyl-4-tert-butyl-1,4-dihydronicotinamide (t-BuBNAH) reacts efficiently with p-benzoquinone (Q) to yield a [2+3] cycloadduct (1) in the presence of Sc(OTf)₃ (OTf = OSO₂CF₃) in deaerated acetonitrile (MeCN) at room temperature, while no reaction occurs in the absence of Sc³⁺. The crystal structure of 1 has been determined by the X-ray crystal analysis. When t-BuBNAH is replaced by 1-benzyl-1,4-dihydronicotinamide (BNAH), the Sc³⁺-catalyzed cycloaddition reaction of BNAH with Q also occurs to yield the [2+3] cycloadduct. Sc³⁺ forms 1:4 complexes with t-BuBNAH and BNAH in MeCN, whereas there is no interaction between Sc³⁺ and Q. The observed second-order rate constant (k_obs) shows a first-order dependence on [Sc³⁺] at low concentrations and a second-order dependence at higher concentrations. The first-order and the second-order dependence of the rate constant (k_et) on [Sc³⁺] was also observed for the Sc³⁺-promoted electron transfer from CoTPP (TPP = tetraphenylporphyrin dianion) to Q. Such dependence of k_et on [Sc³⁺] is ascribed to formation of 1:1 and 1:2 complexes between Q^?- and Sc³⁺ at the low and high concentrations of Sc³⁺, respectively, which results in acceleration of the rate of electron transfer. The formation constants for the 1:2 complex (K₂) between the radical anions of a series of p-benzoquinone derivatives (X - Q^?-) and Sc³⁺ are determined from the dependence of k_et on [Sc³⁺]. The K₂ values agree well with those determined from the dependence of k_obs on [Sc³⁺] for the Sc³⁺-catalyzed addition reaction of t-BuBNAH and BNAH with X - Q. Such an agreement together with the absence of the deuterium kinetic isotope effects indicates that the addition proceeds via the Sc³⁺-promoted electron transfer from t-BuBNAH and BNAH to Q. When Sc(OTf)₃ is replaced by weaker Lewis acids such as Lu(OTf)3, Y(OTf)3, and Mg(ClO₄)₂, the hydride transfer reaction from BNAH to Q also occurs besides the cycloaddition reaction and the k_obs value decreases with decreasing the Lewis acidity of the metal ion. Such a change in the type of reaction from a cycloaddition to a hydride transfer depending on the Lewis acidity of metal ions employed as a catalyst is well accommodated by the common reaction mechanism featuring the metal-ion promoted electron transfer from BNAH to Q.

Full text of DOI:10.1021/ja016370k

J. Am. Chem. Soc. 2001, 123, 10191-10199
10191
Metal Ion-Catalyzed Cycloaddition vs Hydride Transfer Reactions of
NADH Analogues with p-Benzoquinones
Shunichi Fukuzumi,* Yoshinori Fujii, and Tomoyoshi Suenobu
Contribution from the Department of Material and Life Science, Graduate School of Engineering,
Osaka UniVersity, CREST, Japan Science and Technology Corporation (JST), Suita,
Osaka 565-0871, Japan
ReceiVed June 8, 2001
Abstract: 1-Benzyl-4-tert-butyl-1,4-dihydronicotinamide (t-BuBNAH) reacts efficiently with p-benzoquinone
(Q) to yield a [2+3] cycloadduct (1) in the presence of Sc(OTf)3 (OTf ) OSO2CF3) in deaerated acetonitrile
(MeCN) at room temperature, while no reaction occurs in the absence of Sc3+. The crystal structure of 1 has
been determined by the X-ray crystal analysis. When t-BuBNAH is replaced by 1-benzyl-1,4-dihydronico-
tinamide (BNAH), the Sc3+-catalyzed cycloaddition reaction of BNAH with Q also occurs to yield the [2+3]
cycloadduct. Sc3+ forms 1:4 complexes with t-BuBNAH and BNAH in MeCN, whereas there is no interaction
between Sc3+ and Q. The observed second-order rate constant (kobs) shows a first-order dependence on [Sc3+
]
at low concentrations and a second-order dependence at higher concentrations. The first-order and the second-
order dependence of the rate constant (ket) on [Sc3+] was also observed for the Sc3+-promoted electron transfer
from CoTPP (TPP ) tetraphenylporphyrin dianion) to Q. Such dependence of ket on [Sc3+] is ascribed to
formation of 1:1 and 1:2 complexes between Q•- and Sc3+ at the low and high concentrations of Sc3+
,
respectively, which results in acceleration of the rate of electron transfer. The formation constants for the 1:2
complex (K2) between the radical anions of a series of p-benzoquinone derivatives (X-Q•-) and Sc3+ are
determined from the dependence of ket on [Sc3+]. The K2 values agree well with those determined from the
dependence of kobs on [Sc3+] for the Sc3+-catalyzed addition reaction of t-BuBNAH and BNAH with X-Q.
Such an agreement together with the absence of the deuterium kinetic isotope effects indicates that the addition
proceeds via the Sc3+-promoted electron transfer from t-BuBNAH and BNAH to Q. When Sc(OTf)3 is replaced
by weaker Lewis acids such as Lu(OTf)3, Y(OTf)3, and Mg(ClO4)2, the hydride transfer reaction from BNAH
to Q also occurs besides the cycloaddition reaction and the kobs value decreases with decreasing the Lewis
acidity of the metal ion. Such a change in the type of reaction from a cycloaddition to a hydride transfer
depending on the Lewis acidity of metal ions employed as a catalyst is well accommodated by the common
reaction mechanism featuring the metal-ion promoted electron transfer from BNAH to Q.
Introduction
effects of metal ions on hydride transfer reactions from NADH
analogues to substrates have particularly attracted considerable
interest in relation to the essential role of metal ions in the redox
reactions of nicotinamide coenzymes in the native enzymatic
system.1-4,11,12 Metal ions acting as Lewis acids have been
reported to accelerate electron-transfer reactions, where metal
ions bind to the product radical anions produced in the electron-
Mechanisms of hydride transfer reactions of nicotinamide
adenine dinucleotide (NADH) analogues with hydride acceptors
such as carbonyl compounds and organic cations have been
extensively studied chemically1-8 or electrochemically.9,10 The
* Author to whom correspondence should be addressed.
(1) (a) Eisner, U.; Kuthan, J. Chem. ReV. 1972, 72, 1. (b) Stout, D. M.;
Meyers, A. I. Chem. ReV. 1982, 82, 223.
(5) (a) Cheng, J.-P.; Lu, Y.; Zhu, X.; Mu, L. J. Org. Chem. 1998, 63,
6108. (b) Pestovsky, O.; Bakac, A.; Espenson, J. H. J. Am. Chem. Soc.
1998, 120, 13422. (c) Coleman, C. A.; Rose, J. G.; Murray, C. J. J. Am.
Chem. Soc. 1992, 114, 9755. (d) Murray, C. J.; Webb, T. J. Am. Chem.
Soc. 1991, 113, 7426. (e) Cheng, J.-P.; Handoo, K. L.; Xue, J.; Parker, V.
D. J. Org. Chem. 1993, 58, 5050.
(6) (a) Carlson, B. W.; Miller, L. L.; Neta, P.; Grodkowski, J. J. Am.
Chem. Soc. 1984, 106, 7233. (b) Powell, M. F.; Wu, J. C.; Bruice, T. C. J.
Am. Chem. Soc. 1984, 106, 3850. (c) Sinha, A.; Bruice, T. C. J. Am. Chem.
Soc. 1984, 106, 7291.
(7) (a) Tanner, D. D.; Kharrat, A.; Oumar-Mahamat, H. Can. J. Chem.
1990, 68, 1662. (b) Tanner, D. D.; Kharrat, A. J. Org. Chem. 1988, 53,
1646. (c) Liu, Y.-C.; Li, B.; Guo, Q.-X. Tetrahedron 1995, 51, 9671. (d)
Ohno, A.; Ishikawa, Y.; Yamazaki, N.; Okamura, M.; Kawai, Y. J. Am.
Chem. Soc. 1998, 120, 1186. (e) Kanomata, N.; Nakata, T. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 1207. (f) Kanomata, N.; Suzuki, M.; Yoshida, M.;
Nakata, T. Angew. Chem., Int. Ed. Engl. 1998, 37, 1410. (g) Konno, H.;
Sakamoto, K.; Ishitani, O. Angew. Chem., Int. Ed. 2000, 39, 4061.
