Intramolecular H-atom abstraction in γ-azido-butyrophenones: Formation of 1,5 ketyl iminyl radicals

Article abstract of DOI:10.1021/ol900754a

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-nitr

Full text of DOI:10.1021/ol900754a

ORGANIC
LETTERS
2
009
Vol. 11, No. 11
345-2348
Intramolecular H-Atom Abstraction in
γ-Azido-Butyrophenones: Formation of
1,5 Ketyl Iminyl Radicals
2
†
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
Anna.Gudmundsdottir@uc.edu
Received April 7, 2009
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-
nation is a valuable tool in organic synthesis. In comparison,
nitrogen-carbon bonds are generally not produced from
radicals even though nitrogen radicals hold similar promise
radicals expel nitrogen molecules to form iminyl radicals.
By irradiating the R-azidoacetophenones in the solid-state,
the benzoyl and iminyl radical pairs are held in close
proximity and combine to form a new carbon-nitrogen bond
(Scheme 1).
1-3
as carbon radicals in synthesis.
The limited use of nitrogen
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
4
tively by irradiating R-azidoacetophenones in the solid-state.
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,
I.; Matsu, K.; Minakata, S.; Komatsu, M. J. Am. Chem. Soc. 1998, 120,
838
We have further advanced our methodology of using
radicals to form carbon-nitrogen bonds. In this communica-
tion, we demonstrate that 1,5 nitrogen-carbon biradicals can
be used to form carbon-nitrogen bonds in high selectivity
in solution. Thus, these 1,5 biradicals have the potential to
make five-membered heterocyclic derivatives in synthetic
applications. The 1,5 biradicals are formed by irradiating
5
.
(
(
2) Zard, S. S. Chem. Soc. ReV. 2008, 37, 1603
3) (a) McNab, H. Aldrichimica Acta 2004, 31, 19. (b) Hickson, C. L.;
.
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.;
Barclay, G.; Cameron, J. J. Am. Chem. Soc. 1995, 117, 3848. (e) Bencivenni,
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,
R.; Minozzi, M.; Nanni, D.; Scialpi, R.; Spagnolo, P.; Zanardi, G.; Rizzoli,
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.
10.1021/ol900754a CCC: $40.75
Published on Web 05/11/2009
 2009 American Chemical Society

γ-azido butyrophenone derivatives, which consequently
undergo efficient intramolecular γ-H-atom abstraction to
yield 1,4 ketyl biradicals. Expulsion of nitrogen molecules
from the 1,4 biradicals results in the 1,5 ketyl iminyl
biradicals. We used transient spectroscopy, trapping studies
and density functional theory (DFT) calculations to charac-
terize the 1,5 ketyl iminyl biradicals and to support the
proposed mechanism for formation of these biradicals.
Photolysis of 1 in argon-saturated toluene yields 2 as the
major product and smaller amounts of acetophenone and 3
transfer to form the triplet excited state of the azido
chromophore (T1A) of 1, which falls apart to yield triplet
alkyl nitrene 1n and eventually results in formation of 3
(Scheme 3).
Similarly, photolysis of 5 in toluene yields mainly 6 and
trace amounts of 7 and 8. Thus, 5 also reacts mainly by
intramolecular H-atom abstraction to form 6, further indicat-
ing that irradiation of γ-azidobutyrophenone derivatives
generally yield pyrroles.
We theorize that in oxygen-saturated toluene, biradical 1b
must be intercepted with oxygen to form 1bO (Scheme 4).
(
Scheme 2), whereas photolysis of 1 in oxygen-saturated
Scheme 2
Scheme 4
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
γ-H-atom to form biradical 1a (Scheme 3). Expulsion of a
)
Biradical 1bO presumably decays by abstracting H-atoms
from the solvent, followed by autoxidation to form 1d, which
is hydrolyzed to 4.
We used calculations to validate the reaction mechanisms
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. We optimized the structures of 1 and T1K of 1
and calculated their IR spectra. We found that the T1K of 1
Scheme 3
6
,7
is 69 kcal/mol above S
0
. The T1K CdO bond is elongated to
) and has a vibrational
1
.32 Å (compared to 1.22 Å in S
0
-1
stretch at 1394 cm . The progression of the C-O bond and
its IR vibrational stretch fits well with the T1K of 1 having
8
a (n,π*) configuration. 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.
973, 95, 5604.
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(
.
(
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.;
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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.;
Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.;
Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich,
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.;
Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz,
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,
B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian03,
nitrogen molecule from 1a results in iminyl radical 1b, which
cyclizes and dehydrates to give 2. However, a small fraction
of 1a must cleave to form 1-phenylethenol, which tautomer-
izes to acetophenone. Based on the comparison with vale-
rophenone derivatives, where the first two triplet states are
close in energy, we theorize that the second excited state
of the triplet ketone (T2K (π,π*)) of 1 undergoes energy
5
Revisions A.1 and C.02; Gaussian, Inc.: Wallingford, CT, 2004
.
2346
Org. Lett., Vol. 11, No. 11, 2009

