Pentafluorophenylhalocarbenes

Article abstract of DOI:10.1021/ol2019532

Pentafluorophenylchlorocarbene and pentafluorophenylfluorocarbene are highly reactive species and effective carriers of fluorine labels via addition to alkenes and insertion into C-H bonds.

Full text of DOI:10.1021/ol2019532

ORGANIC
LETTERS
2011
Vol. 13, No. 17
4752–4754
Pentafluorophenylhalocarbenes
Robert A. Moss,* Yongmaio Shen, Lei Wang, and Karsten Krogh-Jespersen*
Department of Chemistry and Chemical Biology, Rutgers,
The State University of New Jersey, New Brunswick, New Jersey 08903, United States
moss@rutchem.rutgers.edu; krogh@rutchem.rutgers.edu
Received July 20, 2011
ABSTRACT
Pentafluorophenylchlorocarbene and pentafluorophenylfluorocarbene are highly reactive species and effective carriers of fluorine labels via
addition to alkenes and insertion into CꢀH bonds.
Here, we describe reactions of pentafluorophenylchlor-
Fluorine substituents often modify the biological
properties of organic molecules.1,2 Fluorinated reactive
ocarbene (2, PFPCCl) and pentafluorophenylfluorocar-
bene (3, PFPCF) with alkenes and adamantane; products
are characterized, and several absolute rate constants are
also reported. Singlet ground state carbenes 2 and 3 (see
below) are very reactive and should permit the preparation
of many pentafluorophenyl-labeled derivatives.
Immediate precursors to carbenes 2 and 3 are the
corresponding diazirines, 4a and 4b. Diazirine 4a was
intermediates, such as carbenes1,3,4 or nitrenes,5 can
serve as carriers of fluorine into new molecular con-
structs. However, direct substitution of fluorine on a
carbenic carbon stabilizes the carbene and reduces its
reactivity;3,6 carbenes that bear fluorinated substituents
will be more reactive.
Among candidate substituents, the trifluoromethyl
prepared by Graham hypochlorite oxidation of pentafluor-
and pentafluorophenyl groups are readily accessible.
Trifluoromethyl-substituted carbenes have been extensi-
obenzamidine (5) and characterized spectroscopically.8 In
vely examined,1 but pentafluorophenylcarbenes have re-
ceived only limited attention. Parent pentafluorophenyl-
particular, the UV spectrum of 4a in pentane featured
maxima at 326, 333, and 342 nm.8
carbene (1) is a ground state triplet species which reacts
rapidly via its nearby singlet state with a variety of
substrates; kinetic data have been reported, but not
product characterization.7
Pentafluorophenylfluorodiazirine 4b was prepared
as illustrated in Scheme 1. Here, the key reactions
were Graham hypobromite oxidation9 of
5 to
(1) Grygorenko, O. O.; Artamonov, O. S.; Komarov, I. V.; Mykhailiuk,
P. K. Tetrahedron 2011, 67, 803.
(2) Banks, R. E., Smart, B. E., Tatlow, J. C., Eds. Organofluorine
Chemistry: Principles and Commercial Applications; Plenum Press:
New York, 1994 (especially Chapters 23ꢀ26).
(6) (a) Moss, R. A.; Mallon, C. B.; Ho, C.-T. J. Am. Chem. Soc. 1977,
99, 4105. (b) Rondan, N. G.; Houk, K. N.; Moss, R. A. J. Am. Chem.
Soc. 1980, 102, 1770. (c) Moss, R. A.; Wang, L.; Krogh-Jespersen, K.
J. Am. Chem. Soc. 2009, 131, 2128.
(7) Admasu, A.; Gudmundsdottir, A.; Platz, M. S. J. Phys. Chem. A
1997, 101, 3832.
(8) Wang, L.; Moss, R. A.; Krogh-Jespersen, K. J. Phys. Chem. A
2011, 115, 8113.
(9) Graham, W. H. J. Am. Chem. Soc. 1965, 87, 4396.
(3) Brahms, D. L. S.; Dailey, W. P. Chem. Rev. 1996, 96, 1585.
(4) (a) Moss, R. A.; Ge, C.-S. J. Fluorine Chem. 1995, 73, 101. (b) Ge,
C.-S.; Jefferson, E. A.; Moss, R. A. Tetrahedron Lett. 1993, 34, 7549.
(5) (a) Poe, R.; Schnapp, K.; Young, M. J. T.; Grayzar, J.; Platz,
M. S. J. Am. Chem. Soc. 1992, 114, 5054. (b) Zhai, H; Platz, M. S.
J. Phys. Org. Chem. 1997, 10, 22.
r
10.1021/ol2019532
Published on Web 08/09/2011
2011 American Chemical Society