(8) (a) Kreevoy, M. M.; Ostovic´, D.; Lee, I.-S. H.; Binder, D. A.; King,
G. W. J. Am. Chem. Soc. 1988, 110, 524. (b) Lee, I.-S. H.; Jeoung, E. H.;
Kreevoy, M. M. J. Am. Chem. Soc. 1997, 119, 2722.
(2) (a) Sund, H. Pyridine-Nucleotide Dependent Dehydrogenase; Walter
de Gruyer: West Berlin, Germany, 1977. (b) Kellog, R. M. Top. Curr.
Chem. 1982, 101, 111. Kellog, R. M. Angew. Chem. 1984, 96, 769. (c)
Ohno, A.; Ushida, S. In Lecture Notes in Bioorganic Chemistry, Mechanistic
Models of Asymmetric Reductions; Springer-Verlag: Berlin, Germany, 1986;
p 105. (d) Bunting, J. W. Bioorg. Chem. 1991, 19, 456. (e) He, G.-X.;
Blasko, A.; Bruice, T. C. Bioorg. Chem. 1993, 21, 423. (f) Ohno, A. J.
Phys. Org. Chem. 1995, 8, 567.
(3) (a) Fukuzumi, S. In AdVances in Electron-Transfer Chemistry;
Mariano, P. S., Ed.; JAI Press; Greenwich, CT, 1992; pp 67-175. (b)
Fukuzumi, S.; Tanaka, T. In Photoinduced Electron Transfer; Fox, M. A.,
Chanon, M., Eds.; Elsevier: Amsterdam, The Netherlands, 1988; Part C,
Chapter 10.
(4) (a) Fukuzumi, S.; Koumitsu, S.; Hironaka, K.; Tanaka, T. J. Am.
Chem. Soc. 1987, 109, 305. (b) Fukuzumi, S.; Mochizuki, S.; Tanaka, T. J.
Am. Chem. Soc. 1989, 111, 1497. (c) Fukuzumi, S.; Kitano, T.; Ishikawa,
M. J. Am. Chem. Soc. 1990, 112, 5631. (d) Fukuzumi, S.; Tokuda, Y.;
Kitano, T.; Okamoto, T.; Otera, J. J. Am. Chem. Soc. 1993, 115, 8960. (e)
Fukuzumi, S.; Ohkubo, K.; Tokuda, Y.; Suenobu, T. J. Am. Chem. Soc.
2000, 122, 4286.
10.1021/ja016370k CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/27/2001

10192 J. Am. Chem. Soc., Vol. 123, No. 42, 2001
Fukuzumi et al.
transfer reactions.13-16 Both thermal and photochemical redox
reactions which would otherwise be unlikely to occur have been
made possible efficiently by the catalysis of metal ions on the
rate-determining electron-transfer steps.13-16 Among metal ions,
rare-earth metal ions have attracted much attention as much
more effective Lewis acids than divalent metal ions such as
Mg2+ and Zn2+ in various carbon-carbon bond forming reac-
tions due to the strong affinity to carbonyl oxygen.17-19 How-
ever, there has been no report on rare-earth metal ion-catalyzed
reactions of NADH analogues.
tert-butyl-1,4-dihydronicotinamide (t-BuBNAH) is used as an
NADH analogue in the Sc3+-catalyzed reaction with p-benzo-
quinone, the crystal structure of the cycloadduct was determined
successfully. The cycloaddition of 1,4-dihydropyridine deriva-
tives with p-benzoquinones has been reported in dioxane
solution in the presence of HClO4,20 where BNAH is unstable
toward acid-catalyzed hydrolysis.21 There exist a few other
reports concerning the addition reaction of BNAH or substituted
BNAH with carbonyl compounds.22 However, neither definitive
characterization of the adducts nor the catalytic mechanism has
so far been reported. The kinetic analysis of the Sc3+-catalyzed
cycloaddition reactions involving kinetic deuterium isotope
effects as compared to the authentic electron-transfer reactions
provides valuable information for the catalytic mechanisms of
Sc3+. The effects of other metal ions have also been studied in
comparison with the catalytic effect of Sc3+ to reveal the relation
between the cycloaddition and the hydride transfer reactions of
NADH analogues.
We report herein that novel and efficient [2+3] cycloaddition
reactions of NADH analogues with p-benzoquinone derivatives
rather than the hydride transfer reactions occur in the presence
of scandium triflate (Sc(OTf)3) in MeCN. When 1-benzyl-4-
(9) (a) Anne, A.; Fraoua, S.; Grass, V.; Moiroux, J.; Save´ant, J.-M. J.
Am. Chem. Soc. 1998, 120, 2951. (b) Anne, A.; Fraoua, S.; Moiroux, J.;
Save´ant, J.-M. J. Am. Chem. Soc. 1996, 118, 3938. (c) Anne, A.; Fraoua,
S.; Hapiot, P.; Moiroux, J.; Save´ant, J.-M. J. Am. Chem. Soc. 1995, 117,
7412. (d) Hapiot, P.; Moiroux, J.; Save´ant, J.-M. J. Am. Chem. Soc. 1990,
112, 1337. (e) Anne, A.; Hapiot, P.; Moiroux, J.; Neta, P.; Save´ant, J.-M.
J. Phys. Chem. 1991, 95, 2370. (f) Anne, A.; Hapiot, P.; Moiroux, J.; Neta,
P.; Save´ant, J.-M. J. Am. Chem. Soc. 1992, 114, 4694. (g) Anne, A.;
Moiroux, J.; Save´ant, J.-M. J. Am. Chem. Soc. 1993, 115, 10224.
(10) (a) Miller, L. L.; Valentine, J. R. J. Am. Chem. Soc. 1988, 110,
3982. (b) Klippenstein, J.; Arya, P.; Wayner, D. D. M. J. Org. Chem. 1991,
56, 6736. (c) Bunting, J. W.; Stefanidis, D. J. Org. Chem. 1986, 51, 2060.
(d) Carlson, B. W.; Miller, L. L. J. Am. Chem. Soc. 1985, 107, 479. (e)
Bardea, A.; Katz, E.; Bu¨ckmann, A. F.; Willner, I. J. Am. Chem. Soc. 1997,
119, 9114.
(11) (a) Sigman, D. S.; Hajdu, J.; Creighton, D. J. In Bioorganic
Chemistry; van Tamelen, E. E., Ed.; Academic Press: New York, 1978;
Vol. IV, p 385. (b) Gase, R. A.; Pandit, U. K. J. Am. Chem. Soc. 1979,
101, 7059. (c) Ohno, A.; Yamamoto, H.; Oka, S. J. Am. Chem. Soc. 1981,
103, 2041. (d) Ohno, A.; Shio, T.; Yamamoto, H.; Oka, S. J. Am. Chem.
Soc. 1981, 103, 2045.
(12) (a) Fukuzumi, S.; Nishizawa, N.; Tanaka, T. J. Chem. Soc., Perkin
Trans. 2 1985, 371. (b) Ishikawa, M.; Fukuzumi, S. J. Chem. Soc., Faraday
Trans. 1990, 86, 3531.
(13) (a) Fukuzumi, S. Bull. Chem. Soc. Jpn. 1997, 70, 1. (b) Fukuzumi,
S.; Itoh, S. In AdVances in Photochemistry; Neckers, D. C., Volman, D.
H., von Bu¨nau, G., Eds.; Wiley: New York, 1998; Vol. 25, pp 107-172.
(14) Fukuzumi, S. In Electron Transfer in Chemistry; Balzani, V., Ed.;
Wiley-VCH: Weinheim, Germany, 2001; Vol. 4, pp 3-59.
(15) (a) Fukuzumi, S.; Okamoto, T. J. Am. Chem. Soc. 1993, 115, 11600.
(b) Itoh, S.; Kawakami, H.; Fukuzumi, S. J. Am. Chem. Soc. 1998, 120,
7271. (c) Itoh, S.; Kawakami, H.; Fukuzumi, S. J. Am. Chem. Soc. 1997,
119, 439. (d) Itoh, S.; Kawakami, H.; Fukuzumi, S. Biochemistry 1998,
37, 6562.
(16) (a) Fukuzumi, S.; Okamoto, T.; Otera, J. J. Am. Chem. Soc. 1994,
116, 5503. (b) Fukuzumi, S.; Tanaka, T. In Photoinduced Electron Transfer;
Fox, M. A., Chanon, M., Eds.; Elsevier: Amsterdam, The Netherlands,
1988; Part C, Chapter 11, pp 636-687.
