A singlet aryl-CF3 carbene: 2-benzothienyl(trifluoromethyl) carbene and interconversion with a strained cyclic allene

Article abstract of DOI:10.1021/ol071290s

Matrix-isolated 2-benzothienyl(trifluoromethyl)carbene was generated by irradiation of the corresponding diazirine, and characterized by IR and UV/vis spectroscopy, in situ trapping, and DFT modeling. Experiments and calculations indicate that the carbene

Full text of DOI:10.1021/ol071290s

ORGANIC
LETTERS
2007
Vol. 9, No. 16
3177-3180
A Singlet Aryl-CF3 Carbene:
2-Benzothienyl(trifluoromethyl)carbene
and Interconversion with a Strained
Cyclic Allene
Jian Wang and Robert S. Sheridan*
Department of Chemistry, Mail Stop 216, UniVersity of NeVada, Reno, NeVada 89557
rss@unr.edu
Received May 31, 2007
ABSTRACT
Matrix-isolated 2-benzothienyl(trifluoromethyl)carbene was generated by irradiation of the corresponding diazirine, and characterized by IR
and UV/vis spectroscopy, in situ trapping, and DFT modeling. Experiments and calculations indicate that the carbene is a ground-state singlet,
in contrast to previously characterized aryl(trifluoromethyl)carbenes. The carbene could be interconverted photochemically with a ring-opened
thioquinomethide and a highly strained cyclic allene.
Aryl(trifluoromethyl)carbenes are among the most widely
utilized reactive intermediates in photoaffinity labeling of
biological systems.1,2 Their precursors, trifluoromethyldi-
azirines, are relatively straightforward to prepare, are chemi-
cally stable under physiological conditions, can be attached
to a variety of biologically relevant moieties, and undergo
efficient photocleavage at convenient wavelengths. Despite
the broad application of aryl-CF3 carbenes, only a handful
of studies have probed their chemistry, reactivity, and
electronic structures.3
A question of mechanistic and practical relevance is the
ground state multiplicity of these species. The ability to insert
into, for example, R-H bonds concertedly may make singlet
carbenes more effective in photoaffinity labeling than triplets
in their ability to selectively attach to nearby biomolecules.
Moreover, competing facile reaction with O2 may lead to
less efficient labeling by triplet carbenes. EPR, IR, and UV/
vis spectroscopy indicates that phenyl-4 and p-tolyl-
(trifluoromethyl)carbenes3a are ground state triplets; similar
information on other aryl-CF3 carbenes, however, is sparce.
We now report evidence for the first example of a singlet
ground state aryl-CF3 carbene, 2-benzothienyl(trifluoro-
methyl)carbene (2).
The 2-benzothienyl diazirine 1 was synthesized from the
corresponding trifluoromethylketone5 following standard
procedures. Irradiation of 1 in a N2 matrix at 10 K with 404
nm light converted it cleanly to carbene 2 (Scheme 1).6 The
carbene exhibited a most intense IR band at 1160 cm-1,
(3) (a) Admasu, A.; Gudmundsdottir, A. D.; Platz, M. S.; Watt, D. S.;
Kwiatkowski, S.; Crocker, P. J. J. Chem. Soc., Perkin Trans. 2 1998, 1093.
(b) Zuev, P. S.; Sheridan, R. S. J. Am. Chem. Soc. 2001, 123, 12434. (c)
Sander, W. J. Org. Chem. 1988, 53, 121. (d) Brams, D. L. S.; Dailey, W.
P. Chem. ReV. 1996, 96, 1585. (e) Brunner, J.; Senn, H.; Richards, F. J.
Biol. Chem. 1980, 255, 3313. (f) Turro, N. J.; Butcher, J. A., Jr.; Hefferon,
G. J. Photochem. Photobiol. 1981, 34, 517. (g) Nassal, M. Liebigs Ann.
Chem. 1983, 1510. (g) Nassal, M. J. Am. Chem. Soc. 1984, 106, 7540.
(4) Wasserman, E.; Barash, L.; Yager, W. A. J. Am. Chem. Soc. 1965,
87, 4974.
(1) (a) Nakashima, H.; Hashimoto, M.; Sadakane, Y.; Tomohiro, T.;
Hatanaka, Y. J. Am. Chem. Soc. 2006, 128, 15092 and references cited
therein. (b) Weber, T.; Brunner, J. J. Am. Chem. Soc. 1995, 117, 3084. (c)
Blencowe, A.; Hayes, W. Soft Matter 2005, 1, 178.
(5) (a) Kerdesky, F. A. J.; Basha, A. Tetrahedron Lett. 1991, 32, 2003.
(b) DiMenna, W. S. Tetrahedron Lett. 1980, 21, 2129.
(2) For general references on photoaffinity labeling, see, for example:
(a) Hatanaka, Y.; Sadakane, Y. Curr. Top. Med. Chem. 2002, 2, 271. (b)
Fleming, S. A. Tetrahedron 1995, 51, 12479. (c) Bayley, H. Photogenerated
Reagents in Biochemistry and Molecular Biology; Elsevier: Amsterdam,
The Netherlands, 1983.
(6) For a general description of the matrix isolation instrumentation,
see: Sheridan, R. S.; Zuev, P. S. J. Am. Chem. Soc. 2004, 126, 12220 and
references cited therein. Irradiation wavelengths were selected by a high-
pressure Hg lamp/monochromator assembly, and are (5 nm. See the
Supporting Information for further matrix deposition and irradiation details.
10.1021/ol071290s CCC: $37.00
© 2007 American Chemical Society
Published on Web 07/14/2007

