Intramolecular O-H...O hydrogen-bond-mediated reversal in the partitioning of conformationally restricted triplet 1,4-biradicals and amplification of diastereodifferentiation in their lifetimes

Article abstract of DOI:10.1021/ja8032179

The photoreactivity and nanosecond transient phenomena have been investigated for a rationally designed set of ketones 4-9 in order to gain comprehensive insights concerning the influence of intramolecular hydrogen bonding on (i) the lifetimes of triplet 1,4-biradicals and (ii) the partitioning of the latter between cyclization and elimination. Comparisons of the photochemical results and lifetime data for the biradicals of ketones 6 versus 8 and 7 versus 9 revealed a remarkable influence of hydrogen bonding when superimposed upon steric factors: while 6 and 7 yielded cyclobutanols in poor yields, cyclization was found to be overwhelmingly predominant for 8-anti and moderately so for 9-anti, with a high stereoselectivity in the formation of cyclobutanols (>95% for 8-anti). The diastereochemistry in the case of 8 permitted the occurrence of fragmentation or cyclization almost exclusively (>90% cyclization for 8-anti and >75% elimination for 8-syn). Significantly, the intramolecular hydrogen bonding in the biradicals of 8 and 9 was found to reverse their partitioning between cyclization and elimination compared with the behavior of the biradicals of ketones 3; the ketones 8-anti and 9-anti underwent cyclization in benzene, predominantly leading to cyclobutanols with syn stereochemistry between the C2 and C3 substituents. In accordance with photoproduct profiles, an unprecedented ～2-fold difference in the lifetimes of the intermediate diastereomeric triplet biradicals of ketones 8 in nonpolar solvents (e.g., τ_syn = 123 ns and τ_anti = 235 ns in cyclohexane) was observed via nanosecond laser flash photolysis, while no such difference in lifetimes was found for the triplet biradicals of acetoxy ketones 9. The intriguing diastereodifferentiation in the lifetimes of the diastereomeric triplet 1,4-biradicals of 8 and the product profiles of ketones 6, 7, and 9 are best reconciled via a unified mechanistic picture in which superposition of steric factors over varying magnitudes of O-H...O hydrogen bonding selectively facilitates a particular pathway. In particular, the diastereodifferentiation in the photochemical outcomes for the diastereomers of ketone 8 and in the lifetimes of their triplet biradicals can be understood on the basis of rapid deactivation of the 8-syn triplet biradical via fragmentation and slow cyclization of the 8-anti triplet biradical from chair- and twist-boat-like hydrogen-bonded conformations, respectively. The photolysis in polar aprotic solvents such as DMSO and pyridine was found to reverse the chemoselectivity, yielding reactivity paralleling that of ketones 3, for which the steric factors between the C2 and C3 substituents control the photochemical outcome.

Full text of DOI:10.1021/ja8032179

Published on Web 09/17/2008
Intramolecular O-H· · ·O Hydrogen-Bond-Mediated Reversal in
the Partitioning of Conformationally Restricted Triplet
1,4-Biradicals and Amplification of Diastereodifferentiation in
Their Lifetimes
Jarugu Narasimha Moorthy,*,† Subhas Samanta,† Apurba L. Koner,‡ Satyajit Saha,†
and Werner M. Nau*,‡
Department of Chemistry, Indian Institute of Technology, Kanpur 208 016, India, and School of
Engineering and Science, Campus Ring 1, Jacobs UniVersity Bremen, 28725 Bremen, Germany
Received April 30, 2008; E-mail: moorthy@iitk.ac.in; w.nau@jacobs-university.de
Abstract: The photoreactivity and nanosecond transient phenomena have been investigated for a rationally
designed set of ketones 4-9 in order to gain comprehensive insights concerning the influence of
intramolecular hydrogen bonding on (i) the lifetimes of triplet 1,4-biradicals and (ii) the partitioning of the
latter between cyclization and elimination. Comparisons of the photochemical results and lifetime data for
the biradicals of ketones 6 versus 8 and 7 versus 9 revealed a remarkable influence of hydrogen bonding
when superimposed upon steric factors: while 6 and 7 yielded cyclobutanols in poor yields, cyclization was
found to be overwhelmingly predominant for 8-anti and moderately so for 9-anti, with a high stereoselectivity
in the formation of cyclobutanols (>95% for 8-anti). The diastereochemistry in the case of 8 permitted the
occurrence of fragmentation or cyclization almost exclusively (>90% cyclization for 8-anti and >75%
elimination for 8-syn). Significantly, the intramolecular hydrogen bonding in the biradicals of 8 and 9 was
found to reverse their partitioning between cyclization and elimination compared with the behavior of the
biradicals of ketones 3; the ketones 8-anti and 9-anti underwent cyclization in benzene, predominantly
leading to cyclobutanols with syn stereochemistry between the C2 and C3 substituents. In accordance
with photoproduct profiles, an unprecedented ∼2-fold difference in the lifetimes of the intermediate
diastereomeric triplet biradicals of ketones 8 in nonpolar solvents (e.g., τsyn ) 123 ns and τanti ) 235 ns in
cyclohexane) was observed via nanosecond laser flash photolysis, while no such difference in lifetimes
was found for the triplet biradicals of acetoxy ketones 9. The intriguing diastereodifferentiation in the lifetimes
of the diastereomeric triplet 1,4-biradicals of 8 and the product profiles of ketones 6, 7, and 9 are best
reconciled via a unified mechanistic picture in which superposition of steric factors over varying magnitudes
of O-H· · ·O hydrogen bonding selectively facilitates a particular pathway. In particular, the diastereodif-
ferentiation in the photochemical outcomes for the diastereomers of ketone 8 and in the lifetimes of their
triplet biradicals can be understood on the basis of rapid deactivation of the 8-syn triplet biradical via
fragmentation and slow cyclization of the 8-anti triplet biradical from chair- and twist-boat-like hydrogen-
bonded conformations, respectively. The photolysis in polar aprotic solvents such as DMSO and pyridine
was found to reverse the chemoselectivity, yielding reactivity paralleling that of ketones 3, for which the
steric factors between the C2 and C3 substituents control the photochemical outcome.
particular;1,3 the latter are abundantly generated in both thermal
Introduction
and photochemical processes.4 Mechanistically, initial γ-hy-
One of the fundamental photoreactions of ketones that contain
a hydrogen atom at the γ-position is the Norrish type-II
reaction.1 Since its discovery,2 there has been continual interest
in this reaction from the point of view of understanding the
photoreactivity of dialkyl and aryl alkyl ketones in general1 and
the behavior of the intermediate triplet 1,4-biradicals in
drogen abstraction by the triplet states of ketones via a six-
membered cyclic transition state leads to cisoid triplet 1,4-
biradicals, which may collapse by three possible pathways,
(3) (a) Small, R. D., Jr.; Scaiano, J. C. J. Am. Chem. Soc. 1978, 100,
4512. (b) Scaiano, J. C. Acc. Chem. Res. 1982, 15, 252. (c) Scaiano,
J. C. Tetrahedron 1982, 38, 819. (d) Caldwell, R. A.; Majima, T.;
Pac, C. J. Am. Chem. Soc. 1982, 104, 629. (e) Caldwell, R. A.;
Dhawan, S. N.; Majima, T. J. Am. Chem. Soc. 1984, 106, 6454. (f)
Caldwell, R. A. Pure. Appl. Chem. 1984, 56, 1167. (g) Hasegawa, T.;
Arata, Y.; Endoh, M.; Yoshioka, M. Tetrahedron 1985, 41, 1667. (h)
Caldwell, R. A.; Gupta, S. C. J. Am. Chem. Soc. 1989, 111, 740.
