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Intramolecular H-Atom Abstraction in 2009

Vol. 11, No. 11
γ-Azido-Butyrophenones: Formation of 2345-2348
1,5 Ketyl Iminyl Radicals
Sivaramakrishnan Muthukrishnan,† Jagadis Sankaranarayanan,† Rodney
F. Klima,† Tamara C. S. Pace,‡ Cornelia Bohne,‡ and Anna D. Gudmundsdottir*,†

Department of Chemistry, UniVersity of Cincinnati, PO Box 210172,

Cincinnati, Ohio 45221, and Department of Chemistry, UniVersity of Victoria,
Victoria, Canada V8W 3V6
[Link]@[Link]

Received April 7, 2009

Published on May 28, 2009 on [Link] | doi: 10.1021/ol900754a
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ABSTRACT

Photolysis of γ-azidobutyrophenone derivatives yields 1,4 ketyl biradicals via intramolecular H-atom abstraction. The 1,4 ketyl biradicals expel
a nitrogen molecule to form 1,5 ketyl iminyl biradicals, which decay by ring closure to form a new carbon-nitrogen bond. The 1,5 ketyl iminyl
biradicals were characterized with transient spectroscopy. In argon/nitrogen-saturated solutions, the biradicals have λmax ≈ 300 nm and τ )
15 µs. DFT-TD calculations were used to support the proposed mechanism for formation of the 1,5 ketyl iminyl radicals.

Formation of carbon-carbon bonds through radical combi- radicals expel nitrogen molecules to form iminyl radicals.
nation is a valuable tool in organic synthesis. In comparison, By irradiating the R-azidoacetophenones in the solid-state,
nitrogen-carbon bonds are generally not produced from the benzoyl and iminyl radical pairs are held in close
radicals even though nitrogen radicals hold similar promise proximity and combine to form a new carbon-nitrogen bond
as carbon radicals in synthesis.1-3 The limited use of nitrogen (Scheme 1).
radicals in synthesis is mainly due to the lack of methods
for selectively yielding nitrogen centered radicals. Recently,
we demonstrated that iminyl radicals can be formed selec- Scheme 1
tively by irradiating R-azidoacetophenones in the solid-state.4
The R-azidoacetophenones undergo R-cleavage to form an
azido alkyl and benzoyl radical pair, but the azido alkyl
†
University of Cincinnati.
‡
University of Victoria.
(1) (a) El Kaim, L.; Meyer, C. J. Org. Chem. 1996, 61, 1556. (b) Ryu, We have further advanced our methodology of using
I.; Matsu, K.; Minakata, S.; Komatsu, M. J. Am. Chem. Soc. 1998, 120, radicals to form carbon-nitrogen bonds. In this communica-
5838.
(2) Zard, S. S. Chem. Soc. ReV. 2008, 37, 1603. tion, we demonstrate that 1,5 nitrogen-carbon biradicals can
(3) (a) McNab, H. Aldrichimica Acta 2004, 31, 19. (b) Hickson, C. L.; be used to form carbon-nitrogen bonds in high selectivity
McNab, H. J. Chem. Soc., Perkin Trans. 1 1984, 1569. (c) Hickson, C. L.;
McNab, H. Synthesis 1981, 464. (d) Bucher, G.; Scaiano, J. C.; Sinta, R.; in solution. Thus, these 1,5 biradicals have the potential to
Barclay, G.; Cameron, J. J. Am. Chem. Soc. 1995, 117, 3848. (e) Bencivenni, make five-membered heterocyclic derivatives in synthetic
G.; Lanza, T.; Leardini, T.; Minozzi, M.; Nanni, D.; Spagnolo, P.; Zanardi,
G. J. Org. Chem. 2008, 73, 4721. (f) Benati, L.; Bencivenni, G.; Leardini,
applications. The 1,5 biradicals are formed by irradiating
R.; Minozzi, M.; Nanni, D.; Scialpi, R.; Spagnolo, P.; Zanardi, G.; Rizzoli,
C. Org. Lett. 2004, 6, 417. (g) Montevecchi, P. C.; Navacchia, M. L.; (4) Mandel, S. M.; Singh, P. N. D.; Muthukrishnan, S.; Chang, M.;
Spagnolo, P. J. Org. Chem. 1997, 62, 5846. Krause, J. A.; Gudmundsdottir, A. D. Org. Lett. 2006, 8, 4207.