Scheme 1
together with strong absorptions at 490 and 350 nm in the
UV/vis spectrum (Figures 1 and 2).
Multiple pieces of evidence indicate that carbene 2,
observed under these conditions, possesses a singlet rather
than a triplet ground state. The IR spectrum of 2 (Figure 1)
fits best that predicted by B3LYP/6-31+G** calculations
for singlet carbene 2a, with the CF3 group oriented syn to
sulfur; IR spectra calculated for triplet 2, either syn or anti,
as well as those for singlet anti-2b, were somewhat less
satisfactory.7,8 Similarly, TD B3LYP calculations predict
prominent electronic transitions for syn-2a at 461 (f ) 0.032)
and 321 (f ) 0.37) nm, which parallel the experimentally
observed absorptions (Figure 2). A very weak nπ* transition
predicted at 1004 nm (f ) 0.0009) was not detected. On the
other hand, syn-triplet 2 is predicted to absorb at 626 (f )
0.0003), 530 (f ) 0.013), 438 (f ) 0.0008), 401 (f ) 0.018),
and 334 (f ) 0.010) nm (with very similar transitions for
anti-triplet).
Figure 1. (a) Calculated IR spectrum for singlet syn-carbene 2a.
(b) IR difference spectra showing conversion of carbene 2 (“down
bands”) to allene 4 (“up bands”) on 16 h irradiation at 436 nm in
N2 at 10 K. (c) Calculated IR spectrum for allene 4. (d) IR difference
spectra showing conversion of allene 4 (“down bands”) to thio-
quinomethide 3 (“up bands”) on 2 h irradiation at 366 nm. (e)
Calculated IR spectrum for thioquinomethide 3. All spectra are
displayed with arbitrary absorbance units. Theoretical spectra are
from B3LYP/6-31+G** calculations, and frequencies are unscaled.
The reactivity of 2 also is most consistent with singlet
rather than triplet multiplicity. Numerous studies have shown
that triplet carbenes react readily with O2 at cryogenic
temperatures to give carbonyl oxides.9 Singlet carbenes are
(7) All structures were fully optimized by analytical gradient methods
using Gaussian 03, Revision C.02: 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.; 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. Gaussian
03, Revision C.02; Gaussian, Inc.: Wallingford, CT, 2004. Energies were
corrected for zero-point energy differences (ZPVE) (unscaled).
unreactive under the same conditions. Warming 2 in N2
matrices doped with relatively high concentrations of O2 (up
to 5%), under conditions where triplet carbenes react rapidly,9
showed no evidence for reaction.10 On the other hand,
annealing a 2% HCl-doped N2 matrix containing 2 to 30 K
caused disappearance of the carbene IR bands and growth
of bands due to the trapped product 5 (by comparison to
calculated IR spectra).8
(10) Although matrices are rigid at 10 K, enabling characterization of
highly reactive molecules in the presence of small amounts of trapping
agents (<5%), warming to approximately 30 K permits diffusion of small
dopants. For general details of low-temperature trapping experiments, see,
for example: Bally, T. In ReactiVe Intermediate Chemistry; Moss, R. A.,
Platz, M. S., Jones, M. J., Jr., Eds.; John Wiley & Sons: Hoboken, NJ,
2004; p 797.
(8) Details of the syntheses, calculations, and several additional theroetical
and experimental spectra are given in the Supporting Information.
(9) (a) Sander, W. Angew. Chem., Int. Ed. Engl. 1990, 29, 344. (b)
Sander, W.; Bucher, G.; Wierlacher, S. Chem. ReV. 1993, 93, 1583.
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Org. Lett., Vol. 9, No. 16, 2007