(17) (a) Kagan, H. B.; Namy, J. L. Tetrahedron 1986, 42, 6573. (b)
Molander, G. A. Chem. ReV. 1992, 92, 29. (c) Imamoto, T. Lanthanides in
Organic Synthesis; Katritzky, A. R., Meth-Cohn, O., Rees, C. W., Eds.;
Academic Press: London, UK, 1994. (d) Kobayashi, S. Synlett 1994,
689. (e) Marshmann, R. W. Aldrichim. Acta 1995, 28, 77. (f) Inanaga,
J.; Yamaguchi, M. In New Aspects of Organic Chemistry; Yoshida, Z.,
Shiba, T., Ohshiro, Y., Eds.; VCH: New York, 1989; Chapter 4, p 55.
(g) Molander, G. A.; Harris, C. R. Chem. ReV. 1996, 96, 307. (h)
Shibasaki, M.; Sasai, H.; Arai, T. Angew. Chem., Int. Ed. Engl. 1997, 36,
1236.
(18) (a) Kobayashi, S.; Nagayama, S.; Busujima, T. J. Am. Chem. Soc.
1998, 120, 8287. (b) Kobayashi, S.; Ishitani, H. J. Am. Chem. Soc. 1994,
116, 4083. (c) Marko´, I. E.; Evans, G. R. Tetrahedron Lett. 1994, 35, 2771.
(d) Kawada, A.; Mitamura, S.; Kobayashi, S. Chem. Commun. 1996, 183.
(e) Kobayashi, S.; Araki, M.; Hachiya, I. J. Org. Chem. 1994, 59, 3758.
(19) (a) Ishihara, K.; Kubota, M.; Kurihara, H.; Yamamoto, H. J. Org.
Chem. 1996, 61, 4560. (b) Ishihara, K.; Kubota, M.; Kurihara, H.;
Yamamoto, H. J. Am. Chem. Soc. 1995, 117, 4413, 6639. (c) Kobayashi,
S.; Nagayama, S. J. Am. Chem. Soc. 1998, 120, 2985. (d) Kobayashi, S.;
Hachiya, I.; Araki, M.; Ishitani, H. Tetrahedron Lett. 1993, 34, 3755. (e)
Kawada, A.; Mitamura, S.; Kobayashi, S. Synlett 1994, 689. (f) Kobayashi,
S.; Moriwaki, M.; Hachiya, I. J. Chem. Soc., Chem. Commun. 1995, 1527.
(g) Kobayashi, S.; Nagayama, S. J. Org. Chem. 1996, 61, 2256. (h)
Kobayashi, S.; Nagayama, S. J. Am. Chem. Soc. 1996, 118, 8977. (i) Bisi
Castellani, C.; Carugo, O.; Giusti, M.; Leopizzi, C.; Perotti, A.; Invernizzi
Gamba, A.; Vidari, G. Tetrahedron 1996, 52, 11045. (j) Lacoˆte, E.; Renaud,
P. Angew. Chem., Int. Ed. Engl. 1998, 37, 2259.
Experimental Section
Materials. Preparation of 1-benzyl-1,4-dihydronicotinamide (BNAH)
was described previously.23 The dideuterated compound, 1-benzyl-1,4-
dihydro[4,4′-2H2]nicotinamide (BNAH-4,4′-d2), was prepared from
monodeuterated compound (BNAH-4-d1)24 by three cycles of oxidation
with p-chloranil in dimethylformamide and reduction with dithionite
in deuterium oxide.25 The deuterated p-benzoquinone (p-benzoquinone-
d4) was obtained commercially from Aldrich and used as received. The
tert-butylated BNAH (t-BuBNAH) was prepared by the Grignard
reaction with BNA+Cl- and purified by recrystallization from etha-
nol.26,27 The BNA dimer was prepared according to the literature.28,29
Cobalt(II) tetraphenylporphyrin (CoTPP) was prepared as given in the
literature.30 Scandium triflate [Sc(OTf)3] was prepared by the following
procedure according to the literature.31 A deionized aqueous solution
was mixed (1:1 v/v) with trifluoromethanesulfonic acid (>99.5%, 10.6
mL) obtained from Central Glass, Co., Ltd., Japan. The trifluorometh-
anesulfonic acid solution was slowly added to a flask which con-
tained scandium oxide (Sc2O3) (> 99.9%, 30 mmol) obtained from
Shin Etsu Chemical, Co., Ltd., Japan. The mixture was refluxed at 100
°C for 3 days. After centrifugation, the solution containing scandium
triflate was separated and water was removed by vacuum evapora-
tion. Scandium triflate was dried under vacuum evacuation at 403 K
for 40 h. Similarly, lutetium triflate and yttrium triflate were prepared
by the reaction of lutetium oxide and yttrium oxide with an aqueous
trifluormethanesulfonic acid solution. Anhydrous magnesium perchlo-
(20) (a) Hilgeroth, A.; Kuna, K.; Kuckla¨nder, U. Heterocycles 1998, 48,
1649. (b) Hilgeroth, A.; Brachwitz, K.; Baumeister, U. Heterocycles 2001,
55, 661.
(21) (a) van Eikeren, P.; Grier, D. L.; Eliason, J. J. Am. Chem. Soc.
1979, 101, 7406. (b) Kim, C. S. Y.; Chaykin, S. Biochemistry 1968, 7,
2339. (c) Fukuzumi, S.; Ishikawa, M.; Tanaka, T. Tetrahedron 1986, 42,
1021.
(22) (a) Tagaki, W.; Sakai, H.; Yano, Y.; Ozeki, K.; Shimizu, Y.
Tetrahedron Lett. 1976, 2541. (b) Powell, M. F.; Bruice, T. C. J. Am. Chem.
Soc. 1983, 105, 7139.
(23) Fukuzumi S.; Koumitsu, S.; Hironaka, K.; Tanaka, T. J. Am. Chem.
Soc. 1987, 109, 305.
(24) (a) Anderson, A. G., Jr.; Berkelhammer, G. J. Am. Chem. Soc. 1958,
80, 992. (b) Mauzerall, D.; Westheimer, F. H. J. Am. Chem. Soc. 1955, 77,
2261.
(25) Caughey, W. S.; Schellenberg, K. A. J. Org. Chem. 1966, 31, 1978.
(26) Anne, A. Heterocycles 1992, 34, 2331.
(27) Takada, N.; Itoh, S.; Fukuzumi, S. Chem. Lett. 1996, 1103.
(28) Wallenfels, K.; Gellerich, M. Chem. Ber. 1959, 92, 1406.
(29) Patz, M.; Kuwahara, Y.; Suenobu, T.; Fukuzumi, S. Chem. Lett.
1997, 567.
(30) Shirazi, A.; Goff, H. M. Inorg. Chem. 1982, 21, 3420.
(31) (a) Forsberg, J. H.; Spaziano, V. T.; Balasubramanian, T. M.; Liu,
G. K.; Kinsley, S. A.; Duckworth, C. A.; Poteruca, J. J.; Brown, P. S.;
Miller, J. L. J. Org. Chem. 1987, 52, 1017. (b) Kobayashi, S.; Hachiya, I.
J. Org. Chem. 1994, 59, 3590. (c) Kobayashi, S.; Hachiya, I.; Ishitani, H.;
Araki, M. Synlett 1993, 472. (d) Thom, K. F. U.S. Patent 3615169, 1971;
Chem. Abstr. 1972, 76, 5436a.