(4) (a) Stephenson, L. M.; Cavigli, P. R.; Parlett, J. L. J. Am. Chem. Soc.
1971, 93, 1984, and references therein. (b) Engel, P. S. Chem. ReV.
1980, 80, 99. (c) Johnston, L. J.; Scaiano, J. C. Chem. ReV. 1989, 89,
521.
† Indian Institute of Technology.
‡ Jacobs University Bremen.
(1) (a) Wagner, P. J. Acc. Chem. Res. 1971, 4, 168. (b) Wagner, P. J.;
Park, B.-S. In Organic Photochemistry; Pawda, A., Ed.; Marcel
Dekker: New York, 1991; Vol. 11, Chapter 4. (c) Wagner, P. J. In
CRC Handbook of Organic Photochemistry and Photobiology; Horspool,
W. R., Ed.; CRC Press, Inc.: Boca Raton, FL, 1995; Chapter 38.
(2) (a) Norrish, R. G. W.; Appleyard, M. E. S. J. Chem. Soc. 1934, 874.
(b) Yang, N. C.; Yang, D.-H. J. Am. Chem. Soc. 1958, 80, 2913.
9
13608 J. AM. CHEM. SOC. 2008, 130, 13608–13617
10.1021/ja8032179 CCC: $40.75
2008 American Chemical Society

Conformationally Restricted Triplet 1,4-Biradicals
A R T I C L E S
Scheme 1. Various Pathways for the Collapse of Norrish Type-II
Triplet 1,4-Biradicals
Chart 1
entiating photochemistry of ketones 2 and 3 (Chart 1) and the
associated transient phenomena.9 In the present investigation,
we have examined the behavior of O-H· · ·O hydrogen-bonded
triplet 1,4-biradicals derived from the rationally designed set
of ketones 6-9 and contrasted the results with those for simple
biradicals derived from ketones 3-5 (Chart 1). The 1,4-
biradicals of ketones 3-9 are bisbenzylic, and the location of
substituents at the ꢀ-position in 6-9 permits intramolecular
O-H· · ·O hydrogen bonding via a six- or eight-membered
ring.11-13 Herein, we show that intramolecular hydrogen bond-
ing in diastereomeric triplet 1,4-biradicals of conformationally
restricted ketones 8 and 9 in benzene solution diverts the
preferred pathways of partitioning based on steric effects.
Photolysis in a strongly hydrogen-bond-accepting polar aprotic
solvent such as DMSO or pyridine leads to the reversal of the
biradical partitioning pathways observed in benzene. Intramo-
lecular hydrogen bonding in cyclohexane amplifies the diaste-
reodifferentiation14 to such an extent that the diastereomeric 1,4-
triplet biradicals of ketone 8 exhibit an unprecedented ∼2-fold
difference in their lifetimes, as revealed by nanosecond laser
flash photolysis.
namely, (i) internal disproportionation (with rate constant kd),
(ii) cyclization (kc), and (iii) fragmentation (kf), as shown in
Scheme 1 for a representative phenyl alkyl ketone.1 Internal
disproportionation of the initial triplet 1,4-biradical subsequent
to intersystem crossing results in regeneration of the starting
ketone and is generally responsible for the less-than-unity
photodecomposition quantum yields usually observed.1 The
cisoid conformation may undergo cyclization when the two
singly occupied orbitals are directed toward each other.1a,5
Although the fragmentation may proceed from both the cisoid
and transoid conformations, it is generally ascribed to the latter
because cyclization is kinetically favored from the cisoid
conformation. There exist two schools of thought concerning
the partitioning of triplet 1,4-biradicals between cyclization and
fragmentation, namely, spin inversion accompanying product
formation1b,6 and intersystem-crossing geometries controlling
1,4-biradical reactivity.3c,7 Be this mechanistic dichotomy as it
may, at present there appears to be no clear-cut understanding
of how the triplet biradicals partition themselves between the
cyclization and fragmentation pathways, although their geom-
etries appear to crucially control the product profiles. Insofar
as the lifetimes of triplet 1,4-biradicals are concerned, the
influence of conformational factors, substituents, solvents,
etc.3d,8-10 continue to be as intriguing as they were two decades
ago.3e,h
Results
Synthesis of Ketones 4-9. Ketones 4 and 6-9 were prepared
starting from the products of Aldol reaction of acetophenone
or propiophenone with phenylacetaldehyde, as described in the
Supporting Information. The acetophenone Aldol products were
converted to 6 and 7 by methylation and acetylation reactions
using MeI/Ag2O/diethyl ether15 and Ac2O/CoCl2/CH3CN16 or
Ac2O/DMAP/DCM conditions, respectively. The diastereomeric
We have recently shown that conformational restrictions
imposed via R,ꢀ-disubstitution of γ-phenylbutyrophenone 1
offer unique opportunities for investigating the diastereodiffer-
(11) (a) For the photochemistry of ketones with a heteroatom-containing
groupattheR-position,seeref7candthefollowingreference:Griesbeck,
A. G.; Cygon, P.; Lex, J. Lett. Org. Chem. 2004, 1, 313. (b) Lewis,
F. D.; Turro, N. J. J. Am. Chem. Soc. 1970, 92, 311.
(5) (a) Lewis, F. D.; Hilliard, T. A. J. Am. Chem. Soc. 1970, 92, 6672.
(b) Wagner, P. J.; Kelso, P. A.; Kemppainen, A. E.; McGrath, J. M.;
Schott, H. N.; Zepp, R. G. J. Am. Chem. Soc. 1972, 94, 7506.
(6) Wagner, P. J. Acc. Chem. Res. 1989, 22, 83.
(12) For the photochemistry of ketones with a heteroatom-containing group
at the ꢀ-position, see: (a) Yates, P.; Pal, J. M. J. Chem. Soc. D, Chem.
Commun. 1970, 553. (b) Lindemann, U.; Wulff-Molder, D.; Wessig,
P. J. Photochem. Photobiol., A 1998, 119, 73.
(7) (a) Griesbeck, A. G.; Mauder, H.; Stadtmueller, S. Acc. Chem. Res.
1994, 27, 70. (b) Griesbeck, A. G.; Fiege, M. In Molecular and
Supramolecular Photochemistry; Ramamurthy, V., Schanze, K. S.,
Eds.; Marcel Dekker: New York, 1999; Vol. 6, p 33. (c) Griesbeck,
A. G.; Heckroth, H. J. Am. Chem. Soc. 2002, 124, 396.
(13) For the photochemistry of ketones with a heteroatom-containing group
at the γ- or δ-position, see ref 5b.