Scheme 2. Relative B3LYP/6-31+G** Energies (kcal/mol)a
Figure 2. UV/vis spectrum of carbene 2 generated by irradiation
of allene 4 matrix isolated in N2 at 10 K for 2 h at 404 nm. Results
of wavelengths and relative intensities predicted by TD B3LYP/
6-31+G** calculations are shown for singlet 2a (filled bars) and
triplet 2a (open bars).8 The absolute absorbance scale ranges from
0.7 to 3.7 units. See the Supporting Information for the UV/vis
spectrum of starting diazirine 1
As shown in Scheme 2, B3LYP calculations predict that
singlet syn-2a is lower in energy than singlet anti-2b, and
lower than both conformers of the triplet carbene. Since this
level of theory has been suggested to overemphasize the
stability of triplet carbenes compared to the corresponding
singlets by approximately 2 to 3 kcal/mol,11,12 the singlet-
triplet energy gap for syn-2a is likely greater than the
predicted 2.4 kcal/mol. It is tempting to attribute the
stabilization of singlet 2 to π-donation from the electron-
rich thiophene unit as exemplified by resonance structure
2c.13 It should also be noted, however, that calculations
indicate that the CF3 group actually favors singlet carbenes
relative to triplets, compared to H.14
As we have observed for other five-membered hetereoaryl
carbenes,15 2 was quite photolabile and readily interconverted
with several other intermediates. For example, irradiation of
2 at 436 nm produced a new product, which we attribute to
the strained allene 4 by analogy to our previous studies on
related systems (Figure 1). The IR spectrum observed for
allene 4 fits that predicted by B3LYP calculations. Moreover,
matrices containing 4 displayed absorptions at 360 and 410
nm, close to those predicted by TD calculations (353 nm, f
) 0.04; and 419 nm, f ) 0.03).8
a Chloro derivatives are given in parentheses.15d
Alternatively, irradiation of a matrix containing 2 (or,
likewise, 4) at 366 nm converted the carbene mainly into
the ring-opened thioquinomethide 3, identified by comparison
of the IR spectra to those predicted by B3LYP calculations
(Figure 1). At the same time, the UV/vis absorptions
attributed to 2 were replaced by strong bands at 510 and
350 nm. TD calculations predict absorptions for 3 at 548 (f
) 0.074) and 332 (f ) 0.13) nm, in satisfactory agreement
with this assignment.8
All three intermediates, 2, 3, and 4, could be interconverted
photochemically; any of the isomers could be favored
selectively depending on careful control of irradiation
wavelength. Thus, irradiation of matrices containing either
the thioquinomethide 3 or allene 4 at 404 nm, where carbene
2 absorbs less intensely, cleanly converted them back to
carbene. On the other hand, irradiation of the matrices at
366 nm, where 2 and 4 absorb more strongly than thioqui-
nomethide 3, gave matrices where 3 predominated. Finally,
436 nm pumps the strong absorptions of 2 and 3, producing
mainly allene 4 in the photoequilibria. As we have discussed
previously,15 the ring-opened species 3 offers a logical
mechanistic intermediate connecting carbene 2 and allene
4.
(11) Geise, C. M.; Hadad, C. M. J. Org. Chem. 2000, 65, 8348.
(12) Woodcock, H. L.; Moran, D.; Brooks, B. R.; Schleyer, P.v.R.;
Schaefer, H. F. J. Am. Chem. Soc. 2007, 129, 3763.
(13) For comparison, preliminary calculations at the same theoretical level
predict the triplet cyclopentadienyl carbene corresponding to 2a, where S
is replaced by CH2, to lie 3.8 kcal/mol below the singlet. However, the
singlet benzofuryl carbene (S replaced by O) corresponding to 2a lies 3.9
kcal/mol below the triplet. Jian Wang, unpublished results.
(14) O’Gara, J. E.; Dailey, W. P. J. Am. Chem. Soc. 1994, 116, 12016.
(15) (a) Khasanova, T.; Sheridan, R. S. J. Am. Chem. Soc. 1998, 120,
234. (b) Khasanova, T.; Sheridan, R. S. J. Am. Chem. Soc. 2000, 122, 8585.
(c) Nikitina, A.; Sheridan, R. S. J. Am. Chem. Soc. 2002, 124, 7670. (d)
Nikitina, A.; Sheridan, R. S. Org. Lett. 2005, 7, 4467.
Scheme 2 shows relative energies of the various interme-
diates in this system resulting from B3LYP calculations.7,8
It is interesting to compare these results to the chloro-
Org. Lett., Vol. 9, No. 16, 2007
3179