Cycloaddition Vs Hydride Transfer Reactions
J. Am. Chem. Soc., Vol. 123, No. 42, 2001 10193
Table 1. Summary of X-ray Crystallographic Data of the
Cycloadduct (1)
For 1H NMR measurements, a CD3CN solution (0.4 mL) of
t-BuBNAH (2.0 × 10-2 M) was added to an NMR tube that contained
a CD3CN solution (0.4 mL) of p-benzoquinone (2.0 × 10-2 M) in the
presence of Sc(OTf)3 (1.0 × 10-1 M) under an atmospheric pressure
of argon. Then the solution was degassed by bubbling with argon for
5 min, and the NMR tube was sealed with a rubber septum. The
products in the reaction of t-BuBNAH with p-benzoquinone derivatives
in the presence of Sc(OTf)3 are identified as a mixture of the
corresponding cycloadduct (4, t-BuBNAH-(2,5-Cl2Q); 5, t-BuBNAH-
(2,5-Me2Q); 6, t-BuBNAH-(2,6-Me2Q)), BNA+ (7). The products in
the reaction of t-BuBNAH with Q in the presence of Lu(OTf)3 (1.0 ×
10-1 M), Y(OTf)3 (1.0 × 10-1 M), or Mg(ClO4)2 (1.0 M) are identified
as a mixture of the corresponding cycloadduct (1), BNA+ (7),
t-BuBNA+ (8), and hydroquinone (9). The 1H NMR measurements
were performed with a Japan Electron Optics JNM-GSX-400 (400
MHz) NMR spectrometer at 300 K. Chemical shifts of 1H NMR
were expressed in parts per million downfield from tetramethylsilane
as an internal standard (δ ) 0). FAB mass spectra were obtained with
compound
empirical formula
formula weight
crystal system
space group
a, Å
t-BuBNAH-Q
C25H31N2O3.5
415.53
monoclinic
C2/c (no. 15)
28.519(8)
b, Å
14.996(3)
c, Å
10.628(3)
R, deg
â, deg
96.35(3)
γ, deg
V, Å3
4517(2)
Z
8
F(000)
D
1784.00
1.222
calc, g/cm3
T, °C
23.0
crystal size, mm
µ(Mo KR), cm-1
diffractometer
radiation
scan type
2θmax, deg
scan width, deg
scan rate in ω, deg/min
no. of reflns measd
no. of reflns obsd [I > 3.00σ(I)]
no. of variables
R
0.20 × 0.20 × 0.40
a JEOL JMS-DX303 HF mass spectrometer. 1: UV-vis [MeCN, λmax
,
0.81
Rigaku AFC5R
nm (ꢀ, Μ-1 cm-1)] 289 (1.5 × 104). FAB-MS: mass calcd. for
C23H26N2O3, 379; found 379. 1H NMR (CD3CN) δ (ppm) 7.60 (s, 1H),
7.37-7.26 (m, 5H), 7.16 (s, 1H), 6.75 (d, J ) 2.4 Hz, 1H), 6.62 (d, J
) 8.3 Hz, 1H), 6.52 (ddd, J ) 8.3, 2.4, 1.0 Hz, 1H), 5.7 (s, 2H), 5.48
(d, J ) 7.8 Hz, 1H), 4.42 (d, J ) 14.7 Hz, 1H), 4.17 (d, J ) 14.7 Hz,
1H), 4.01 (d, J ) 7.8 Hz, 1H), 2.96 (d, J ) 1.0 Hz, 1H), 0.87 (s, 9H).
MoKR (0.71069 Å)
ω - 2θ
55.1
1.84 + 0.35 tan θ
10.0
5610
1181
272
0.065
1
2: FAB-MS: mass calcd. for C19H18N2O3, 322; found 322. H NMR
(CD3CN) δ (ppm) 9.48 (s, 1H), 7.37-7.26 (m, 5H), 7.27 (s, 1H), 6.72
(d, J ) 2.6 Hz, 1H), 6.58 (dd, J ) 8.4, 2.6 Hz, 1H), 6.55 (d, J ) 8.4
Hz, 1H), 5.91 (s, 2H), 5.41 (d, J ) 6.6 Hz, 1H), 4.54 (d, J ) 15.4 Hz,
1H), 4.40 (d, J ) 15.4 Hz, 1H), 3.30 (d, J ) 7.3 Hz, 1H), 2.58 (dd, J
) 15.8, 6.6 Hz, 1H), 2.14 (dd, J ) 15.8, 7.3 Hz, 1H). 3: 1H NMR
(CD3CN) δ (ppm) 7.95 (s, 1H), 7.39-7.33 (m, 5H), 6.66 (d, J ) 8.4
Hz, 1H), 6.60 (d, J ) 2.6 Hz, 1H), 6.57 (ddd, J ) 8.4, 2.6, 1.1 Hz,
1H), 5.33 (d, J ) 7.0 Hz, 1H), 4.62 (d, J ) 14.7 Hz, 1H), 4.46 (d, J
) 14.7 Hz, 1H), 3.94 (d, J ) 7.0 Hz, 1H), 2.76 (d, J ) 1.1 Hz, 1H),
1.82 (m, 1H), 1.00 (d, J ) 7.0 Hz, 3H), 0.76 (d, J ) 7.0 Hz, 3H). 4:
1H NMR (CD3CN) δ (ppm) 8.07 (s, 1H), 7.42-7.32 (m, 5H), 6.83 (s,
1H), 5.53 (d, J ) 7.8 Hz, 1H), 4.60 (d, J ) 14.3 Hz, 1H), 4.48 (d, J
) 14.3 Hz, 1H), 4.43 (d, J ) 7.8 Hz, 1H), 3.56 (s, 1H), 0.87 (s, 9H).
5: 1H NMR (CD3CN) δ (ppm) 8.09 (s, 1H), 7.41-7.31 (m, 5H), 6.43
(s, 1H), 5.39 (d, J ) 7.8 Hz, 1H), 4.68 (d, J ) 14.3 Hz, 1H), 4.46 (d,
J ) 14.3 Hz, 1H), 4.26 (d, J ) 7.8 Hz, 1H), 2.98 (s, 1H), 2.17 (s, 3H),
2.05 (s, 3H), 0.89 (s, 9H). 6: 1H NMR (CD3CN) δ (ppm) 8.11 (s, 1H),
7.44-7.34 (m, 5H), 6.46 (s, 1H), 5.42 (d, J ) 8.1 Hz, 1H), 4.65 (d, J
) 14.3 Hz, 1H), 4.48 (d, J ) 14.3 Hz, 1H), 4.28 (d, J ) 8.1 Hz, 1H),
2.94 (s, 1H), 2.25 (s, 3H), 2.12 (s, 3H), 0.90 (s, 9H). 7: UV-vis
[MeCN, λmax, nm (ꢀ, Μ-1 cm-1)] 266 (7.0 × 103). 1H NMR (CD3CN)
δ (ppm) 9.17 (s, 1H), 8.86 (d, J ) 6.0 Hz, 1H), 8.84 (d, J ) 7.9 Hz,
1H), 8.14 (dd, J ) 7.9, 6.0 Hz, 1H), 7.51-7.43 (m, 5H), 5.80 (s,
2H). 8: 1H NMR (CD3CN) δ (ppm) 8.68 (s, 1H), 8.63 (d, J ) 6.8 Hz,
1H), 8.08 (d, J ) 6.8 Hz, 1H), 7.50-7.42 (m, 5H), 5.67 (s, 1H),
1.44 (s, 9H). 9: UV-vis [MeCN, λmax, nm (ꢀ, Μ-1 cm-1)] 225 (6.6 ×
Rw
0.070
rate was obtained from Nacalai Tesque. Acetonitrile (MeCN) used as
a solvent was purified and dried by the standard procedure.32 Aceto-
nitrile-d3 (CD3CN) and chloroform-d were obtained from EURI
SO-TOP, CEA, France.
Reaction Procedures and Analysis. The isolation of the cycloadduct
of t-BuBNAH with p-benzoquinone was performed as follows. Typi-
cally, an MeCN solution of t-BuBNAH (2.0 × 10-2 M, 50 mL) was
added to the reaction vessel that contained a solution (50 mL) of
p-benzoquinone (Q; 2.0 × 10-2 M) in the presence of Sc(OTf)3 (6.0 ×
10-2 M) under an atmospheric pressure of argon. After the reaction
was completed in 30 min, the resulting solution was evaporated. The
residue was dissolved in diethyl ether and washed with deionized water.
The organic layer was separated and the solvent was removed from
the reaction mixture by distillation at 313 K under vacuum. The
yellowish white solid residue was dried in a vacuum. The isolated yield
of the cycloadduct (1, t-BuBNAH-Q) was 90%. The cycloadducts (2,
BNAH-Q; 3, i-PrBNAH-Q) were isolated in the same manner as 1.
The elemental analysis of isolated product (1) gave the satisfactory
result. 1: Anal. Calcd for C23H26N2O3‚0.5(C2H5)2O: C, 72.26; H, 7.52;
N, 6.74. Found: C, 72.05; H, 7.33; N, 6.86.