(8) (a) Small, R. D., Jr.; Scaiano, J. C. Chem. Phys. Lett. 1977, 50, 431.
(b) Small, R. D., Jr.; Scaiano, J. C. Chem. Phys. Lett. 1978, 59, 246.
(9) (a) Singhal, N.; Koner, A. L.; Mal, P.; Venugopalan, P.; Nau, W. M.;
Moorthy, J. N. J. Am. Chem. Soc. 2005, 127, 14375. (b) Moorthy,
J. N.; Koner, A. L.; Samanta, S.; Singhal, N.; Nau, W. M.; Weiss,
R. G. Chem.sEur. J. 2006, 12, 8744.
(14) For diastereo- and enantiodifferentiation in photochemical processes,
see: (a) Miranda, M. A.; Mart´ınez, L. A.; Samadi, A.; Bosca´, F.;
Morera, I. M. Chem. Commun. 2002, 280. (b) Bach, T.; Aechtner, T.;
Neumu¨ller, B. Chem.sEur. J. 2002, 8, 2464. (c) Bosca´, F.; Andreu,
I.; Morera, I. M.; Samadi, A.; Miranda, M. A. Chem. Commun. 2003,
1592. (d) Pischel, U.; Abad, S.; Domingo, L. R.; Bosca´, F.; Miranda,
M. A. Angew. Chem., Int. Ed. 2003, 42, 2531. (e) Chen, S.; Patrick,
B. O.; Scheffer, J. R. J. Org. Chem. 2004, 69, 2711. (f) Abad, S.;
Bosca´, F.; Domingo, L. R.; Gil, S.; Pischel, U.; Miranda, M. A. J. Am.
Chem. Soc. 2007, 129, 7407.
(10) For unusually long (microsecond) lifetimes of triplet 1,4-biradicals
reported recently, see: Cai, X.; Cygon, P.; Goldfuss, B.; Griesbeck,
A. G.; Heckroth, H.; Fujitsuka, M.; Majima, T. Chem.sEur. J. 2006,
12, 4662.
9
J. AM. CHEM. SOC. VOL. 130, NO. 41, 2008 13609

A R T I C L E S
Moorthy et al.
Figure 1. Molecular structures of (a) ketone 9-anti and the cyclobutanols obtained from photolysis of (b) 8-anti, (c, d) 9-anti, and (e, f) 9-syn. It should be
noted that cyclobutanol CB1 of 9-syn was hydrolyzed and the resultant dihydroxy product derivatized as a 3,5-dinitrobenzoyl ester. In (b-d), the substituents
at carbons C2 and C3 (Me and OMe/OAc, respectively) are syn, while in (e, f), the C2 and C3 substituents (Me and OCOAr/OAc, respectively) are anti.
syn and anti aldols derived from the Aldol reaction of pro-
piophenone with phenylacetaldehyde were separated, and each
diastereomer was converted to its methoxy (8) or acetoxy (9)
analogue via the same approach as for 6 or 7, respectively.
Ketone 5 was prepared by 1,4-conjugate addition of R,ꢀ-
unsaturated butyrophenone with PhCH2Cu(CN)ZnBr, as de-
scribed in the Supporting Information.17
experiments, the progress of reaction and formation of products
were monitored by TLC and H NMR analyses. For all cases
1
except ketones 6 and 8-syn, the Norrish type-II photoproducts
(i.e., cyclobutanols, acetophenone/propiophenone, and olefin)
were the sole products; for 6 and 8-syn, tetrahydrofuranol
derivatives were found to be formed in ∼4 and 15-20% yields,
respectively, via competitive δ-hydrogen abstraction (eq 1):6,12a
The stereochemistries of the methoxy and acetoxy diastere-
omers were established by X-ray crystal structure determination
of one of the diastereomers of acetoxy ketone 9, which was
found to be anti (Figure 1). On this basis, the aldol that led to
9-anti as well as the methoxy ketone 8 derived from this aldol
were assigned anti stereochemistry. Of course, the other
diastereomer in each case was assigned syn stereochemistry by
default.
In the case of 8-syn, a small amount (∼2-5%) of a new
cyclobutanol with stereochemistry similar to that of the cy-
clobutanol CB1 derived from the anti diastereomer was also
found (Table 2).18
Photolysis of Ketones 4-9 and Characterization of Photo-
products. The photobehavior of ketones 4-9 was examined by
steady-state irradiation of their solutions (contained in pyrex
tubes) in a photoreactor fitted with 350 nm lamps. In qualitative
9
13610 J. AM. CHEM. SOC. VOL. 130, NO. 41, 2008

Conformationally Restricted Triplet 1,4-Biradicals
A R T I C L E S
Table 1. Yields of Cyclobutanols Formed upon Photolysis of
In preparative-scale photolyses involving ∼0.5-1.0 mmol of
the ketone, cyclobutanols were isolated in each case. The
isolated yields of the cyclobutanols obtained from ketones 4-9
are given in Table 1. The stereochemical assignments of the
structures of the cyclobutanols obtained from diastereomeric
ketones 8 and 9 were made on the basis of X-ray crystal
structure determinations and nuclear Overhauser effects (NOEs)
in 1H NMR spectroscopy (see the Supporting Information).
More specifically, the structures of the cyclobutanols derived
from 8-anti and 9-anti were determined by X-ray crystal-
lography. The stereochemistries of the cyclobutanols derived
from 8-syn were established on the basis of NOE effects and
the chemical shifts of the methyl groups; the methyl group that
has a hydroxy group on the adjacent carbon of the cyclobutanol
in a syn relationship generally exhibits downfield shift by ∼0.3
ppm.12b,19 As the major cyclobutanol product of 9-syn was not
crystalline, it was hydrolyzed under MeOH/K2CO3 conditions
to the corresponding diol, and the latter was esterified with 3,5-
dinitrobenzoyl chloride to yield a crystalline derivative suitable
for X-ray diffraction studies (eq 2).
Ketones 1-9 in Benzene and Lifetimes of Their Respective Triplet
1,4-Biradicals in Various Solvents
product yields (%)a
triplet biradical lifetimes (ns)b
entry ketone
cyclization fragmentation benzene DMSO cyclohexane MeOH
1
2
3
4
5
6
7
8
9
1c
10
90
>93
34
57
74
80
66
<10
>75
49
-
71
65
90
50
94
84
232
141
110
99
-
-
55c
61
46
70
35
146
161
158
160
135
90
105
145
110
120
115
3-antid <7
3-synd 66
-
4
5
6
7
43
162
136
87
105
95
90
102
114
26
20 (4)e
34
100
78
235
123
95
8-anti >90
8-syn <10 (15)e
10 9-anti 51
11 9-syn 54
46
85
a The photolyses (λ ) 350 nm) were carried out on solutions in dry
benzene under a N2 gas atmosphere for 8-10 h. The reported values
refer to isolated yields, with the remainder identified as elimination
products by 1H NMR spectroscopy (see the Supporting Information).
b Determined by fitting the decay of the transient absorptions at 310 nm
to a single exponential function, with errors of (10%; typically, 8-15
× 10-3 M solutions of the ketones (OD@355 nm ≈ 0.15) were
subjected to laser flash photolysis. c For product distributions and
lifetimes in heptanes, see refs 5b and 3d, respectively. d Data taken from
ref 9b. e The value in parentheses is the isolated yield of the
tetrahydrofuranol derivative formed by initial δ-hydrogen abstraction.
results from photolysis of the R,ꢀ-dimethyl-substituted analogue
3. Particularly noteworthy are the large yields of cyclobutanols
from the 8-anti (>90%) and 9-anti (51%) diastereomers (Table
1, entries 8 and 10), for which the cyclization should be
disfavored on the basis of simple steric considerations, as in
the case of the R,ꢀ-dimethyl-substituted analogue 3-anti (see
below). Furthermore, one observes that the cyclobutanols were
formed with high stereoselectivity from 8-anti and predomi-
nantly from 9-anti (Table 2, entries 2 and 5).