give a singlet ground state for PFPCCl (2), with
ΔGS-T = 4.2 kcal/mol.8,13 Similar calculations show
that ΔGS-T = 14.9 kcal/mol in PFPCF (3).11 Singlet
states of carbenes are more sensitive to substituents
than triplet states, and the singlet state of PFPCF is
preferentially stabilized by the strong π-donating/
σ-withdrawing abilities of the fluoro substituent.
PFPCCl and PFPCF readily cyclopropanated a ser-
ies of olefins, including tetramethylethylene, 2-ethyl-1-
butene, trans-butene, and cis-butene; cf. Scheme 2.
Additionally, both carbenes inserted into the tertiary
CꢀH bond of adamantane.
Scheme 1. Preparation of Pentafluorophenylfluorodiazirine
pentafluorophenylbromodiazirine 4c and conversion
of the latter to the desired fluorodiazirine 4b by a
diazirine exchange reaction with tetrabutylammo-
nium fluoride.10,11 Fluorodiazirine 4b was character-
ized by IR, UV, and 13C and 19F NMR spectroscopy.11
In particular, the UV spectrum in pentane revealed
maxima at 323 and 338 nm. Note that diazirine 4c was
used only as a relay compound in the preparation of
fluorodiazirine 4b. No doubt photolysis of 4c would
provide pentafluorophenylbromocarbene and a par-
allel series of products (7-Brꢀ10-Br).
Laser flash photolysis (LFP) of diazirine 4a in pentane
generated PFPCCl (2) which displayed π(phenyl) f
p(carbene) absorptions at 300 and 372 nm and a σ(carbene)
f p(carbene) absorption at 596 nm.8 LFP of diazirine 4b
produced PFPCF (3) which afforded a similar UVꢀvis
spectrum; cf. Figure 1. Here, charge-transfer type transitions
from the nearly degenerate set of high-lying phenyl π orbitals
to the vacant carbenic p orbital are responsible for the
absorptions at 292 and 324 nm, whereas the weak absorption
at 564 nm is associated with electron promotion from the
carbene’s filled σ orbital (HOMO) to its vacant p orbital
(LUMO). The absorptions are computed11,12 at 271 nm
(f = 0.287), 342 nm (f = 0.051), and 621 nm (f = 0.0045).
Both PFPCCl and PFPCF give intense N-ylide spec-
tra with pyridine in pentane. The ylides, 6a and 6b, each
absorbed at 468 nm and formed very rapidly with
k = 8.1 ꢁ 109 Mꢀ1 sꢀ1 (6a) or 6.4 ꢁ 109 Mꢀ1 sꢀ1 (6b).11
Figure 1. Calibrated UVꢀvis spectrum of PFPCF (3) in pen-
tane 200 ns after laser pulse; π (phenyl) f p(carbene) absorp-
tions at 292 and 324 nm, σ(carbene) f p(carbene) absorption
at 564 nm.
Olefin-pentane solutions containing diazirine 4a or 4b
were irradiated for 18 h in Pyrex tubes with a 200 W
focused Osram XE mercury lamp at room temperature.
The cyclopropane products were isolated from the sol-
vent-stripped residues by column chromatography over
silica gel with pentane elution. The products are shown in
1
structures 7ꢀ10; their identities were established by H,
13C, and 19F NMR spectroscopy and by mass spec-
troscopy.11 Isolated yields appear in Table 1 and range
from 59 to 87%. GC demonstrated product purities in
excess of 95%.
In keeping with the singlet nature of PFPCCl and
PFPCF, capillary GC analysis of their reaction products
with cis- and trans-butene showed the products to have
been formed with >99% stereospecificity. With PFPCF
and cis-butene, where the syn-F and anti-F isomers of
product 10-F could be separated, NMR analysis indicated
that the syn-F isomer predominated by a factor of 2.2.14
This stereoselectivity resembles that observed with PhCF
and cis-butene, where syn-F/anti-F was about 1.6.15
Although PFPCH (1) possesses a triplet ground
state,7 computational studies at the CCSD(T) level
(10) (a) Moss, R. A. Acc. Chem. Res. 2006, 39, 267. (b) Cox, D. P.;
Moss, R. A.; Terpinski, J. J. Am. Chem. Soc. 1983, 105, 6513.
(11) See the Supporting Information for details.
(12) Results obtained at the TD-B3LYP/6-311þG(d)//B97D/
6-311þG(d) level applying the polarizable conductor self-consistent
reaction field model (CPCM) and n-pentane as the solvent.
(13) CCSD(T) denotes a calculation based on the Coupled Cluster
method that includes single and double excitations fully and triple
(14) In the 19F NMR spectrum, the syn-F isomer has the more
shielded F atom and the smaller vic-HꢀF coupling.11,15
excitations via perturbation theory. With this methodology, ΔGS-T
=
ꢀ5.6 kcal/mol for PFPCH, with the triplet state being more stable than
(15) (a) Moss, R. A.; Lawrynowicz, W. J. Org. Chem. 1984, 49, 3828.
(b) Moss, R. A.; Przybyla, J. Tetrahedron 1969, 25, 647.
the singlet state.8
Org. Lett., Vol. 13, No. 17, 2011
4753

