Orbital-overlap control of the reactivity of a bicyclic 1-hydroxy-1,4-biradical

Article abstract of DOI:10.1002/anie.200500983

Radical reform: Cleavage of the enantiotopic C2-C3 or C2-C3′ bonds in bicyclic 1-hydroxy-1,4-biradicals (see structure) leads to enantiomeric products. Absolute configuration correlations demonstrate that, in the crystalline state, cleavage occurs mainly

Full text of DOI:10.1002/anie.200500983

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biradical behavior reflects the geometry in which the singlet
biradical is formed by intersystem crossing (isc) from the
triplet, which may differ significantly from the geometry of
the conformationally equilibrated species.[7] For these rea-
sons, we have elected to work with compounds in the
crystalline state, where molecular conformation is fixed and
determinable by X-ray crystallography, and where the singlet
biradical formed by isc has the same geometry as its triplet
precursor. We have shown that 1-hydroxy-1,4-biradicals can
be generated conveniently in the solid state by the Norrish–
Yang type II reaction, and that because hydrogen-atom
transfer occurs with very little movement of the associated
heavy atoms, the structure and conformation of the biradicals
can be inferred directly from the X-ray crystal structures of
their ground-state precursors.[8] Herein, we compare and
contrast the behavior of 1-hydroxy-1,4-biradicals of general
structures 1 and 2. These biradicals are interesting because,
Biradicals
DOI: 10.1002/anie.200500983
Orbital-Overlap Control of the Reactivity of a
Bicyclic 1-Hydroxy-1,4-Biradical**
Chao Yang, Wujiong Xia, John R. Scheffer,*
Mark Botoshansky, and Menahem Kaftory
1,4-Biradicals are among the most ubiquitous reactive inter-
mediates in organic chemistry, and are formed or implicated
in a variety of reactions including [2+2] photocycloaddition,[1]
the Paterno–Büchi reaction (oxetane formation),[2] the Nor-
rish–Yang type II reaction,[3] and the elimination of nitrogen
from cyclic azo compounds.[4] Once formed, 1,4-biradicals
suffer two main fates: closure to form compounds containing
a four-membered ring, and cleavage of the central bond to
produce a pair of double-bond-containing fragments.[5] Based
on organic intuition backed by semiempirical calculations,[6]
and supported by a wide variety of product studies,[1–4] the
generally accepted qualitative picture of biradical reactivity is
that cleavage is favored when the conformation allows the
radical-containing orbitals at positions 1 and 4 to overlap with
the sigma bond between positions 2 and 3. Increasing
amounts of cyclization are observed as this overlap dimin-
ishes, provided that the radical termini are within reasonable
bonding distance of one another.
unlike the majority of biradicals studied previously, they have
only one significant degree of conformational freedom,
À
namely, rotation about the C1 C2 bond. Among the ques-
tions we wished to answer about these biradicals were: 1) how
does the orientation of the p orbital at the C1 position affect
the ratio of cyclization to cleavage; and 2) can we correlate
the orientation of the p orbital at C1 with preferential
À
À
cleavage of either the C2 C3 or C2 C3’ bond? As described
below, satisfactory answers to these questions were obtained
by generating biradicals 1 and 2 in the crystalline state and
correlating their behavior in this medium with their con-
formations as determined by X-ray crystallography.
We are not the first to study biradicals of types 1 and 2.