The dependence of the product distributions on the solvent
was investigated in more detail for ketones 8 and 9 using the
polar aprotic solvents DMSO and pyridine, which act as strong
hydrogen-bond acceptors of the intermediary triplet 1-hydroxy-
1,4-diphenyl-1,4-biradicals.8b,20 For the anti diastereomers of
8 and 9, photolysis in DMSO and pyridine led to cyclobutanols
in considerably lower yields (Table 2). For 8-anti, the yield of
cyclobutanol dropped from >90% in benzene to ∼25% in
DMSO and pyridine, suggesting that the elimination is pro-
moted. In contrast, cyclization was found to be enhanced for
8-syn: the yield of cyclobutanols was found to increase from
10% in benzene to ∼50% in DMSO and pyridine. Notably, a
mixture of two cyclobutanols together with 15-20% tetrahy-
drofuranol derived from initial δ-hydrogen abstraction6,12a was
obtained (entries 9-11, Table 2). A similar albeit less pro-
nounced trend with variation of the solvent from benzene to
DMSO/pyridine was observed for the photolysis of 9. The
structures of all of the cyclobutanols were established by X-ray
crystallography and/or NOE experiments.
However, the minor cyclobutanol product was a solid that
crystallized readily in a mixture of ethyl acetate and petroleum
ether. In the case of 8 and 9, it should be noted that for the
cyclobutanols derived from the anti and syn diastereomers of
the ketones, the X-ray structures as well as the NOE experiments
revealed that the stereochemical relationships between the
substituents at C2 and C3 are syn and anti, respectively (Figure
1); this is very pertinent for providing mechanistic insights into
the behavior of the precursor triplet biradicals, as discussed
below.
A perusal of the results from photolysis in benzene collected
in Table 1 shows that R-methyl substitution increased the yield
of cyclobutanols while ꢀ-methyl substitution decreased it. The
ꢀ-methoxy and ꢀ-acetoxy substituents in 6 and 7, respectively,
modified the yield of cyclobutanols by 6-14% relative to that
observed for the methyl analogue 5. Cyclization yields and the
stereochemistries and relative ratios of the cyclobutanols derived
from 8 and 9 are given in Table 2, along with the corresponding
(18) The formation of the cyclobutanol with a syn relationship between
the substituents at C2 and C3 may be rationalized in terms of initial
δ-hydrogen abstraction followed by a very rare 1,4-transfer of a
hydrogen atom, as discussed in ref 6 and the following reference:
Wagner, P. J.; Chiu, C. J. Am. Chem. Soc. 1979, 101, 7134.
(19) Lewis, F. D.; Hilliard, T. A. J. Am. Chem. Soc. 1972, 94, 3852.
(20) (a) Wagner, P. J. J. Am. Chem. Soc. 1967, 89, 5898. (b) Wagner,
P. J.; Kochevar, I. E.; Kemppainen, A. E. J. Am. Chem. Soc. 1972,
94, 7489.
(15) Menche, D.; Hassfeld, J.; Li, J.; Rudolph, S. J. Am. Chem. Soc. 2007,
129, 6100.
(16) Velusamy, S.; Punniyamurthy, T. Tetrahedron Lett. 2004, 45, 4917.
(17) Berk, S. C.; Yeh, M. C. P.; Jeong, N.; Knochel, P. Organometallics
1990, 9, 3053.
9
J. AM. CHEM. SOC. VOL. 130, NO. 41, 2008 13611

A R T I C L E S
Moorthy et al.
Table 2. Results of Preparative Photolysis of Ketones 8 and 9 in
Different Solventsa Compared with Those of Ketones 3b in
Benzene
intercepts the precursors of the triplet biradical intermediates.
From changes in the initial absorbances of the transients and
the assumption of diffusion-controlled quenching by 1,3-
pentadiene, lifetimes of the triplets of the diastereomeric ketones
8 were estimated to be ∼10 ns as an upper limit.
ratio of cyclobutanolsd
entry ketone
solvent
cyclization yield (%)c
CB1
CB2
The decay kinetics for ketones 4-9 were determined at 310
nm. The transient decays were found to be monoexponential,
and the fits afforded the triplet biradical lifetimes (each the mean
of three or more independent experiments) reported in Table 1.
As can be seen, the lifetimes in most cases were relatively longer
in the polar protic methanol solvent than in cyclohexane or
benzene;8b in view of the short triplet lifetimes, photolysis in
solvents such as cyclohexane and methanol are less likely to
lead to products of reactions with solvent. Otherwise, a more
discernible and meaningful trend is noteworthy in cyclohexane
and benzene solvents: R-methyl substitution in 4 increased the
lifetime relative to 1 while ꢀ-methyl substitution in 5 had the
opposite effect (Table 1, entries 1, 4 and 5). The methoxy and
acetoxy substituents at the ꢀ-position increased the lifetimes,
with a more pronounced effect being observed for the former
(entries 6 and 7). While only a marginal difference was observed
for the two diastereomers of acetoxy ketone 9 (entries 10 and
11), a remarkable discrimination was found for the syn and anti
diasteromers of R-methyl-ꢀ-methoxy ketone 8 (entries 8 and
9): the triplet biradical lifetime of the anti diastereomer was
found to be ∼2-fold higher than that of the syn diastereomer in
the nonpolar solvents.
e
e
1
2
3
4
5
6
7
3-anti benzene
8-anti benzene
pyridine
dimethyl sulfoxide
9-anti benzene
<6-7
>90
27
22
51
-
>98
>98
>98
66
-
f
-
f
-
f
-
34
f
pyridine
dimethyl sulfoxide
24
30
100
100
-
f
-
e
8
9
10
11
3-syn benzene
8-syn benzene
<66
>97
50
82
85
90
-
h
<10(15)g
47(20)g
54(16)g
54
-
pyridine
dimethyl sulfoxide
12h
12h
10
8
12 9-syn benzene
13
14
pyridine
dimethyl sulfoxide
68
68
92
94
6
a All of the photolyses were conducted under a N2 atmosphere in a
photoreactor fitted with 350 nm lamps. Mass balances for all cases were
>90% as monitored by 1H NMR spectroscopy. b Data from ref 9b.
c Isolated yield. d Normalized to 100%. e Not characterized. f Not
detected. g Isolated yield of the tetrahydrofuranol derivative formed by
initial δ-hydrogen abstraction (see text). h The remainder was another
cyclobutanol with stereochemistry similar to that of CB1 derived from
8-anti (see text).