10.1021/ol900754a CCC: $40.75  2009 American Chemical Society

Published on Web 05/11/2009
 γ-azido butyrophenone derivatives, which consequently transfer to form the triplet excited state of the azido
undergo efficient intramolecular γ-H-atom abstraction to chromophore (T1A) of 1, which falls apart to yield triplet
yield 1,4 ketyl biradicals. Expulsion of nitrogen molecules alkyl nitrene 1n and eventually results in formation of 3
from the 1,4 biradicals results in the 1,5 ketyl iminyl (Scheme 3).
biradicals. We used transient spectroscopy, trapping studies Similarly, photolysis of 5 in toluene yields mainly 6 and
and density functional theory (DFT) calculations to charac- trace amounts of 7 and 8. Thus, 5 also reacts mainly by
terize the 1,5 ketyl iminyl biradicals and to support the intramolecular H-atom abstraction to form 6, further indicat-
proposed mechanism for formation of these biradicals. ing that irradiation of γ-azidobutyrophenone derivatives
Photolysis of 1 in argon-saturated toluene yields 2 as the generally yield pyrroles.
major product and smaller amounts of acetophenone and 3 We theorize that in oxygen-saturated toluene, biradical 1b
(Scheme 2), whereas photolysis of 1 in oxygen-saturated must be intercepted with oxygen to form 1bO (Scheme 4).

Scheme 2
Scheme 4
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toluene results mainly in 4, 2 and trace amounts of acetophe-

none. We propose that the lowest excited triplet ketone (T1K)
of 1, that presumably has a (n,π*) configuration, abstracts a Biradical 1bO presumably decays by abstracting H-atoms
γ-H-atom to form biradical 1a (Scheme 3). Expulsion of a from the solvent, followed by autoxidation to form 1d, which
is hydrolyzed to 4.
We used calculations to validate the reaction mechanisms
Scheme 3
shown in Schemes 3 and 4. The calculations were done using
Gaussian03 at B3LYP level of theory and 6-31+G(d) as the
basis set.6,7 We optimized the structures of 1 and T1K of 1
and calculated their IR spectra. We found that the T1K of 1
is 69 kcal/mol above S0. The T1K CdO bond is elongated to
1.32 Å (compared to 1.22 Å in S0) and has a vibrational
stretch at 1394 cm-1. The progression of the C-O bond and
its IR vibrational stretch fits well with the T1K of 1 having
a (n,π*) configuration.8 The energy of the T1K of 1 is
considerably lower than the measured energy of T1K in the
analog valerophenone, which has a T1K that is 74 kcal/mol

(5) Wagner, P. J.; Kemppainen, A. E.; Schott, H. N. J. Am. Chem. Soc.

1973, 95, 5604.
(6) (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648. (b) Lee, C.; Yang,
W.; Parr, R. G. Phys. ReV. B 1988, 37, 785.
(7) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K. N.;
Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.;
Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.;
Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li,
X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.;
nitrogen molecule from 1a results in iminyl radical 1b, which Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.;
cyclizes and dehydrates to give 2. However, a small fraction Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich,
of 1a must cleave to form 1-phenylethenol, which tautomer- S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.;
Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.;
izes to acetophenone. Based on the comparison with vale- Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz,
rophenone derivatives, where the first two triplet states are P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.;
Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson,
close in energy,5 we theorize that the second excited state B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian03,
of the triplet ketone (T2K (π,π*)) of 1 undergoes energy Revisions A.1 and C.02; Gaussian, Inc.: Wallingford, CT, 2004.

2346 Org. Lett., Vol. 11, No. 11, 2009

 above S0.9 However, we have previously shown that DFT
underestimates the energy of triplet ketones with a (n,π*) Scheme 6a
configuration.10 In comparison, time dependent density
functional theory (TD-DFT)11 calculations show that the T1K
and T2K of 1 are 76 and 77 kcal/mol above S0, respectively.
We plotted stationary points on the triplet energy surface of
1 to form 1b and 1n in Scheme 5. The transition state

Scheme 5a a
Calculated energies are in kcal/mol. Numbers in parentheses are the
calculated energies in methanol.

photolysis (Excimer laser, λ ) 308 nm, 17 ns; YAG lasers,

λ ) 355 nm, 15 ns)12 of 1 in nitrogen-saturated acetonitrile
and methanol produced a transient spectrum with λmax ≈ 300
nm (Figure 1). This transient absorption was formed im-

a
Calculated energies are in kcal/mol. Numbers in parentheses are the
calculated energies in methanol.
Published on May 28, 2009 on [Link] | doi: 10.1021/ol900754a

(TS-1) for the intramolecular H-atom abstraction from the

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T1K of 1 to form 1a is located 4 kcal/mol above the T1K of