The solution-phase behavior of biradical 2 (Ar= Ph) was
reported in 1972 by Padwa and Eisenberg and shown to
consist of 66% cleavage and 30% cyclization.[9] Similarly,
Alexander and Uliana showed in 1976 that, in solution,
biradical 1 (Ar= Ph) bearing a phenyl substituent at the C2
position undergoes 100% cyclization.[10] In both cases, the
biradicals were formed by a Norrish–Yang type II photo-
reaction of the corresponding ketone. In the present work, we
chose to investigate ketones in which the aryl group bears a
carboxylic acid substituent in the para position, that is,
ketones of general structures 3 and 6 (Scheme 1). This choice
was based on the following considerations: previous work
from our group had shown that when achiral keto acids such
as 3a and 6a are treated with optically pure amines, the
resulting salts (3b and 6b) crystallize with the carboxylate
anions in homochiral conformations.[11] In principle, these
salts could react when photolyzed in the solid state to
produce, after diazomethane workup, the achiral Yang
cyclization products 4c/7c along with the chiral Norrish
type II cleavage products 5c/8c (Scheme 1). Cleavage of the
However, quantitative experimental tests of this hypoth-
esis are rare, in part as a result of the difficulty of establishing
structure–reactivity relationships for conformationally
mobile systems in fluid media. In the case of triplet 1,4-
biradicals, the picture is complicated by the likelihood that
[*] Dr. C. Yang, Dr. W. Xia, Prof. Dr. J. R. Scheffer
Department of Chemistry, University of British Columbia
2036 Main Mall, Vancouver, B.C. V6T1Z1 (Canada)
Fax: (+1)604-822-3496
E-mail: scheffer@chem.ubc.ca
Dr. M. Botoshansky, Prof. Dr. M. Kaftory
Department of Chemistry, Technion
Haifa 32000 (Israel)
[**] We thank the Natural Sciences and Engineering Research Council of
Canada for financial support. J.R.S. is grateful to the Rockefeller
Foundation for a one-month residency at their Bellagio Study
Center, where this paper was written.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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An independent, enantioselective synthesis of photo-
product 8c was carried out to determine whether the major
enantiomer produced in these photolysis reactions was of R or
S configuration. Optically pure (S)-2-cyclopentene-1-acetic
acid was prepared by resolution of the racemate with brucine
according to the procedure of Mislow and Steinberg.[14] This
material was then converted by reduction with lithium
aluminum hydride, oxidation with pyridinium chlorochro-
mate (PCC), addition of p-carbomethoxyphenylmagnesium
iodide, and oxidation with PCC to (S)-8c, which proved to be
dextrorotatory ([a]2D2 = + 98.08, c = 0.45, MeOH). According
to the sign of rotation shown in Table 1, this means that
compound 8c formed in the photolysis of the (S)-(À)-1-
phenylethylamine salt of keto acid 6a has the R absolute
configuration. On the basis of the very close structural
similarity between photoproducts 8c and 5c, we assume that
the latter also has the R-(À) absolute configuration.
Concomitant with the photochemical and synthetic stud-
ies, the X-ray crystal structures of the (S)-(À)-1-phenylethyl-
amine salts of keto acids 3a and 6a were determined (see
Figure 1). A number of important geometric parameters were
Scheme 1. Ketone reactants and their cyclization/cleavage
photoproducts.
À
À
C2 C3 bond leads to (R)-5c/8c and cleavage of the C2 C3’
bond leads to (S)-5c/8c. Thus, by determining the absolute
configuration of the cleavage product in each case and
correlating this information with the absolute conformation
of the carboxylate anion obtained by X-ray crystallography,
we were able to establish which bond was cleaved and its
degree of overlap with the p orbital on C1.
Although a number of different salts were prepared and
their solid-state photochemistry investigated, we limit the
present discussion to the two salts whose X-ray crystal
structures were successfully determined, namely, the (S)-
(À)-1-phenylethylamine salts of keto acids 3a and 6a.[12]
Polycrystalline samples of these salts (2–5 mg) were crushed
between pyrex microscope slides and the resulting sandwiches
taped together, sealed under nitrogen in polyethylene bags,
and irradiated (450-W medium-pressure mercury lamp) on
both sides at various temperatures for different lengths of
time. Even at high conversions, no melting could be detected.
After photolysis, the crystals were treated with diazomethane
in ether to remove the ionic chiral auxiliaries and form the
corresponding methyl esters. The reaction mixtures were then
subjected to GC analysis to determine the cyclization-to-
cleavage ratios, and to chiral HPLC analysis to measure the
enantiomeric excess (ee) in which photoproducts 5c and 8c
were formed. The results are summarized in Table 1.[13]
Figure 1. X-ray crystal structures of (S)-(À)-1-phenylethylamine salts of
keto acids a) 3a and b) 6a.
calculated from the crystal structures, including the g-hydro-
gen-atom abstraction geometries as well as the geometric
relationships relevant to the cyclization and cleavage of the 1-
hydroxy-1,4-biradical intermediates (see Table 2).
To begin our discussion of the geometric parameters, we
note that the value of dO–H4, the distance between the carbonyl
oxygen atom and the g-hydrogen atom on C4, is similar for
both salts and well within the guidelines established by us for
Table 1: Solid-state photochemistry of (S)-(À)-1-phenylethylamine salts
of keto acids 3a and 6a.