Discussion
Alkyl phenyl ketones react predominantly from their triplet
states, and those that contain a γ-hydrogen react to yield triplet
1,4-biradicals quantitatively.24 As mentioned earlier, the less-
than-unity quantum yield generally observed for ketone disap-
pearance is traceable to internal disproportionation of (hydrogen
back-transfer in) the triplet 1,4-biradicals (Scheme 1).1 It has
long been known that R- and ꢀ-substituents influence the
partitioning of triplet 1,4-biradicals between cyclization and
elimination. The strong dependence of the photochemical
outcome on the location of the substituent(s) has been reconciled
on the basis of the influences of stereochemical and electronic
factors on the geometries of the transition states for cyclization
and elimination; the transition state favoring cyclization requires
overlap of the radical orbitals, while that for elimination must
Nanosecond Laser Flash Photolysis and Lifetimes of the
Transient Triplet 1,4-Biradicals. The transient phenomena for
ketones 4-9 were studied by subjecting their solutions to laser
flash photolysis at 355 nm. The concentrations of the solutions
were ∼8-15 × 10-3 M with an optical density (OD) of ∼0.15.
Laser flash photolysis produced a strong transient absorption
for all of the ketones 4-9 at ∼310-320 nm and a weak, broad
band at 400-450 nm in cyclohexane and 400-550 nm in
benzene.21 These absorption spectra are characteristic of hy-
droxyphenylmethyl and benzylic radicals.9b,22,23 The typical
absorption spectra recorded for the two representative diaster-
eomers of ketone 8 in cyclohexane and benzene are shown in
Figure 2.
On the basis of a comparison of the absorption features with
those reported for 1 and closely related analogous ketones,9,23
the transients of ketones 4-9 were assigned to the bisbenzylic
triplet 1,4-biradicals generated by Norrish type-II hydrogen
abstraction from the γ-benzylic site; the ketones undergo
γ-hydrogen abstraction to afford triplet biradicals quantita-
tively.24 The assignment of the transients to triplet 1,4-biradicals
was independently verified by quenching studies involving
piperylene. It has been reported by Caldwell et al.3d that the
transient absorption in the unsubstituted ketone 1 and its closely
related analogues was not affected by a diene such as isoprene
up to concentrations as high as 0.1 M. In our experiments, the
lifetimes of the transients of the representative cases 8-syn and
8-anti were found to be similarly unaffected by 1,3-pentadiene
at a concentration of 0.06 M, but the absorbances of the
transients decreased. This suggests that the added quencher
(21) The transient absorption spectroscopy of more dilute solutions of
ketones 6, 8, and 9 using 308 nm excimer lasers was complicated by
the observation of an intriguing transient absorption with a maximum
at ∼390 nm. This unexpected absorption, which seemingly submerged
the shoulder in the 400-450 nm region, was found to be significantly
stronger for the anti diastereomer than for the syn counterpart.
Furthermore, the species responsible for the transient absorption was
found to be long-lived (τ ≈ 1.5-2.0 µs). From control experiments
with partially and fully photolyzed samples, it was firmly established
that the transient absorption originated from the photoproducts of
certain ketones that were formed and excited instantaneously during
the laser flashes. As the additional transient did not interfere during
experiments using 355 nm irradiation (the third-harmonic of a Nd-
YAG laser), where the aryl ketones fortunately displayed a sufficiently
strong absorption (ε ≈ 35 M-1 cm-1), the spectral acquisitions and
lifetime determinations were carried out at this wavelength. Further
studies are in progress to characterize and unravel the origin of these
unexpected transients, which were also noted for the first time in our
previous study (ref 9a). The results of these investigations will be
reported in due course.
(22) Font-Sanchis, E.; Miranda, M. A.; Pe´rez-Prieto, J.; Scaiano, J. C. J.
Org. Chem. 2002, 67, 6131.
(23) (a) Lutz, H.; Bre´he´ret, E.; Lindqvist, L. J. Phys. Chem. 1973, 77, 1758.
(b) Claridge, R. F. C.; Fischer, H. J. Phys. Chem. 1983, 87, 1960.
9
13612 J. AM. CHEM. SOC. VOL. 130, NO. 41, 2008

Conformationally Restricted Triplet 1,4-Biradicals
A R T I C L E S
Figure 2. Transient absorption spectra of triplet 1,4-biradicals generated by 355 nm nanosecond laser flash photolysis of (red squares) 8-anti and (blue
circles) 8-syn in (left) cyclohexane (recorded 70 and 50 ns, respectively, after the laser pulse) and (right) benzene (recorded 110 and 70 ns, respectively, after
the pulse). The insets show the decay profiles for (red) anti and (blue) syn diastereomeric triplet 1,4-biradicals of ketones 8 in the corresponding solvents.
Scheme 2. Mechanistic Rationalization of the Formation of
Predominant Products from the syn and anti Diastereomers of
repulsion between the methyl groups at C2 and C3 in the cisoid
Ketones 3
that are favored on the basis of steric considerations alone: steric
conformation of the biradical of the anti diastereomer favors
adoption of the transoid geometry, so elimination is predomi-
nantly observed; the opposite holds true for the biradical of the
syn diastereomer, for which cyclization becomes the major
pathway. Clearly, the stereochemical considerations simplify
rationalizations based on spin-statistical factors,3c spin-orbit
coupling efficiencies and associated geometries,7 etc. Of course,
implicit in our criteria of favored conformations for partitioning
of the intermediate triplet 1,4-biradicals is the fact that the latter
are sufficiently long-lived for equilibrium to be established
between the various conformations. This is likely to be true
when the triplet biradical lifetimes are on the order of tens of
nanoseconds, which is the case, in particular, for bisbenzylic
biradicals such as those generated from the ketones investigated
herein.
We adhere to the same mechanistic formulation to understand
the photochemistry of ketones 4-9. As the intermediate triplet
1,4-biradicals are uniformly bisbenzylic for all of the ketones,
the differences in the photochemical outcomes for 4-9 (i.e.,
cyclization vs elimination) as well as the lifetimes of the triplet
1,4-biradicals in Table 1 should again be explicable by the
differences in the conformational preferences of the biradicals
that arise from the varying substitution patterns at either the R
entail maximum overlap of the p orbitals of the two radical
or ꢀ positions (4-7) or both (8 and 9).
centers with the C2-C3 σ bonding orbital.1,5 It must also be
Effect of r- and ꢀ-Substituents on and Intramolecular
O-H· · ·O Hydrogen-Bond-Mediated Reversal of 1,4-Triplet
Biradical Partitioning. The effect of simple alkyl substitution
mentioned that the stereochemical requirements are thought to
be more stringent for elimination than for cyclization.