The isolated cycloadduct (1, t-BuBNAH-Q) were dissolved in MeCN
and recrystallized from MeCN under an atmospheric pressure of di-
ethyl ether vapor. The X-ray experiments were carried out on the
Rigaku AFC-5R diffractometer with graphite-monochromatized Mo KR
radiation and a rotating anode generator. The absorption effect was
corrected empirically on the basis of azimuthal scans of three reflec-
tions. The crystal structures were solved by direct method and refined
by full-matrix least-squares techniques. The non-hydrogen atoms were
refined anisotropically, while the hydrogen atoms located from the
final stage of difference Fourier maps were included with isotropic
thermal parameters. All the calculations were performed with the
TEXSAN program package.33 A summary of the fundamental crys-
tal data and experimental parameters for structure determinations are
given in Table 1. Atomic coordinates, thermal parameters, and
intramolecular bond distances and angles have been deposited as
Supporting Information.
1
103), 294 (3.5 × 103). H NMR (CD3CN) δ (ppm) 6.63 (s, 4H), 6.35
(s, 2H).
Spectral Measurements. The formation of rare-earth ion com-
plexes with t-BuBNAH was examined from the change in the UV-
vis spectra of t-BuBNAH (1.0 × 10-4 M) at λ ) 321 nm in the pres-
ence of various concentrations of Sc(OTf)3 (2.0 × 10-3 to 2.0 × 10-2
M), Lu(OTf)3, Y(OTf)3 (1.0 × 10-2 to 3.0 × 10-2 M), and Mg(ClO4)2
(1.0 × 10-4 to 5.0 × 10-1 M) using a Hewlett-Packard 8453 diode
array spectrophotometer. The formation constants were obtained from
the change in the UV-vis spectra due to the formation of the
complexes: t-BuBNAH-Sc3+ (λmax ) 364 nm), t-BuBNAH-Lu3+ (λmax
) 346 nm), t-BuBNAH-Y3+ (λmax ) 344 nm), and t-BuBNAH-Mg2+
(λmax ) 330 nm).
Kinetic Measurements. Kinetic measurements of cycloaddition
reactions of BNAH derivatives with substituted p-benzoquinones were
performed on a Hewlett-Packard 8453 diode array spectrophotometer.
Typically, a deaerated MeCN solution of t-BuBNAH (1.0 × 10-4 M)
was added to a quartz cuvette (i.d. 10 mm) containing an MeCN solution
of p-benzoquinone (2.0 × 10-3 M) and Sc(OTf)3 (1.0 × 10-3 to 5.0 ×
(32) Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory
Chemicals; Butterworth-Heinemann: Oxford, UK, 1988.
(33) TEXSAN, Single-Crystal Structure Analysis Software, Version 5.0;
Molecular Structure Corp.: The Woodlands, TX 77381, 1989.

10194 J. Am. Chem. Soc., Vol. 123, No. 42, 2001
Fukuzumi et al.
10-2 M) by means of a microsyringe under argon with stirring. Rates
of Sc3+-catalyzed cycloaddition reactions of t-BuBNAH with substituted
p-benzoquinones were monitored by measuring the decrease in absorp-
tion band at λmax ) 364 nm (ꢀmax ) 1.1 × 104 M-1 cm-1) due to the
t-BuBNAH-Sc3+ complex in MeCN at 298 K in the dark. In the reaction
of other BNAH derivatives with p-benzoquinone, the monitored
absorption bands are located at λmax ) 380 nm (ꢀmax ) 1.4 × 104 M-1
cm-1) for BNAH and λmax ) 372 nm (ꢀmax ) 1.3 × 104 M-1 cm-1) for
i-PrBNAH. Measurements of rates of electron-transfer reaction from
CoTPP (8.0 × 10-6 to 1.2 × 10-5 M) to p-benzoquinone derivatives
(2.6 × 10-4 M) in the presence and absence of Sc(OTf)3 (5.0 × 10-3
to 7.6 × 10-2 M) were performed using a Union RA-103 stopped-
flow spectrophotometer. The rates were monitored by the rise and decay
of the absorption band at 434 and 412 nm due to CoTPP+ and CoTPP
in MeCN at 298 K, respectively. All kinetic measurements were carried
out under pseudo-first-order conditions where concentrations of p-
benzoquinones were maintained at more than 10-fold excess of CoTPP
concentrations at 298 K. Pseudo-first-order rate constants were
determined by least-squares linear curve fits using a personal computer.
The pseudo-first-order plots were linear for 3 or more half-lives with
the correlation coefficient F > 0.999.
Figure 1. Spectral change observed in the cycloaddition reaction of
t-BuBNAH (5.0 × 10-5 M) with p-benzoquinone (5.0 × 10-5 M) in
the presence of Sc(OTf)3 (5.0 × 10-2 M) in deaerated MeCN at 298 K
(60 s interval). Inset: First-order plot based on the absorption change
at λ ) 360 nm in the cycloaddition reaction of t-BuBNAH (1.0 ×
10-4 M) with Q (2.0 × 10-3 M) in the presence of Sc(OTf)3 (2.0 ×
10-2 M) in deaerated MeCN at 298 K (3 s interval).
Theoretical Calculations. Density functional calculations were
performed on a COMPAQ DS20E computer using the spin-restricted
B3LYP functional for the open shell BNAH•+.34 The B3LYP geometry
of BNAH•+ was determined by using the 6-31++G(d) basis and the
Gaussian 98 program.35 The S2 value was determined as 0.773,
indicating a good representation of the doublet state. Graphical output
of the computational result was generated with the Cerius2 software
program developed by Molecular Simulations Inc.
Results and Discussion
Cycloaddition of NADH Analogues with p-Benzoquinone.
Upon addition of t-BuBNAH (1.0 × 10-4 M) to a deaerated
MeCN solution of p-benzoquinone (Q; 2.0 × 10-3 M) in the
presence of Sc(OTf)3 (1.0 × 10-2 M), the cycloaddition reaction
of t-BuBNAH with Q occurs efficiently at 298 K (see the
Experimental Section, R ) But in eq 1). As the reaction
proceeds, the absorption bands due to t-BuBNAH (λmax ) 364
nm) and Q (λmax ) 241 nm) decrease, and these are ac-
companied by the appearance of a new absorption band (λmax
) 320 nm) due to the formation of cycloadduct 1 with three
clear isosbestic points at 208, 262, and 337 nm (Figure 1). The
same spectral changes were observed in the reaction of BNAH
with Q (R ) H in eq 1). The product absorption band at 320
nm seen in Figure 1 agrees with that for the previously reported
water adduct of N-alkyl-1,4-dihydronicotinamide with a satu-
Figure 2. ORTEP drawing of the cycloadduct (1).
rated C(5)-C(6) bond.36 The cycloadducts 1 and 2 were isolated
and a single crystal of 1 was obtained for X-ray crystal structure
determination (see the Experimental Section). The ORTEP
drawing of 1 is shown in Figure 2 (the crystallographic data
are given in Table 1 and selected bond distances and angles for
the crystal structures of 1 are given in the Supporting Informa-
tion, S1).
(34) Becke, A. D. J. Chem. Phys. 1993, 98, 5648-5652.
(35) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A., Jr.;
Stratmann, R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels, A.
D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.; Barone, V.; Cossi,
M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford, S.;
Ochterski, J.; Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.; Malick,
D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Cioslowski, J.;
Ortiz, J. V.; Baboul, A. G.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz,
P.; Komaromi, I.; Gomperts, R.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-
Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Gonzalez, C.; Challacombe,
M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Andres, J. L.;
Gonzalez, C.; Head-Gordon, M.; Replogle, E. S.; Pople, J. A. Gaussian
98, Revision A.7; Gaussian, Inc.; Pittsburgh, PA, 1998.
Complex Formation between NADH Analogues and
Sc(OTf)3. The UV-vis absorption spectra of t-BuBNAH in
MeCN are significantly affected by the addition of metal ions
as shown in Figure 3. The absorption band at 321 nm due to
t-BuBNAH (1.0 × 10-4 M) is red shifted and the new absorption
band at 364 nm appeared with a distinct isosbestic point at 327
nm in the presence of Sc(OTf)3. Such spectroscopic changes
(36) (a) Johnston, C. C.; Gardner, J. L.; Suelter, C. H.; Metzler, D. E.
Biochemistry 1963, 2, 689. (b) Yoon, C.-J.; Ikeda, H.; Kojin, R.; Ikeda, T.;
Toda, F. J. Chem. Soc., Chem. Commun. 1986, 1080.