Acid
T [8C]
Conversion [%][a]
CY/CL[b]
ee [%][c]
a[d]
3a
3a
3a
6a
6a
6a
À20
20
20
45
38
72
85
21
53
88:10
87:11
87:11
21:75
20:79
21:77
90
87
70
98
>98
98
(À)
(À)
(À)
(À)
(À)
(À)
Table 2: Geometric data derived from the X-ray crystal structures of the
(S)-(À)-1-phenylethylamine salts of keto acids 3a and 6a.
Acid
d
O–H4 [Š][a]
dC1–C4 [Š][b]
b [8][c]
f1 [8][d]
f4 [8][e]
À20
20
3a
6a
2.67
2.62
2.81
2.82
22
32
22 (67)
16 (78)
43 (43)
35 (35)
20
=
À
[a] Determined by GC. [b] Ratio of cyclization (CY) to cleavage (CL). [c]
Determined by chiral HPLC. [d] Sign of rotation of major enantiomer at
sodium D line.
[a] C O···H4 distance. [b] C1 C4 distance. [c] Angle between p orbital on
À
À
C1 and the C2 C4 vector. [d] Angle between p orbital on C1 and C2 C3
À
À
À
(C2 C3’). [e] Angle between p orbital on C4 and C2 C3 (C2 C3’).
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data can be obtained free of charge from the Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
successful Norrish type II hydrogen abstraction in the crys-
talline state (d = 2.7 Æ 0.2 Š).[15] Similarly, the value of dC1–C4
,
the distance between atoms C1 and C4 in the biradical
produced by hydrogen abstraction, is the same for both salts.
As a result, distance factors can be excluded as the source of
the cyclization-to-cleavage ratio differences. The parameter b,
Received: March 17, 2005
Published online: July 20, 2005
Keywords: asymmetric synthesis · photochemistry · radicals ·
À
defined as the angle between the p orbital on C1 and the C2
.
solid-state reactions · structure–activity relationships
C4 vector, is ideal for cyclization when b = 08, that is, when the
p orbitals are pointing directly at one another. The values of b
in Table 2 indicate that the 3a-derived biradical is better
arranged for cyclization than the 6a-derived species.
[1] D. Andrew, A. C. Weedon, J. Am. Chem. Soc. 1995, 117, 5647,
and references therein.
The parameters f1 and f4 represent the angles formed
[2] a) A. G. Griesbeck, H. Mauder, S. Stadtmüller, Acc. Chem. Res.
1994, 27, 70; b) A. G. Griesbeck, S. Buhr, M. Fiege, H.
Schmickler, J. Lex, J. Org. Chem. 1998, 63, 3847.
À
between the p orbitals on atoms C1 and C4 and the C2 C3
À
À
and C2 C3’ bonds (the values of f1 and f4 for the C2 C3’
bond are shown in parentheses). The best arrangement for
cleavage is expected when f1 and f4 = 08, and the data
[3] a) P. J. Wagner, P. Klµn in CRC Handbook of Organic Photo-
chemistry and Photobiology, 2nd ed. (Eds.: W. Horspool, F.
Lenci), CRC, Boca Raton, 2004, chap. 52; b) P. J. Wagner in CRC
Handbook of Organic Photochemistry and Photobiology, 2nd ed.
(Eds.: W. Horspool, F. Lenci), CRC, Boca Raton, 2004, chap. 58.
[4] a) W. Adam, C. Sabin in CRC Handbook of Organic Photo-
chemistry and Photobiology (Eds.: W. M. Horspool, P.-S. Song),
CRC, Boca Raton, 1995, p. 937; b) W. Adam, A.V. Trofimov in
CRC Handbook of Organic Photochemistry and Photobiology,
2nd ed. (Eds.: W. Horspool, F. Lenci), CRC, Boca Raton, 2004,
chap. 93.
[5] In the case of 1-hydroxy-1,4-biradicals generated in the photo-
chemical Norrish–Yang type II reaction, a third possibility is
reverse hydrogen transfer to regenerate the ground-state ketone,
a quantum yield-lowering process.
[6] a) P. J. Wagner, A. E. Kemppainen, J. Am. Chem. Soc. 1968, 90,
5896; b) R. Hoffmann, S. Swaminathan, B. G. Odell, R. Gleiter,
J. Am. Chem. Soc. 1970, 92, 7091.
[7] a) J. C. Scaiano, Tetrahedron 1982, 38, 819; b) A. G. Griesbeck,
H. Heckroth, J. Am. Chem. Soc. 2002, 124, 396; c) A. G.
Griesbeck, Synlett 2003, 451.