1. The transistion state (TS-2) for 1a expeling a nitrogen
molecule to yield 1b is only 1.1 kcal/mol above 1a, indicating
that formation of 1b is very feasible at ambient temperature.
It is important to note that the energy for TS-1 is lower than
the energy for T2K making this mechanistic pathway ener-
getically feasible. Finally, the T1A of 1 is 43 kcal/mol above
its S0, and the transition state (TS-3) for the T1A to form 1n
and a nitrogen molecule is only 0.4 kcal/mol above T1A.
We calculated stationary points on the triplet energy
surface of the reaction of 1 with oxygen (Scheme 6). The
calculations support the idea that 1b reacts efficiently and
irreversibly with oxygen to form 1bO, whereas formation
of 1bP must be reversible since the nitrogen-oxygen bond Figure 1. Transient spectra of (A) 1b in nitrogen-satured acetoni-
is weaker than the carbon-oxygen bond in 1bO. Since we trile. (Inset) Decay of 1b at 300 nm. (B) 1bO in oxygen-saturated
did not observe 1e (Scheme 4), we conclude that 1bO does acetonitrile. (Inset) Decay of 1bO at 290 nm. The blue bars are
not undergo intersystem crossing to form 1e. Rather, 1bO calculated electronic transitions for 1b (×4) and 1bO.
must decay by H-atom abstraction from the solvent and
autoxidation to form 1d.
We used laser flash photolysis to further support the mediately after the laser pulse and the lifetime of this
proposed mechanism for the photoreactivity of 1. Laser flash transient (as determined by its monoexponential decay at 300
nm) was ∼15 µs in methanol and acetonitrile (Figure 1A).
(8) (a) Srivastava, S.; Yourd, E.; Toscano, J. P. J. Am. Chem. Soc. 1998, We assigned this transient absorption to 1b based on TD-
120, 6173. (b) He, H.-Y.; Fang, W.-H.; Phillips, D. L. J. Phys. Chem. A DFT calculations. In acetonitrile, the most intense band is
2004, 108, 5386. (c) Fang, W.-H.; Phillips, D. L. Chem. Phys. Chem. 2002,
3, 889. (d) Fang, W.-H.; Phillips, D. L. J. Theor. Comput. Chem. 2003, 2, calculated to be at 297 nm (f ) 0.1152) and is due to the
23. transition of an electron from the half full p-orbital of the
(9) Murov, S. L.; Carmichael, I.; Hug, G. L. Handbook of Photochem- carbon atom of the hydroxyl group into the π* orbital (Figure
istry; Marcel Dekker: New York, 1993.
(10) (a) Muthukrishnan, S.; Mandel, S. M.; Hackett, J. C.; Singh, 2). The calculations also show less intense electronic
P. N. D.; Hadad, C. M.; Krause, J. A.; Gudmundsdottir, A. D. J. Org. Chem. transitions at 290, 315, 340, and 374 nm (Figure 2).
2007, 72, 2757. (b) Klima, R. F.; Jadhav, A. V.; Singh, P. N. D.; Chang,
M.; Vanos, C.; Sankaranarayanan, J.; Vu, Mai; Ibrahim, N.; Ross, E.; Furthermore, the TD-DFT calculations rule out assignment
McCloskey, S.; Murthy, R. S.; Krause, J. A.; Ault, B. S.; Gudmundsdottir, of this absorption to 1a (see Supporting Information where
A. D. J. Org. Chem. 2007, 72, 6372.
(11) (a) Density Functional Methods in Chemistry; Labanowski, J., Ed.;
an absoption between 360 and 400 nm was predicted).
Springer-Verlag: Heidelberg, 1991. (b) Parr, R. G.; Weitao, Y. Density-
Functional Theory in Atoms and Molecules; Oxford University Press: New (12) (a) Liao, Y.; Bohne, C. J. Phys. Chem. 1996, 100, 734. (b) Gritsan,
York, 1989. (c) Bauernschmitt, R. Chem. Phys. Lett. 1996, 256, 454. (d) N. P.; Zhai, H. B.; Yuzawa, T.; Karwiek, D.; Brooke, J.; Platz, M. S. J.
Stratmann, R. J. Chem. Phys. 1998, 109, 8218. (e) Foresman, J. J. Phys. Phys. Chem. A 1997, 108, 3783. (c) Cosa, G.; Scaiano, J. C. Photochem.
Chem. 1992, 96, 135. Photobiol. 2004, 80, 159. (d) See Supporting Information.