Cycloaddition Vs Hydride Transfer Reactions
J. Am. Chem. Soc., Vol. 123, No. 42, 2001 10195
Figure 3. Spectral change observed upon addition of Sc(OTf)3 (0-
4.0 × 10-5 M) to a deaerated MeCN solution containing t-BuBNAH
(1.0 × 10-4 M). Inset: The absorption change at λ ) 360 nm.
Figure 4. Dependence of kobs on [Sc3+] for (a) the cycloaddition
reaction of t-BuBNAH (1.0 × 10-4 M) with p-benzoquinone (2.0 ×
10-3 M) and (b) electron transfer from CoTPP (8.0 × 10-6 M) to
p-benzoquinone (2.6 × 10-4 M) in the presence of Sc(OTf)3 in deaerated
MeCN at 298 K.
shown in Figure 3 are ascribed to formation of the complex
between t-BuBNAH and Sc(OTf)3. The stoichiometry is estab-
lished by spectral titration (see the inset of Figure 3), where
t-BuBNAH forms a 4:1 complex with Sc3+ (eq 2).37 The same
spectral changes were observed for the complex formation of
obeyed second-order kinetics, showing a first-order dependence
on each reactant concentration. The dependence of the ob-
served electron-transfer rate constant (ket) on [Sc3+] was also
examined for electron transfer from CoTPP to Q at various
concentrations of Sc3+. The results are shown in Figure 4b,
where the ket value increases linearly with [Sc3+] to show a
first-order dependence on [Sc3+] at low concentrations, changing
to a second-order dependence at high concentrations as is the
case of the Sc3+-catalyzed cycloaddition of t-BuBNAH with Q
in Figure 4a.
4 t-BUBNAH + Sc3+ a (t-BuBNAH)4Sc3+
(2)
BNAH (λmax ) 348 nm) with Sc3+ ((BNAH)4Sc3+; λmax ) 380
nm). Other rare earth metal ions (Lu3+, Y3+) also form
complexes with t-BuBNAH ((t-BuBNAH)4Lu3+, λmax ) 346
nm; (t-BuBNAH)4Y3+, λmax ) 344 nm).
Kinetics of Sc3+-Catalyzed Cycloaddition and Electron-
Transfer Reactions. The rates of reactions of t-BuBNAH with
Q in the presence of Sc3+ (2.0 × 10-2 M) in MeCN at 298 K
were determined by monitoring the disappearance of absorbance
There is no interaction between Q and Sc3+ as indicated by
the lack of spectral change of Q in the presence of Sc3+. In
such a case, the acceleration of electron transfer from CoTPP
to Q is ascribed to the complexation of Sc3+ with Q•-. Since
due to the t-BuBNAH-Sc3+ complex (λmax ) 364 nm, ꢀmax
)
1.1 × 104 M-1 cm-1). The rates obeyed pseudo-first-order
kinetics in the presence of a large excess of Q and Sc3+ relative
to the concentration of t-BuBNAH (see inset of Figure 1). The
pseudo-first-order rate constant increases proportionally with
Q concentration (see the Supporting Information, S3). Thus,
the rate exhibits the second-order kinetics showing a first-order
dependence on each reactant concentration.
there are two carbonyl oxygens which can interact with Sc3+
,
Q
•- may form not only a 1:1 complex (n ) 1 in eq 3) but also
a 1:2 complex (n ) 2 in eq 3) with Sc3+. The complex for-
mation of Q•- and Sc3+ should result in the positive shift of
the one-electron reduction potential of Q (Ered) and the
Nernst equation is given by eq 4, where E0 is the one-elec-
red
The dependence of the observed second-order rate constant
(kobs) on [Sc3+] was examined for the cycloaddition reactions
of t-BuBNAH with Q at various concentrations of Sc3+. The
tron reduction potential of Q in the absence of Sc3+, where K1
Ered ) E0red + (2.3RT/F) logK1[Sc3+](1 + K2[Sc3+]) (4)
k
obs value increases with an increase in [Sc3+] to exhibit a first-
order dependence on [Sc3+] at low concentrations, changing to
a second-order dependence at high concentrations as shown in
Figure 4a.
and K2 are the formation constants for the 1:1 and 1:2 complexes
between Q•- and Sc3+, respectively. Since Sc3+ has no effect
on the oxidation potential of CoTPP, the free energy change of
electron transfer from CoTPP to Q in the presence of Sc3+
(∆Get) can be expressed by eq 5, where ∆G0et is the free energy
change in the absence of Sc3+. Thus, electron transfer from
Such a mixture of first-order and second-order dependence
on [Sc3+] is also observed in electron transfer from CoTPP (TPP
) tetraphenylporphyrin dianion) to Q. No electron transfer from
CoTPP to Q has occurred in MeCN at 298 K. In the presence
of Sc(OTf)3, however, an efficient electron transfer from CoTPP
to Q occurs to yield CoTPP+ (eq 3). The electron-transfer rates
∆Get ) ∆G0et - (2.3RT) log(K1[Sc3+] + K1K2[Sc3+]2) (5)
CoTPP to Q becomes more favorable energetically with an
increase in concentration of Sc3+. If such a change in the
energetics is directly reflected in the transition state of electron
transfer, the dependence of the observed rate constant of electron
(37) The rate of formation of the complex may be diffusion-limited
because the rate was too fast to be followd with a stopped-flow tech-
nique.

10196 J. Am. Chem. Soc., Vol. 123, No. 42, 2001
Fukuzumi et al.
respective of different reactivities of NADH analogues (see k0K1
values in Table 2). In each case, the K2 value agrees within the
experimental error with the value (40 M-1) determined from
the Sc3+-promoted electron transfer reaction (Table 2). Such
an agreement strongly indicates that the catalytic function of
Sc3+ in the cycloaddition reactions of NADH analogues with
Q is essentially the same as the function in electron transfer
from CoTPP to Q. This means that the cycloaddition of the
NADH analogues with Q proceeds via a rate-determining elec-
tron transfer from NADH analogues to Q, which is accelerated
by formation of the 1:1 and 1:2 complex between Q•- with Sc3+
as in the case of an electron transfer from CoTPP to Q.
The K2 value may change depending on the substituents on
Q. This was examined by determining the dependence of kobs
and ket on [Sc3+] for the cycloaddition of t-BNAH with
substituted p-benzoquinone derivatives and also the electron
transfer from CoTPP to the same p-benzoquinone derivatives.
The linear plots of kobs/[Sc3+] vs [Sc3+] and ket/[Sc3+] vs [Sc3+
]
are shown in Figure 6, parts a and b, respectively. The K2 values
determined from the linear plots are also listed in Table 2. The
K2 value (25 M-1) determined in the Sc3+-promoted electron
transfer from CoTPP to a p-benzoquinone derivative with
electron-withdrawing substituents (2,5-dichloro-p-benzoquinone)
is smaller than the corresponding K2 value of p-benzoquinone
(40 M-1) as expected from the weaker basicity of the radical
anion with the electron-withdrawing substituents as compared
to the basicity of the unsubstituted semiquinone radical anion.
In each case, the K2 value determined from the Sc3+-catalyzed
cycloaddition reactions with the p-benzoquinone derivative
agrees with the value determined from the corresponding Sc3+
-
Figure 5. (a) Plots of kobs/[Sc3+] vs [Sc3+] for the cycloaddition reaction
(O) of t-BuBNAH (1.0 × 10-4 M) with Q (2.0 × 10-3 M) and electron
transfer from CoTPP to Q (b) in the presence of Sc(OTf)3 in deaerated
MeCN at 298 K. (b) Plots of kobs/[Sc3+] vs [Sc3+] for the cycloaddition
reaction of BNAH i-PrBNAH (1.0 × 10 -4 M) with Q (2.0 × 10-3 M)
in the presence of Sc(OTf)3 in deaerated MeCN at 298 K.
promoted electron-transfer reaction (Table 2). Such an agree-
ment confirms that the Sc3+-catalyzed cycloaddition of the
NADH analogues with the p-benzoquinone derivative (X-Q)
proceeds via the rate-determining Sc3+-promoted electron
transfer from NADH analogues to X-Q.
Detection of Semiquinone Radical Anion-Sc3+ Complexes.