[8] D. Braga, S. Chen, H. Filson, L. Maini, M. R. Netherton, B. O.
Patrick, J. R. Scheffer, C. Scott, W. Xia, J. Am. Chem. Soc. 2004,
126, 3511.
[9] A. Padwa, W. Eisenberg, J. Am. Chem. Soc. 1972, 94, 5852.
[10] E. C. Alexander, J. Uliana, J. Am. Chem. Soc. 1976, 98, 4324.
[11] B. O. Patrick, J. R. Scheffer, C. Scott, Angew. Chem. 2003, 115,
3905; Angew. Chem. Int. Ed. 2003, 42, 3775.
À
indicate that cleavage of the C2 C3 bond is favored over
À
cleavage of the C2 C3’ bond for both salts. This finding
predicts that cleavage photoproducts 5c and 8c should have
the R absolute configuration, a prediction that agrees with the
configurational assignment made by independent synthesis of
optically pure (S)-(+)-8c. It is interesting to speculate that the
ee for 5c is lower (70–90%) than that for 8c (98%), because
the difference in f1 for the former is less (67À22 = 458) than
that for the latter (78À16 = 628). Of course, supramolecular
factors[16] could contribute to the difference in ee, but the fact
that the (S)-1-phenylethylammonium ion is common to both
salts supports the notion that the major determinant of solid-
state biradical behavior in these systems is the structure and
conformation of the carboxylate anion.
The values of f1 and f4 also show that the biradical
derived from 6a has a better geometry for cleavage (f1 = 168,
f4 = 358) than that from 3a (f1 = 228, f4 = 438). Taken
together with the earlier conclusion that the biradical from
3a has a better geometry for cyclization than that from 6a, the
data clearly predict that salts derived from keto acid 3a
should have a higher Norrish–Yang cyclization-to-cleavage
ratio than those derived from keto acid 6a. This prediction is
in accordance with the counterintuitive result that Yang
photocyclization predominates in the bicyclo[1.1.1]pentane
system 3a, even though the cyclobutanol product in this case
is more strained than that formed from the bicyclo-
[2.1.1]hexane reactant 6a.
The work reported herein complements our previous
research in this area[8] and highlights, in a quantitative fashion,
the fact that relatively small differences in geometry can have
a profound effect on 1-hydroxy-1,4-biradical behavior. Fur-
thermore, it demonstrates once again the efficacy of the solid-
state ionic chiral auxiliary approach to asymmetric synthesis
in organic photochemistry.[17]
[12] See the Supporting Information for
a description of the
preparation and solid-state photochemistry of the salts whose
structures were not determined by X-ray crystallography.
[13] The photoreactions were significantly less selective in solution.
The cyclization-to-cleavage ratio resulting from irradiation of
keto ester 3c in acetonitrile was 77:23 and that from 6c was
30:66; in both cases, the cleavage products were racemic.
[14] K. Mislow, I. V. Steinberg, J. Am. Chem. Soc. 1955, 77, 3807.
[15] J. R. Scheffer in Molecular and Supramolecular Photochemistry:
Chiral Photochemistry, Vol. 11 (Eds.: V. Ramamurthy, Y. Inoue),
Marcel Dekker, New York, 2004, p. 463.
[16] By supramolecular factors, we refer to the interaction of the
reactant with the surrounding crystal lattice during reaction. For
a qualitative treatment of this aspect of solid-state photochem-
istry, see: R. G. Weiss, V. Ramamurthy, G. S. Hammond, Acc.
Chem. Res. 1993, 26, 530; for a quantitative treatment, see: H. E.
Zimmerman, E. E. Nesterov, Acc. Chem. Res. 2002, 35, 77.
[17] For reviews, see: a) J. R. Scheffer, Can. J. Chem. 2001, 79, 349;
b) “Organic Solid State Reactions”: J. R. Scheffer, W. Xia, Top.
Curr. Chem. 2005, 254, 233.
Experimental Section
Full experimental details on the synthesis of the starting materials,
photolysis of the salts in the crystalline state, the diazomethane
workup procedure, and the characterization of the photoproducts are
available in the Supporting Information. CCDC 265554 and 265555
contain the supplementary crystallographic data for this paper. These
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