(TME) and 2-ethyl-1-butene and compared these data
to the analogous rate constants for additions of PhCCl
and PhCF.16 In these LFP experiments, we monitored
the pseudo-first-order rate constant for carbene decay
as a function of alkene concentration in pentane.11 The
derived second-order addition rate constants are col-
lected in Table 2.
Scheme 2. Preparation of Cyclopropanes
Table 2. Absolute Rate Constants for Carbene-Alkene
Additionsa
alkene
PFPCClb
PhCCl
PFPCFb
PhCF
TMEc
2-E-1-Be
1.3 ꢁ 109
2.8 ꢁ 108 d
1.8 ꢁ 109
1.6 ꢁ 108 d
1.1 ꢁ 108
6.3 ꢁ 106 b
1.7 ꢁ 108
7.8 ꢁ 105 b
a In pentane solution at 25 °C; rate constants in Mꢀ1 sꢀ1
.
b This work.
c Tetramethylethylene. d From ref 16. e 2-Ethyl-1-butene.
Both PFPCCl and PFPCF are highly reactive in
addition reactions; with TME, kadd > 109 Mꢀ1 sꢀ1
while, with the less nucleophilic 2-ethyl-1-butene, kadd
,
is ∼10 times smaller, but still exceeds 108 Mꢀ1 sꢀ1 17
.
Table 1. Isolated Yields of Cyclopropane Products
Given that PhCCl is more reactive toward alkenes than
PhCF,16 it is somewhat surprising that PFPCF appears
to be slightly more reactive than PFPCCl toward the
two alkenes of Table 2.
cyclopropane
X = Cl (%)
X = F (%)
7
83
73
78
87a
59
80
81
77b
8
The activating effect of the pentafluorophenyl group is
evident from comparisons of kadd for PFPCCl with PhCCl
and of PFPCF with PhCF (Table 2). The PFP carbenes are
∼1ꢀ2 orders of magnitude more reactive than their non-
fluorinated phenyl analogues. The PFP group is more
electron-withdrawing than the phenyl group,8 which de-
stabilizes PFPCX relative to PhCX and enhances the
reactivity of PFPCX.
In conclusion, PFPCCl and PFPCF are highly reactive
singlet carbenes and effective carriers of fluorine labels via
addition to alkenes or insertion into CꢀH bonds.
9
10
a The syn and anti isomers of 10-Cl could not be separated. b 53%
yield of syn-F isomer; 24% yield of anti-F isomer.
Photolysis of diazirines 4a or 4b with excess adamantane
in benzene solution afforded CꢀH insertion products
11-Cl or 11-F in isolated yields of 30% and 45%, respec-
tively. Structures were established by NMR and mass
spectroscopy.11
Acknowledgment. We are grateful to the National
Science Foundation for financial support.
Supporting Information Available. Spectra of diazir-
ines, ylides, and products 7ꢀ10 (X = Cl, F); details
of kinetics and computations. This material is avail-
able free of charge via the Internet at http://pubs.acs.
org.
We measured the absolute rate constants for addi-
tions of PFPCCl and PFPCF to tetramethylethylene
(17) A competition experiment between the insertion of PFPCF into
adamantane and itsꢀa1ddition to 2-ethyl-1-butene led to an estimated
kins = 2.1 ꢁ 105
M
s
ꢀ1, statistically corrected for the presence of 4
(16) Moss, R. A.; Lawrynowicz, W.; Turro, N. J.; Gould, I. R.; Cha,
Y. J. Am. Chem. Soc. 1986, 108, 7028.
equivalent tertiary CꢀH bonds in adamantane.
4754
Org. Lett., Vol. 13, No. 17, 2011