The 1:2 complex formation between Q•- and Sc3+ has been
confirmed by observation of the ESR spectrum of the Q•--2Sc3+
complex which shows the superhyperfine structure due to the
interaction of Q•- with two equivalent Sc nuclei. Since the Q•--
2Sc3+ complex is unstable because of the facile disproportion-
ation reaction, the complex was generated in photoinduced
electron transfer from dimeric 1-benzyl-1,4-dihydronicotinamide
[(BNA)2]39,40 to Q at low temperatures. The (BNA)2 is known
to act as a unique electron donor to produce the radical anions
of electron acceptors.40 The photochemical reaction was carried
out in an ESR cavity where an ESR tube containing a
propionitrile (EtCN) solution of (BNA)2, Q, and Sc3+ was
irradiated with a mercury lamp at 203 K. Propionitrile was used
instead of MeCN to avoid freezing the solvent at 203 K. The
observed ESR spectrum of Q•- in the presence of Sc3+ (4.4 ×
10-2 M) is shown in Figure 7a. The well-resolved 19 lines of
the spectrum clearly indicate the hyperfine splitting (a(H)) due
to 4 protons of semiquinone radical anions and superhyperfine
transfer (ket) on [Sc3+] is derived from eq 5, as given by eq 6,
where k0 is the rate constant in the absence of Sc3+. The validity
of eq 6 is confirmed by the linear plot of ket/[Sc3+] vs [Sc3+
]
for the Sc3+-promoted electron transfer from CoTPP to Q as
ket /[Sc3+] ) k0K1(1 + K2[Sc3+])
(6)
shown in Figure 5a (closed circles).38 From the slopes and
intercepts are obtained the K2 value, which is listed in Table 2,
together with the k0K1 value.
There is a striking similarity with respect to the dependence
of ket (or kobs) on [Sc3+] between the electron-transfer reactions
from CoTPP to Q (Figure 4a) and the cycloaddition reaction of
t-BuBNAH with Q (Figures 4b), despite the large difference in
their reactivities. Thus, the same plot as in eq 6 for the Sc3+
-
promoted electron transfer from CoTPP to Q can be applied
for the Sc3+-catalyzed cycloaddition reactions of t-BuBNAH
with Q as shown in Figure 5a (open circles). The K2 value for
the 1:2 complex formation between Q•- and Sc3+ is obtained
from the linear plot as listed in Table 2. The dependence of
kobs on [Sc3+] was also determined for the cycloaddition reac-
tions of BNAH and i-PrBNAH with Q. The K2 values are also
determined from the linear plots of kobs/[Sc3+] vs [Sc3+] in Fig-
ure 5b and they are listed in Table 2. These K2 values (46-49
M-1) are essentially the same within experimental error ir-
7
splitting (a(Sc)) of two equivalent Sc3+ nuclei (I ) /2). The
coupling constants are almost the same between a(H) and a(Sc),
resulting in the overall nuclear spin ) 9 that causes 19 lines.
The computer simulation spectrum with a(H) ) 1.15 G, a(Sc)
) 1.15 G with a line width (∆Hmsl) ) 0.50 G is shown in Figure
5b for comparison. The observed ESR spectrum in Figure 5b
clearly demonstrates the formation of the 1:2 complex between
(39) Patz, M.; Kuwahara, Y.; Suenobu, T.; Fukuzumi, S. Chem. Lett.
1997, 567.
(40) Fukuzumi, S.; Suenobu, T.; Patz, M.; Hirasaka, T.; Itoh, S.;
Fujitsuka, M.; Ito, O. J. Am. Chem. Soc. 1998, 120, 8060.
(38) Since Sc3+ is bound to the reaction product (eq 3), the reaction is
called “Sc3+-promoted” electron transfer. In the case of the cycloaddition
reactions (eq 1), Sc3+ acts as a real catalyst.

Cycloaddition Vs Hydride Transfer Reactions
J. Am. Chem. Soc., Vol. 123, No. 42, 2001 10197
Table 2. Rate Constants (k0K1) of Sc3+-Catalyzed Cycloaddition Reactions of NADH Analogues with p-Benzoquinone Derivatives (X-Q) and
the Formation Constants (K2) of the X-Q•--2Sc3+ Complexes in Deaerated MeCN at 298 Ka
NADH analogue
p-benzoquinone derivative
k0K1,b M-2 s-1
K2,b M-1
t-BuBNAH
i-PrBNAH
BNAH
BNAH
BNAH
p-benzoquinone
p-benzoquinone
p-benzoquinone
2,5-dichloro-p-benzoquinone
2,5-dimethyl-p-benzoquinone
2,6-dimethyl-p-benzoquinone
7.3 × 102 (2.7 × 105)
4.7 × 103 (2.7 × 105)
1.3 × 104 (2.7 × 105)
2.2 × 102 (9.3 × 105)
6.6 × 10 (1.1 × 105)
1.0 × 10 (8.0 × 104)
4.6 × 10 (4.0 × 10)
4.9 × 10 (4.0 × 10)
4.9 × 10 (4.0 × 10)
2.6 × 10 (2.5 × 10)
4.8 × 10 (4.3 × 10)
4.3 × 10 (4.7 × 10)
BNAH
a K1 and K2 are the formation constants for the 1:1 and 1:2 complexes between Q•- and Sc3+, respectively; k0 is the rate constant in the absence
of Sc3+ (see text). b Determined from the dependence of kobs on [Sc3+] based on eq 6. The experimental error is 10%. Values in parentheses are
those determined for Sc3+-promoted electron transfer from CoTPP to X-Q.
Figure 7. (a) ESR spectrum of a propionitrile solution containing
(BNA)2 (1.6 × 10-2 M), p-benzoquinone (4.9 × 10-2 M), and
Figure 6. Plots of kobs/[Sc3+] vs [Sc3+] for (a) the cycloaddition
Sc(OTf)3 (4.4 × 10-2 M) irradiated with a high-pressure mercury lamp
reactions of t-BuBNAH and (b) electron-transfer reactions of CoTPP
at 203 K. (b) Computer simulation spectrum with g ) 2.0034, a(4H)
with 2,5-dichloro-p-benzoquinone, 2,5-dimethyl-p-benzoquinone, and
) a(2Sc) ) 1.15 G, and ∆Hmsl ) 0.50 G.
2,6-dimethyl-p-benzoquinone in MeCN at 298 K.
Me2Q•-) and Sc3+ is confirmed by the ESR spectra of the
2,5-Me2Q•--2Sc3+ complex and the corresponding computer
simulation spectra as shown in Figure 7, parts c and d, re-
spectively.
Q•- and Sc3+ (eq 7).41 Similarly, the 1:2 complex formation
Mechanisms of Metal Ion-Catalyzed Cycloaddition vs
Hydride Transfer Reactions. In the cycloaddition reactions
of t-BNAH and BNAH with Q (eqs 1 and 2, respectively), the
C-H bond of Q is cleaved to yield the adducts. If the Sc3+
-
promoted electron transfer from t-BNAH and BNAH to Q is
the rate-determining step as indicated from the catalytic function
of Sc3+ in comparison with that in the electron-transfer reaction
with CoTPP (vide supra), the C-H bond cleavage process
should be fast enough that no primary kinetic isotope effect
can be observed. This is confirmed by the primary kinetic
deuterium isotope effect (kH/kD) in the Sc3+-catalyzed cycload-
dition reaction of t-BuBNAH with Q, where the deuterium-
(41) The 1:2 complex between Q•- and Sc3+ is exclusively formed at
203 K probably because of the large K2 value at the low temperature as
compared to the value at 298 K in Table 2.
between the radical anion of 2,6-dimethyl-p-benzoquinone (2,5-

10198 J. Am. Chem. Soc., Vol. 123, No. 42, 2001
Fukuzumi et al.
Table 3. Yields of Products in Reactions of BNAH and
t-BuBNAH with p-Benzoquinone in the Presence of a Metal Ion
[Sc(OTf)3, Lu(OTf)3, Y(OTf)3 (1.0 × 10-1 M), or Mg(ClO4)2 (1.0
M)] and Rate Constants (kobs) of Reactions of t-BuBNAH (1.0 ×
10-4 M) with p-Benzoquinone (2.0 × 10-3 M) in the Presence of
Metal Ions (3.0 × 10-2 M) in Deaerated MeCN at 298 K
yield (%)
t-BuBNAH
BNAH
metal
102kobs
,
ion cycloadduct BNA+ t-BuBNA+ cycloadduct BNA+ M-1 s-1
Sc3+
Lu3+
Y3+
100
72
59
0
28
41
5
0
0
0
100
33
21
7
0
67
79
93
5.3 × 103
6.1
3.1
Mg2+
35
60
0.26a
a Mg(ClO4)2 (5.0 × 10-1 M).
labeled Q (Q-2,3,5,6-d4) was utilized (eq 8). The kH/kD value is
Figure 8. Dependence of kobs on [M3+] for the reaction of t-BuBNAH
(1.0 × 10-4 M) with Q (2.0 × 10-3 M) in the presence of Sc(OTf)3
(O), Lu(OTf)3 (4), or Y(OTf)3 (b) in deaerated MeCN at 298 K.