substituted carbene system that we have reported previously.15d
As shown, the corresponding singlet chlorocarbenes are
considerably lower in energy (in parentheses) relative to the
other isomeric intermediates, consistent with the well-
recognized stabilizing effect of halogen substitution.16 On
the other hand, the calculations suggest only small differences
between the CF3-allene 4 and the corresponding chloro-
compound 7. Isodesmic calculations shown in Scheme 3
Not surprisingly, the theoretically predicted geometries of
4 and the chloroallene15d are also quite similar. Hence, H
and CF3 are twisted 145.6° and 150.4°, respectively, out of
the plane defined by the three allenic carbons in 4. Corre-
sponding values for 7 are 156.6° and 146.4° for H and Cl.
Similarly, the CdCdC angles for 4 and 7 are 134.9° and
131.8°, respectively. The visible electronic absorbances for
4 and 7,15d due to transition from the HOMO, which has
significant lone-pair character on the central allenic carbon,
to a π* LUMO, are very similar at 425 and 410 nm,
respectively. Finally, the energy to planarize the trifluoro-
methyl allene 4, giving the zwitterionic transition state 6, is
similar to that for the chloroallene 7.
Scheme 3. Isodesmic Reactions to Compare the B3LYP/
6-31+G** Energies of Cl and CF3 Allenes
In conclusion, we have found that 2 is a ground-state
singlet, in contrast to previously spectroscopically character-
ized aryl(trifluoromethyl)carbenes. We tentatively attribute
this inversion of favored spin states to π-electron donation
of the thiophene moiety in the singlet. Carbene 2, ring-opened
thioquinomethide 3, and strained cyclic allene 4 have distinct
UV/vis absorptions that enable selective generation by careful
wavelength control. These results suggest the possibility of
new approaches to structural/electronic control of photo-
affinity labeling reagents.1,2
Acknowledgment. We thank the National Science Foun-
dation (CHE-0456280) for financial support.
Supporting Information Available: Synthetic, spectro-
scopic, and calculational details. This material is available
free of charge via the Internet at http://pubs.acs.org.
suggest that the inherent instabilities of the strained allenic
moieties in 4 and the chloro analogue 7 are comparable.
(16) Moss, R. A.; Fantina, M. E. J. Am. Chem. Soc. 1978, 100, 6788.
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