Innermolecular reactions of fluorophenylcarbene inside a hemicarcerand

Article abstract of DOI:10.1021/ol901474u

Photolysis of fluorophenyldiazirine, incarcerated in hemicarcerand 2, affords fluorophenylcarbene, which attacks an aryl unit of the host, leading (after rearrangement) to a fluoromethoxy/phenyltropone derivative of the hemicarcerand. The incarcerated car

Full text of DOI:10.1021/ol901474u

ORGANIC
LETTERS
2009
Vol. 11, No. 17
3866-3869
Innermolecular Reactions of
Fluorophenylcarbene inside a
Hemicarcerand
Zhifeng Lu, Robert A. Moss,* Ronald R. Sauers, and Ralf Warmuth*
Department of Chemistry and Chemical Biology, Rutgers, The State UniVersity of New
Jersey, New Brunswick, New Jersey, 08903
moss@rutchem.rutgers.edu; warmuth@rutchem.rutgers.edu
Received June 29, 2009
ABSTRACT
Photolysis of fluorophenyldiazirine, incarcerated in hemicarcerand 2, affords fluorophenylcarbene, which attacks an aryl unit of the host,
leading (after rearrangement) to a fluoromethoxy/phenyltropone derivative of the hemicarcerand. The incarcerated carbene is probably unstable
at temperatures above 100 K.
Molecular incarceration can alter the chemistry and lifetimes
of reactive intermediates in solution at ambient temperature.1
Cyclobutadiene,2 o-benzyne,3 and cycloheptatetraene4 are
among the evanescent species rendered persistent by entrap-
ment within molecular containers. In the case of carbenes,
cyclodextrins, zeolites, and hemicarcerands have been studied
as agents of reactivity control. Brinker and Rosenberg, in
particular, have focused on cyclodextrins,5 observing chemo-
specific innermolecular reactions of, e.g., adamantanylidene6
and chlorophenylcarbene7 with their R-cyclodextrin hosts.
Cozens and Moya-Barrios found that the lifetimes and
reactivity of arylchlorocarbenes generated within the cavities
of alkalai metal cation-exchanged zeolites depended on the
identity of the zeolite’s charge-balancing cations.8
In 2005, we reported that the otherwise fleeting fluorophe-
noxycarbene (1)9 was persistent and stable for days at
ambient temperature when generated inside hemicarcerand
2, thus permitting detailed NMR studies.10 Incarceration not
only prevented the dimerization of 1 but altered its confor-
mation and reactivity toward water as a consequence of a
substantially lowered basicity inside the rigid hydrophobic
container molecule 2.10
(1) For a brief review, see: Kirmse, W. Angew. Chem., Int. Ed 2005,
44, 2476.
(2) Cram, D. J.; Tanner, M. E.; Thomas, R. Angew. Chem., Int. Ed.
1991, 30, 1024.
(3) Warmuth, R. Angew. Chem., Int. Ed. 1997, 36, 1347.
(4) (a) Warmuth, R.; Marvel, M. A. Angew. Chem., Int. Ed. 2000, 39,
1117. (b) Warmuth, R.; Marvel, M. A. Chem.sEur. J. 2001, 7, 1209. (c)
Warmuth, R. J. Am. Chem. Soc. 2001, 123, 6955. (d) Kerdelhue, J.-L.;
Langenwalter, K. J.; Warmuth, R. J. Am. Chem. Soc. 2003, 125, 973. (e)
Warmuth, R.; Yoon, J. Acc. Chem. Res. 2001, 34, 95.
(5) (a) Rosenberg, M. G.; Brinker, U. H. Eur. J. Org. Chem. 2006, 5423.
(b) Rosenberg, M. G.; Brinker, U. H. AdV. Phys. Org. Chem. 2005, 40, 1.
(c) Brinker, U. H.; Rosenberg, M. G. AdV. Carbene Chem. 1998, 2, 29.
(6) Krois, D.; Bobek, M. M.; Werner, A.; Kahlig, H.; Brinker, U. H.
Org. Lett. 2000, 2, 315.
(7) Rosenberg, M. G.; Brinker, U. H. J. Org. Chem. 2003, 68, 4819.
10.1021/ol901474u CCC: $40.75
Published on Web 08/05/2009
 2009 American Chemical Society