We have recently shown that the diastereodifferentiating
at the R and/or ꢀ positions will be considered first. The parent
unsubstituted γ-phenylbutyrophenone 1 affords cyclization
products only in 10% yield (Table 1).5b While the ꢀ-methyl
group in 5 exerts only a small effect on the product distribution
(entry 5), R-methyl substitution in 4 raises the cyclization yield
quite steeply to 43% (entry 4).5a This can be traced to the fact
that the biradicals of ketones containing an R-substituent would
be subject to severe 1,2-eclipsing interactions between the
R-substituent and the hydroxyl/phenyl group, preventing the p
orbitals of the radicals from aligning parallel with the C2-C3
σ bond in the transoid conformation.5 For the biradicals of
ketones 6-9, intramolecular hydrogen bonding additionally
photobehavior of R,ꢀ-disubstituted ketones can be reconciled
on the basis of (i) stereocontrolled stabilization of the geometry
(cisoid/transoid) of the derived triplet biradical and (ii) the
premise that cyclization will be observed only if the triplet
biradical assumes the cisoid geometry while fragmentation
occurs predominantly from the transoid geometry.9b As shown
in Scheme 2, the divergent product profiles from the syn (66%
cyclization) and anti (>93% elimination) diastereomers of
ketone 3 are understood in terms of the biradical conformations
(24) Wagner, P. J.; Kelso, P. A.; Zepp, R. G. J. Am. Chem. Soc. 1972, 94,
7480.
9
J. AM. CHEM. SOC. VOL. 130, NO. 41, 2008 13613

A R T I C L E S
Moorthy et al.
Scheme 3. Mechanistic Rationalization of the Formation of Photoproducts of Diastereomeric Ketones
interferes, modifying the conformational preferences and hence
the product distributions. We shall first discuss the diastereo-
differentiating reactivity of ketones 8 and 9 and then consider
a rationalization of the photobehavior of ketones 6 and 7.
Scheme 3 shows the consequences of photoexcitation of the
syn and anti diastereomers of R-methyl-ꢀ-methoxy ketone 8.
γ-Hydrogen abstraction by triplet excited ketones via six-
membered cyclic transition states yields the corresponding triplet
1,4-biradicals, which may directly undergo intramolecular
hydrogen bonding in a nonpolar solvent such as benzene. Indeed,
the location of the methoxy group in both diastereomers of 8
permits O-H· · ·O hydrogen bonding of the triplet 1,4-biradical
in a chair geometry. For the biradical of the anti diastereomer,
the singly occupied p orbitals lie apart in the hydrogen-bonded
chair conformation, precluding cyclization. Also, the elimination
does not appear to be facile because of the fact that the p orbital
of the hydroxyphenyl radical cannot align parallel with the
C2-C3 σ bond; analysis of a ball-and-stick model revealed that
the location of the methyl group in the equatorial position
hinders such an arrangement. Nevertheless, the hydrogen-bonded
chair conformer of the 1,4-biradical of the anti diastereomer is
likely to undergo elimination, since cyclization cannot occur
because the radical centers in this conformation lie so far apart.
On the other hand, a simultaneous rotation about the C2 and
C3 carbons in opposite directions may lead to a hydrogen-
bonded twist-boat geometry in which the radical p orbitals may
be oriented nicely for cyclization to become a predominant
pathway. In fact, the stereorelationship between the substituents
in the twist-boat is exactly transferred to the cyclobutanol,
whose structure was established by X-ray crystallography
(Figure 1). For the syn diastereomer, the hydrogen-bonded triplet
biradical would be devoid of the steric inhibition of collinearity
of the p orbitals with the C2-C3 σ bonding orbital that occurs
in the case of the anti diastereomer; the methyl group at C2
would occupy the axial position, readily promoting elimination.
For ketones that are R,ꢀ-disubstituted, the steric interactions
between the C2 and C3 substituents in the biradicals of the syn
and anti diastereomers determine the conformational preferences
and the partitioning between cyclization and elimination. As
described earlier, the triplet biradical of ketone 3-syn prefer-
entially adopts the cisoid conformation, leading to predominant
cyclization (Scheme 2), and the cyclobutanols are formed with
anti stereochemistry between the C2 and C3 substituents. In
contrast, the transoid conformation is favored for the biradical
of the 3-anti diastereomer, so elimination is the major pathway.
Indeed, the photobehavior of R-acetamido ketones observed by
Griesbeck et al.7c,11a can also be nicely accommodated within
this mechanistic paradigm of stereocontrolled stabilization of
cisoid/transoid conformation and associated reactivity. However,
this trend was found to be reversed for photolysis of ketones 8
and 9 in benzene in that the anti diastereomers predominantly
afford cyclization products, leading to cyclobutanols with syn
stereochemistry between the substituents at C2 and C3, while
the syn diastereomers predominantly undergo elimination (Table
2); the syn stereochemistry of the cyclobutanols in the former
case was unequivocally established by X-ray crystal structure
determinations (Figure 1). Furthermore, a very high diastereo-
selectivity is observed for the formation of cyclobutanol from
8-anti. Clearly, the arguments based on steric effects alone are
inadequate in these cases, and the dramatic reversal in the
product profiles for 8 and 9 compared with those for 3 should
be attributed to intramolecular hydrogen-bonding effects.
9
13614 J. AM. CHEM. SOC. VOL. 130, NO. 41, 2008

Conformationally Restricted Triplet 1,4-Biradicals
A R T I C L E S
The reactivity from the higher-energy twist-boat conformation
may not arise at all in this case.
difference in the lifetimes in cyclohexane and benzene, which
attests to H-bond control of the deactivation. This differentiation
in the lifetimes of the syn and anti diastereomers (123 and 235
ns, respectively, in cyclohexane) is remarkably higher than what
we previously documented for ketones 3 for the first time.9b
In principle, the lifetimes of triplet 1,4-biradicals are deter-
mined by internal disproportionation (kd), cyclization (kc), and
fragmentation (kf) (Scheme 1). While different rates of internal
disproportionation might apply for the triplet biradicals of 1-8,
we found that their partitioning between the other pathways (i.e.,
cyclization and elimination) as reflected in the product analyses
can be nicely correlated with their triplet biradical lifetimes.
Accordingly, R-substituents that hinder elimination appear to
increase the lifetimes (Table 1, entry 4), as do ꢀ-substituents
that stabilize the biradicals via intramolecular hydrogen bonding
(entries 6 and 7). The ꢀ-methyl substituent that seemingly offers
less hindrance to elimination reduces the lifetime (entry 5). In
other words, any factor that affects elimination appears to
influence the lifetimes in a more pronounced way. Thus, the
diastereomeric differentiation observed in the lifetimes of the
biradicals of ketones 8 can be reconciled on the basis of
retardation of elimination (or lack thereof) in their hydrogen-
bonded chair conformations. Incidentally, it is the location of
the R-methyl group that controls elimination. As may be seen
from Scheme 3, the methyl group hinders elimination in the
case of the anti biradical but exerts no such influence on
the syn biradical. Rather less perceptible differentiation in the
lifetimes of the diastereomeric biradicals of 9 should be
attributed to weaker hydrogen bonding (if any exists) via an
eight-membered ring, which augments the stereoelectronic
requirement for elimination.