9
above S
0
. However, we have previously shown that DFT
underestimates the energy of triplet ketones with a (n,π*)
Scheme 6a
1
0
configuration. In comparison, time dependent density
11
functional theory (TD-DFT) calculations show that the T1K
and T2K of 1 are 76 and 77 kcal/mol above S , respectively.
We plotted stationary points on the triplet energy surface of
0
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,
1
2
λ ) 355 nm, 15 ns) 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.
(
T
1
TS-1) for the intramolecular H-atom abstraction from the
1K of 1 to form 1a is located 4 kcal/mol above the T1K of
. 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 S
0
, 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
is weaker than the carbon-oxygen bond in 1bO. Since we
did not observe 1e (Scheme 4), we conclude that 1bO does
not undergo intersystem crossing to form 1e. Rather, 1bO
must decay by H-atom abstraction from the solvent and
autoxidation to form 1d.
Figure 1. Transient spectra of (A) 1b in nitrogen-satured acetoni-
trile. (Inset) Decay of 1b at 300 nm. (B) 1bO in oxygen-saturated
acetonitrile. (Inset) Decay of 1bO at 290 nm. The blue bars are
calculated electronic transitions for 1b (×4) and 1bO.
mediately after the laser pulse and the lifetime of this
transient (as determined by its monoexponential decay at 300
nm) was ∼15 µs in methanol and acetonitrile (Figure 1A).
We assigned this transient absorption to 1b based on TD-
DFT calculations. In acetonitrile, the most intense band is
calculated to be at 297 nm (f ) 0.1152) and is due to the
transition of an electron from the half full p-orbital of the
carbon atom of the hydroxyl group into the π* orbital (Figure
2). The calculations also show less intense electronic
transitions at 290, 315, 340, and 374 nm (Figure 2).
Furthermore, the TD-DFT calculations rule out assignment
of this absorption to 1a (see Supporting Information where
an absoption between 360 and 400 nm was predicted).
We used laser flash photolysis to further support the
proposed mechanism for the photoreactivity of 1. Laser flash
(
8) (a) Srivastava, S.; Yourd, E.; Toscano, J. P. J. Am. Chem. Soc. 1998,
1
2
3
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(
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007, 72, 2757. (b) Klima, R. F.; Jadhav, A. V.; Singh, P. N. D.; Chang,
(
2
M.; Vanos, C.; Sankaranarayanan, J.; Vu, Mai; Ibrahim, N.; Ross, E.;
McCloskey, S.; Murthy, R. S.; Krause, J. A.; Ault, B. S.; Gudmundsdottir,
A. D. J. Org. Chem. 2007, 72, 6372.
(
11) (a) Density Functional Methods in Chemistry; Labanowski, J., Ed.;
Springer-Verlag: Heidelberg, 1991. (b) Parr, R. G.; Weitao, Y. Density-
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N. P.; Zhai, H. B.; Yuzawa, T.; Karwiek, D.; Brooke, J.; Platz, M. S. J.
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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, ꢀ-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 ꢀ-H-atoms is less
1
3
feasible than for γ-H-atoms. Similarly, R-azidoacetophe-
none derivatives undergo intramolecular energy transfer to
form triplet alkyl nitrenes from their triplet ketone with a
Figure 2. Major elecronic transitions in (A) 1b and (B) 1bO. (C)
Minimal energy conformers of 1bO.
(π,π*) configuration and R-azidoacetophenones also undergo
R-cleavage from their triplet ketones with a (n,π*) config-
uration to form benzoyl and azido alkyl radicals. However,
the R-cleavage is not selective in solution. In constrast, the
γ-H-atom abstraction reaction described here leads to good
selectivity for the ring closed products.We expect this
methodology to be applicable for the synthesis of 2-arylpyr-
roles with numerous functional groups and thus be comple-
We did not observe 1a or the T1K of 1, presumably because
their lifetimes are less than the time resolution of the laser
flash apparatus (17 ns). We attribute the short lifetime of
T
1K of 1 to the fact that the transition state for H-atom
abstraction to form 1a is located only a few kcal/mol above
1K of 1. Similarly, 1a is short-lived because the transition
T
state for it to form 1b is less than 1 kcal/mol above 1a and
thus 1b is formed very efficiently at ambient temperature.
Laser flash photolysis of 1 in the oxygen-saturated
solutions produced a different transient spectrum than in the
nitrogen-saturated solution. This transient spectrum has λmax
14
mentary to metal catalyzed functionlization of pyrroles.
Acknowledgment. This work was supported by the NSF
(CHE-0703920) and the Ohio Supercomputer Center. C.B.
and T.C.S.P. thank the Natural Science and Engineering
Research Council (NSERC) for funding at Victoria and
T.C.S.P. thanks NSERC for a CGS-D scholarship. We thank
Prof. M. S. Platz at The Ohio State Univ. and J. C. Scaiano
at the Univ. of Ottawa for use of their instrumentation.
≈
295 nm and its lifetime (as determined by its monoex-
ponential decay at 290 nm) was 1.2 ms and 650 µs in
acetonitrile and methanol, respectively. We assign this
transient absorption to 1bO based on TD-DFT calculations.
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
nm (f ) 0.0029). The band at 304 nm is due to an electronic
transition from the π-orbital of CdN to the antibonding
orbital of the O-O bond, whereas the 284 nm band is due
to an electronic excitation from the π-orbital of O-O to its
antibonding orbital (Figure 2). The TD-DFT calculations
were affected somewhat by the conformer of 1bO (see
Supporting Information). Thus, we calculated the electronic
transition for the conformers B and C of 1bO (see Figure
Supporting Information Available: Experiments and
calculations. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL900754A
(13) (a) Singh, P. N. D.; Mandel, S. M.; Sankaranarayanan, J.;
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ers in Figure 1B. The lifetime of 1bO being shorter in
2348
Org. Lett., Vol. 11, No. 11, 2009