Scheme 1
unity at various Sc3+ concentrations (see the Supporting
Information, S3). The kH/kD value for the Sc3+-catalyzed
cycloaddition reaction of BNAH with Q (Q-2,3,5,6-d4) is also
found to be unity at various Sc3+ concentrations (S3).
When Sc3+ is replaced by other metal ions such as Lu3+ [Lu-
(OTf)3], Y3+ [Y(OTf)3], or Mg2+ [Mg(ClO4)2] in the reaction
of t-BuBNAH with Q, BNA+ is formed together with the
cycloadduct. The product yields are listed in Table 3. In the
case of Mg2+, the cycloaddition is no longer the main reaction,
but a hydride transfer from t-BuBNAH to Q occurs to yield
t-BNA+ as the major product (60%) (Table 3). Thus, there are
three types of reactions depending on the type of metal ion, as
shown in Scheme 1, where one is the cycloaddition reaction,
another is a transfer of t-Bu- to Q, and the other is a hydride
transfer from t-BuBNAH to Q. The catalytic reactivity is also
changed drastically by the type of metal ions employed as the
catalyst. The kobs values were determined from the rates of
disappearance of the absorption band due to t-BuBNAH-metal
ion complexes in the reactions with Q in MeCN at 298 K. The
dependence of kobs on the metal ion concentration is shown in
Figure 8. The kobs values thus determined in the presence of a
fixed metal ion concentration are listed in Table 3, where the
kobs decreases in order Sc3+ . Lu3+ > Y3+ > Mg2+. This order
agrees with the Lewis acidity of the metal ions.42
When t-BuBNAH is replaced by BNAH in the reaction with
Q catalyzed by metal ions other than Sc3+, a hydride transfer
from BNAH to Q becomes the main reaction and the yield of
BNA+ increases in order Lu3+ (67%) < Y3+ (79%) < Mg2+
(93%) with a decrease in the Lewis acidity of the metal ion
(Table 3). The reaction mechanisms of Mg2+-catalyzed hydride
transfer from BNAH to Q have been extensively studied
chemically or electrochemically.3,12 However, this is the first
report disclosing the minor reaction pathway of the cycloaddition
(7%) competing with the major hydride transfer reaction
pathway (93%).
The Mg2+-catalyzed hydride transfer from BNAH to Q is
known to proceed via a Mg2+-promoted electron transfer from
BNAH to Q, followed by a proton transfer from the resulting
BNAH•+ to the Q•--2Mg2+ complex and the subsequent fast
electron transfer from BNA• to QH--Mg2+ 3a,12
The change in
.
the type of reaction depending on the Lewis acidity of the metal
ion in Scheme 1 is well accommodated in the electron-transfer
mechanism in Scheme 2. The initial rate-determining electron
transfer from t-BuBNAH to Q results in the formation of a
radical ion pair (t-BuBNAH•+ and Q•-) where Q•- forms 1:1
and 1:2 complexes with Sc3+ 43
. This is followed by fast radical
coupling between Q•- and t-BuBNAH•+ to give the zwitterionic
intermediate that is eventually converted to the cycloadduct 1.
In the same manner, the Sc3+-catalyzed cycloaddition reaction
of BNAH with Q proceeds via the Sc3+-promoted electron
transfer from BNAH to Q. The spin density distribution of
BNAH•+ calculated by using a density functional theory at the
UB3LYP/6-31++G* level is shown in Figure 9. There is a large
spin density (F ) 0.466) at C(5) of BNAH•+. Thus, the radical
coupling of C(5) of BNAH•+ with Q•--2Mn+ may occur
(43) The NADH analogue (t-BuBNAH) in Scheme 2 forms a 4:1 complex
with Sc3+ (eq 2), which reacts with Q, since the absorption maximum (364
nm) due to the complex remains the same during the reaction. For clarity
the complex formation is omitted in Scheme 2.
(42) Fukuzumi, S.; Ohkubo, K. Chem. Eur. J. 2000, 6, 4532.

Cycloaddition Vs Hydride Transfer Reactions
J. Am. Chem. Soc., Vol. 123, No. 42, 2001 10199
complex. This may be the reason the hydride transfer pathway
from BNAH to Q becomes dominant in the presence of a much
weaker Lewis acid (e.g., Mg2+) as compared to the selective
cycloaddition reaction in the presence of Sc3+ (see the product
yields in Table 3).44
In the case of t-BuBNAH, the C(4)-C bond of t-BuBNAH•+
is known to be cleaved to produce t-Bu•,9g,27,40 which can
combine with Q•--2Mn+ (pathway b in Scheme 2), leading to
the overall transfer of t-Bu- to Q. With decreasing the Lewis
acidity of the metal ion, the C(4)-C bond cleavage of t-BNAH•+
may also be accelerated due to the stronger basicity of the Q•--
2Mn+ complex. This may be the reason the overall transfer of
t-Bu- to Q (pathway b in Scheme 2) starts to compete with the
cycloaddition pathway as the Lewis acidity of the metal ion is
decreased (see the product yields in Table 3). The deprotonation
of t-BuBNAH•+ may be much slower as compared to that of
BNAH•+, since the replacement of one active hydrogen of
NADH analogues by an alkyl group is known to retard the
deprotonation of the radical cations.4d,e,9g Thus, only in the case
of Mg2+, which is the weakest Lewis acid employed as a catalyst
in this study, does the proton transfer from t-BuBNAH to Q•--
2Mn+ (pathway c in Scheme 2) compete with the radical
coupling process (pathway a in Scheme 2) to yield the hydride
transfer product (60% yield in Table 3).
Figure 9. Spin density distribution of BNAH•+ calculated by using a
density functional theory at the UB3LYP/6-31++G* level.
Scheme 2
Summary and Conclusions
Novel cycloaddition reactions have been accomplished via
the Sc3+ ion-catalyzed reaction of BNAH or substituted BNAH
with p-benzoquinones in MeCN at room temperature. The
crystal structure of the cycloadduct between BNAH derivatives
(t-BuBNAH) and p-benzoquinone was determined for the first
time.
The dependence of the rate constants of cycloaddition
reactions of BNAH analogues with p-benzoquinones on Sc3+
concentration agrees well with those of the electron-transfer rate
constants from CoTPP to the corresponding p-benzoquinones
on Sc3+ concentration. This indicates that the addition proceeds
via the Sc3+-promoted electron transfer from BNAH analogues
to Q, which is the rate-determining step. It has been shown for
the first time how the hydride transfer pathway is changed to
the cycloaddition pathway through the metal ion-promoted
electron transfer from NADH analogues to p-benzoquinone
derivatives depending on the Lewis acidity of the metal ion
(Scheme 2).
Acknowledgment. This work was partially supported by a
Grant-in-Aid for Scientific Research Priority Area (Nos. 11228205
and 13031059) from the Ministry of Education, Culture, Sports,
Science and Technology, Japan.
Supporting Information Available: Selected bond distances
and angles for the crystal structures of 1 (S1), a plot of the
pseudo-first-order rate constant vs [Q] (S2), and plots of kH/kD
vs [Sc3+] (S3) (PDF); an X-ray crystallographic file (CIF). This
material is available free of charge via the Internet at
http://pubs.acs.org.
efficiently (pathway a) in competition with the proton transfer
from BNAH•+ to Q•--2Mn+, which leads to the overall hydride
transfer from BNAH to Q (pathway c). With decreasing the
Lewis acidity of the metal ion, the metal ion-promoted electron
transfer from BNAH to Q is decelerated because of the weaker
binding of the metal ion with Q•- as shown in Table 3. On the
other hand, the proton transfer from BNAH•+ to the Q•--2Mn+
complex is accelerated with decreasing the Lewis acidity to the
metal ion (Mn+) due to the stronger basicity of the Q•--2Mn+
JA016370K
(44) The cation charge/radius ratio or d-orbitals of Sc3+ may also help
to stabilize the cycloaddition activated complex.