Org. Lett., Vol. 11, No. 11, 2009 2347

 methanol than in acetonitrile supports the idea that 1bO
decays by H-atom abstraction to form 1d. Furthermore, the
observed transient absorption in oxygen-saturated solutions
cannot be due to 1e because its calculated absorption
spectrum has no absorption bands above 290 nm (see
Supporting Information).
Thus, product studies, calculations and transient spectros-
copy support the idea that γ-azidobutyrophenones undergo
intramolecular H-atom abstraction from the T1K state with a
(n,π*) configuration to form 1,4 biradicals, which efficiently
expel nitrogen molecules to form 1,5-ketyl iminyl biradicals.
In the absence of oxygen, the ketyl iminyl biradicals decay
by intramolecular cyclization, whereas they are efficiently
trapped with oxygen in oxygen-saturated solutions. In
comparison, β-azidopropiophenone derivatives undergo ef-
ficient intramolecular energy transfer from their T2K state
(π,π*) to form triplet alkyl nitrenes in solution, because
intramolecular H-atom abstraction of β-H-atoms is less
feasible than for γ-H-atoms.13 Similarly, R-azidoacetophe-
Figure 2. Major elecronic transitions in (A) 1b and (B) 1bO. (C) none derivatives undergo intramolecular energy transfer to
Published on May 28, 2009 on [Link] | doi: 10.1021/ol900754a

Minimal energy conformers of 1bO. form triplet alkyl nitrenes from their triplet ketone with a
(π,π*) configuration and R-azidoacetophenones also undergo
R-cleavage from their triplet ketones with a (n,π*) config-
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We did not observe 1a or the T1K of 1, presumably because uration to form benzoyl and azido alkyl radicals. However,
their lifetimes are less than the time resolution of the laser the R-cleavage is not selective in solution. In constrast, the
flash apparatus (17 ns). We attribute the short lifetime of γ-H-atom abstraction reaction described here leads to good
T1K of 1 to the fact that the transition state for H-atom selectivity for the ring closed [Link] expect this
abstraction to form 1a is located only a few kcal/mol above methodology to be applicable for the synthesis of 2-arylpyr-
T1K of 1. Similarly, 1a is short-lived because the transition roles with numerous functional groups and thus be comple-
state for it to form 1b is less than 1 kcal/mol above 1a and mentary to metal catalyzed functionlization of pyrroles.14
thus 1b is formed very efficiently at ambient temperature.
Laser flash photolysis of 1 in the oxygen-saturated Acknowledgment. This work was supported by the NSF
solutions produced a different transient spectrum than in the (CHE-0703920) and the Ohio Supercomputer Center. C.B.
nitrogen-saturated solution. This transient spectrum has λmax and T.C.S.P. thank the Natural Science and Engineering
≈ 295 nm and its lifetime (as determined by its monoex- Research Council (NSERC) for funding at Victoria and
ponential decay at 290 nm) was 1.2 ms and 650 µs in T.C.S.P. thanks NSERC for a CGS-D scholarship. We thank
acetonitrile and methanol, respectively. We assign this Prof. M. S. Platz at The Ohio State Univ. and J. C. Scaiano
transient absorption to 1bO based on TD-DFT calculations. at the Univ. of Ottawa for use of their instrumentation.
TD-DFT of the lowest energy conformer A of 1bO has two
of the most intense bands at 304 nm (f ) 0.0048) and 285 Supporting Information Available: Experiments and
nm (f ) 0.0029). The band at 304 nm is due to an electronic calculations. This material is available free of charge via the
transition from the π-orbital of CdN to the antibonding Internet at [Link]
orbital of the O-O bond, whereas the 284 nm band is due OL900754A
to an electronic excitation from the π-orbital of O-O to its
antibonding orbital (Figure 2). The TD-DFT calculations (13) (a) Singh, P. N. D.; Mandel, S. M.; Sankaranarayanan, J.;
were affected somewhat by the conformer of 1bO (see Muthukrishnan, S.; Chang, M.; Robinson, R. M.; Lahti, P. M.; Ault, B. S.;
Gudmundsdottir, A. D. J. Am. Chem. Soc. 2007, 129, 16263. (b) Sankara-
Supporting Information). Thus, we calculated the electronic narayanan, J.; Bort, L.; Krause, J. A.; Mandel, S. M.; Chen, P.; Brooks,
transition for the conformers B and C of 1bO (see Figure E. E.; Tsang, P.; Gudmundsdottir, A. D. Org. Lett. 2008, 10, 937.
(14) (a) Rieth, R. D.; Mankad, N. P.; Calimano, E.; Sadighi, J. P. Org.
2) and included the electronic transition for these 3 conform- Lett. 2004, 6, 3981. (b) Seregin, I. V.; Gevorgyan, V. Chem. Soc. ReV.
ers in Figure 1B. The lifetime of 1bO being shorter in 2007, 36, 1173.

2348 Org. Lett., Vol. 11, No. 11, 2009