In contrast to the lifetimes of the triplet biradicals in benzene,
those in MeOH and DMSO do not fit into a readily conceivable
pattern. Nonetheless, the lifetimes observed for the biradicals
of diastereomeric ketones 8 in DMSO are quite instructive. As
this solvent may exclude the influence of intramolecular
hydrogen bonding, the lifetimes should be expected to be
controlled largely by steric factors; of course, the latter modify
the conformational preferences and partitioning pathways. A
perusal of the lifetimes in Table 1 reveals almost similar
lifetimes for the diastereomeric biradicals of ketones 8 and 9
(Table 1, entries 8-11), pointing to the absence of intramo-
lecular hydrogen-bonded stabilization of the biradicals. The
product distributions discussed above for the diastereomers of
8 and 9 in DMSO and benzene nicely correlate with the lifetime
data. It thus emerges that the conformational factors, at least in
polar solvents, are less likely to drastically affect the lifetimes
of triplet 1,4-biradicals, insofar as they are subject to mere steric
factors. However, the lifetimes in conjunction with the product
profiles observed here for the diastereomeric biradicals of
ketones 8 in nonpolar solvents confirm the dramatic influence
of intramolecular hydrogen bonding and disprove the conclusion
reached by Caldwell and co-workers3e,h nearly two decades ago,
namely, that the lifetimes of triplet biradicals are invariant to
conformational factors.
Poor selectivity in the partitioning between cyclization and
elimination in the biradicals of the acetoxy derivatives 9, which
is reflected in the cyclization and elimination yields (Table 1),
can similarly be reconciled on the basis of hydrogen-bonding
and stereoelectronic factors. As the hydrogen bonding in these
cases would occur via an eight-membered ring, the biradical
geometries should be less rigidly defined. Thus, the stereoelec-
tronic arguments discussed above for the biradicals of ketones
8 should also be less stringent, accounting for the lower
cyclization yield as well as the poorer diastereoselectivity in
the formation of cyclobutanols for the anti diastereomer in
benzene. A comparison of the photochemical results for ketones
8 and 9 with those for 6 and 7 is compelling from a mechanistic
point of view. The poor cyclization yields in the latter two
ketones due to the absence of an R-methyl substituent underscore
the importance of conformational restrictions on the triplet 1,4-
biradicals that undergo intramolecular hydrogen bonding. The
low cyclization yields should be explicable in terms of competi-
tive elimination from the hydrogen-bonded chair conformer
(Scheme 3).
Solvent Effects. The photobehavior of the diastereomeric
ketones 8 and 9 in the nonpolar benzene solvent illustrates the
effect of intramolecular hydrogen bonding on the otherwise
conformationally restricted (by R,ꢀ-disubstitution) triplet 1,4-
biradicals, which may partition between two distinct pathways.
As intramolecular hydrogen bonding is prone to be destroyed
intermolecularly by strongly hydrogen-bond-accepting solvents,
ketones 8 and 9 represent unique cases for deconvoluting the
hydrogen-bonding and steric effects and exploring the extent
to which solvents can modify the partitioning of the derived
triplet 1,4-biradicals. As one may envisage, the exclusion of
intramolecular hydrogen bonding should cause the steric
interactions between the C2 and C3 substituents to become
decisive in determining the conformational preferences and
hence the photochemical outcomes in a manner akin to that
observed for the biradicals of ketones 3. We have photolyzed 8
and 9 in two polar aprotic solvents, DMSO and pyridine, which
solvate triplet hydroxyl-1,4-biradicals and enhance quantum
yields of decomposition by suppressing internal disproportion-
ation back to the precursor ketones (Scheme 1).20 The results
in Table 2 show that the cyclization yield for 8-anti dropped
from >90% in benzene to ∼25% in the polar aprotic solvents,
while that for 8-syn increased from <10% to ∼50%. Alterna-
tively, elimination and cyclization became predominant for the
anti and syn diastereomers, respectively, of ketone 8 in the polar
aprotic solvents. This is in accordance with the trend observed
for ketones 3, whose triplet biradicals undergo partitioning solely
based on steric factors.
Amplification of Diastereodifferentiation in the Triplet
Lifetimes of the Bisbenzylic 1,4-Biradicals. As the triplet
biradicals of ketones 4-9 are uniformly bisbenzylic, they readily
lend themselves to detection by nanosecond laser flash pho-
tolysis. For all of the ketones, the lifetimes of the triplet
biradicals followed a regular trend in the two nonpolar solvents
cyclohexane and benzene (Table 1). The data for ketones 1, 4,
and 5 suggest that R- and ꢀ-methyl groups exert opposing effects
on the biradical lifetimes: while the R-Me group increased the
lifetime, the ꢀ-Me group decreased it slightly. Incidentally,
the hydrogen-bonding substituents (OMe and OAc) increased
the lifetimes despite being located at the ꢀ-position. For the
diastereomeric biradicals of ketones 8, we observed an ∼2-fold
Generalizations Regarding the Chemoselectivity (Cyclization
versus Fragmentation) of Hydrogen-Bonded Triplet 1,4-Biradi-
cals. The triplet hydroxy-1,4-diyls generated via photoinduced
γ-hydrogen abstraction may in principle be intramolecularly
hydrogen-bonded in a number of cyclic geometries, depending
on the location (i.e., R, ꢀ, γ, or δ) as well as the nature of the
heteroatom-containing groups. Thus, the manner in which the
intramolecular hydrogen-bond-controlled geometries of the triplet
9
J. AM. CHEM. SOC. VOL. 130, NO. 41, 2008 13615

A R T I C L E S
Moorthy et al.
Scheme 4. Ketones Whose Triplet Biradicals May Be Intramolecularly Hydrogen-Bonded via Five- to Eight-Membered Cyclic Geometries
and their Yields (%) of Photoinduced Yang Cyclization
biradicals affect their partitioning between fragmentation and
cyclization as well as the stereochemistry of the product cyclobu-
tanols is of fundamental importance. Scheme 4 categorizes a
variety of ketones whose triplet biradicals may be internally
hydrogen-bonded via five-, six-, seven-, or eight-membered
cyclic geometries. Also given for each case is the yield of
cyclization product(s). A perusal of the latter data shows that
hydrogen-bonding-controlled geometries influence cyclization
yields significantly. For example, the yields of cyclobutanols
from methoxy-substituted butyrophenones vary from 0 to 28%
for R-, ꢀ-, and γ-methoxybutyrophenones. Remarkably, the
steric congestion in hydrogen-bonded biradicals results in
enhancement of cyclization yields, as observed for a range of
R-acetamido ketones7c with increasing methyl substitution (see
the seven-membered hydrogen-bonding systems in Scheme 4).
However, the fact that the chemoselectivity (i.e., cyclization vs
fragmentation) depends crucially on the stereodisposition of the
substituents emerges from the diastereodifferentiating photo-
behavior observed for both the R-acetamido ketones and
ꢀ-methoxybutyrophenones of the present study; the triplets of
9
13616 J. AM. CHEM. SOC. VOL. 130, NO. 41, 2008

Conformationally Restricted Triplet 1,4-Biradicals
A R T I C L E S
the former and the latter may hydrogen bond via seven- and
six-membered rings, respectively. Although it is evident from
Scheme 4 that the chemoselectivity varies with the strength of
intramolecular hydrogen bonding as well as the triplet biradical
geometry, it is the superposition of steric and hydrogen-bonding
interactions (as in the methoxy ketones 8) that appears to permit
one of the two disparate pathways (either cyclization or
fragmentation) to be observed almost exclusively. While steric
effects alone may bring about high chemoselectivity, as we have
shown previously for 3,9b the present study illustrates that
intramolecular hydrogen bonding in conjunction with steric
interactions reverses the chemoselectivity based on steric effects
alone. Further, it also emerges from a comparison of the
photochemical results for ketones 8 with those for the acetoxy
analogues 9 that the almost exclusive occurrence of either
fragmentation or cyclization depends crucially on steric as well
as rigid hydrogen-bonded geometries, as in the case of 8; indeed,
weaker hydrogen bonding in triplet biradicals has been shown
by Griesbeck et al.7c,11a to affect both cyclization efficiency and
diastereoselectivity.
profiles of ketones 6, 7, and 9 can be best reconciled via a
unified mechanistic picture in which superposition of varying
magnitudes of O-H · · · O hydrogen bonding over steric
factors selectively facilitates a particular pathway. In par-
ticular, the diastereodifferentiation between the photochemical
outcomes for the diastereomers of ketone 8 and the lifetimes
of their triplet biradicals are readily rationalized by rapid
deactivation (8-syn) and slow cyclization (8-anti) from chair-
and twist-boat-like hydrogen-bonded conformations of the
corresponding triplet biradicals, respectively.
The behavior of 1,4-biradicals in general continues to be
an enigma. Attempts to understand the factors that influence
the lifetimes of triplet 1,4-biradicals and their modes of
partitioning continue to be of contemporary interest in view
of the importance of the Norrish type-II reaction in several
applications.22,25 In particular, Yang cyclization and Norrish
fragmentation are being increasingly explored in asymmetric
synthesis,14b,26 photocyclizations,27 photorelease of vola-
tiles,28 and photodeprotections29 and as probes of microen-
vironments.30 Since 1,4-biradicals are also intermediates in
Paterno-Buchi cycloaddition reactions,7a,b we believe that
the insights uncovered in this work significantly enhance our
understanding of the behavior of triplet 1,4-biradicals as
important reactive intermediates.
Conclusions
Comparisons of the photochemical results and lifetime data
for the biradicals of ketones 6 versus 8 and 7 versus 9 have
revealed a remarkable influence of hydrogen bonding super-
imposed upon steric factors: while 6 and 7 yielded cyclobu-
tanols in poor yields, cyclization became overwhelmingly
predominant for 8-anti and moderately so for 9-anti, with a
high diastereoselectivity in the formation of cyclobutanols
(>95% for 8-anti). The diastereochemistry in the case of 8
permitted the occurrence of either fragmentation and cy-
clization almost exclusively (>90% cyclization for anti and
>75% elimination for syn). Most significant is the fact that
the intramolecular hydrogen bonding in the biradicals of 8
and 9 reversed their partitioning between cyclization and
elimination compared with the behavior of the biradicals of
ketones 3: the ketones 8-anti and 9-anti predominantly
underwent cyclization in benzene, leading to cyclobutanols
with syn stereochemistry between the C2 and C3 substituents.
Photolyses of 8 and 9 in hydrogen-bond-accepting solvents
such as DMSO and pyridine yielded dramatically modified
product distributions that reflected photochemistry paralleling
that of ketones 3, for which the intermediate biradicals cannot
undergo intramolecular hydrogen bonding. The nanosecond
laser flash photolysis studies revealed an unprecedented
diastereodifferentiation in the lifetimes of the triplet 1,4-
biradicals of ketones 8 in nonpolar solvents: the syn and anti
triplet biradicals exhibited an ∼2-fold difference in their
lifetimes. The intriguing product stereochemistry and the
accompanying dramatic variation in the lifetimes of the
diastereomeric triplet 1,4-biradicals of 8 as well as the product
Acknowledgment. Generous funding from the Department of
Science and Technology (DST) of India is gratefully acknowledged.
J.N.M. is thankful to the RSC for a Journal Grants Fellowship that
facilitated collaborative research at Jacobs University. S.S. and S.S.
are grateful to CSIR for their research fellowships. W.M.N.
acknowledges support by the Fonds der Chemischen Industrie and
the graduate program “Nanomolecular Science”.
Supporting Information Available: Experimental details of
synthesis and photolysis of ketones, characterization details
of photoproducts (including figures showing the NOE
interactions), description of laser-flash-photolysis studies,
transient absorption spectra of valerophenone in cyclohexane
and benzene, and details of the X-ray crystal structure deter-
mination and CIF files for all of the crystal structures in Figure
1. This material is available free of charge via the Internet at
http://pubs.acs.org.
JA8032179
(26) (a) Steiner, A.; Wessig, P.; Polborn, K. HelV. Chim. Acta 1996, 79,
1843. (b) Bach, T.; Aechtner, T.; Neumuller, B. Chem. Commun. 2001,
607. (c) Natarajan, A.; Mague, J. T.; Ramamurthy, V. J. Am. Chem.
Soc. 2005, 127, 3568.
(27) (a) Wessig, P.; Mu¨hling, O. Angew. Chem., Int. Ed. 2001, 40, 1064.
(b) Wessig, P.; Mu¨hling, O. In Molecular and Supramolecular
Photochemistry; Griesbeck, A. G., Mattay, J., Eds.; Marcel Dekker:
New York, 2005; Vol. 12, p 41 and references therein. (c) Roscini,
C.; Davies, D. M. E.; Berry, M.; Orr-Ewing, A. J.; Booker-Milburn,
K. I. Angew. Chem., Int. Ed. 2008, 47, 2283.
(25) (a) Cheung, E.; Netherton, M. R.; Scheffer, J. R.; Trotter, J. Org. Lett.
2000, 2, 77. (b) Braga, D.; Chen, S.; Filson, H.; Maini, L.; Netherton,
M. R.; Patrick, B. O.; Scheffer, J. R.; Scott, C.; Xai, W. J. Am. Chem.
Soc. 2004, 126, 3511. (c) Broyles, D. A.; Carpenter, B. K. Org. Biomol.
Chem. 2005, 3, 1757. (d) Goez, M.; Zubarev, V. Angew. Chem., Int.
Ed. 2006, 45, 2135.
(28) (a) Levrand, B.; Herrmann, A. Photochem. Photobiol. Sci. 2002, 1,
907. (b) Levrand, B.; Herrmann, A. Chimia 2007, 61, 661. (c)
Herrmann, A. Angew. Chem., Int. Ed. 2007, 46, 5836.
(29) Bochet, C. G. J. Chem. Soc., Perkin Trans. 1 2002, 125.
(30) (a) Kell, A. J.; Stringle, D. L. B.; Workentin, M. S. Org. Lett. 2000,
2, 3381. (b) Kell, A. J.; Workentin, M. S. Langmuir 2001, 17, 7355.
9
J. AM. CHEM. SOC. VOL. 130, NO. 41, 2008 13617