Scheme 1. Conversion of Hemicarceplex 2.3 to Product 6 (R ) n-C5H11)
Kirmse notes that “Taking carbene incarceration to its
limits will be a fascinating endeavor.”1 Here we explore the
effect of changing the carbene’s substituents on the efficacy
of carbene incarceration. Relative to methylene (CH2),
PhOCF (1) is stabilized by 59.7 kcal/mol by its PhO and F
substituents.11 “Excision” of the oxygen atom converts 1 to
fluorophenylcarbene (3), where the stabilization relative to
CH2 is reduced by 14 to 45.7 kcal/mol.11 Will the less stable
3 also be persistent when generated within hemicarcerand
2, or will it undergo innermolecular reactions with its
molecular “prison”?
2-methyltetrahydrofuran, or diethyl ether, the color was stable
to extended irradiation at 77 K. Similarly, photolysis of the
colorless hemicarciplex 2.5 in CH2Cl2 at 77 K gave a deep
blue-colored material, presumably 2.3. The color was stable
to further irradiation but bleached upon warming to ∼100
K. We interpret these results to suggest the formation of
transient complexes between PhCF and oxygen-containing
solvents or hemicarcerand 2, which deactivate the carbene’s
excited state and render it photostable at temperatures below
100 K. The insolubility of 2.5 in common low temperature
organic glasses prevented detailed spectroscopy of 2.3.
1H, 13C, and 19F NMR studies at -80 °C or above gave
no evidence for the incarcerated carbene 2.3. Instead, the
spectra support compound 6 as the product of the reaction
of PhCF with hemicarcerand 2.13 The reaction conducted at
77 K, followed by warming to ambient temperature, gave 6
in 55% isolated yield; the NMR yield was similar.
Treatment of diol 44a and excess 3-fluoro-3-phenyldiazirine
(5)12 with MsO(CH2)4OMS (Ms ) SO2Me) and Cs2CO3 in
HMPA gave the hemicarceplex 2.5 in 28% purified yield.13
Photolysis of diazirine 5 in CH2Cl2 or 3-methylpentane at
77 K with light of λ > 320 nm gave the deep blue PhCF,
λmax ) 547 nm,14 but the color disappeared upon continued
irradiation. However, in ethereal solvents such as anisole,
A mechanistic rationale for the formation of hemicarcerand
derivative 6 is presented in Scheme 1. The incarcerated PhCF
of 2.3 adds to one of the tris-alkoxy activated aryl units of
2, yielding the norcaradiene derivative 7, which opens to
the cycloheptatriene unit of hemicarcerand 8.15 Next, ioniza-
(8) (a) Moya-Barrios, R.; Cozens, F. L. J. Am. Chem. Soc. 2006, 128,
14836. (b) Moya-Barrios, R.; Cozens, F. L. Org. Lett. 2004, 6, 881.
(9) Moss, R. A.; Kmiecik-Lawrynowicz, G.; Krogh-Jespersen, K. J. Org.
Chem. 1986, 51, 2168.
(10) Liu, X.; Chu, G.; Moss, R. A.; Sauers, R. R.; Warmuth, R. Angew.
Chem., Int. Ed. 2005, 44, 1994.
(11) Rondan, N. G.; Houk, K. N.; Moss, R. A. J. Am. Chem. Soc. 1980,
102, 1770.
(15) Calculations at the B3LYP/6-31G(d) level indicate that the addition
of PhCF to 1,2,3-trimethoxybenzene (a model for hemicarcerand 2) at the
C(1)-C(2) “double bond” requires 14.7 kcal/mol of activation energy and
affords the corresponding norcaradiene with an exothermicity of 27.6 kcal/
mol. Further reactions of the norcaradiene afford a tropone with an additional
exothermicity of 16.1 kcal/mol. A reaction/enthalpy scheme appears in
Supporting Information.
(12) Moss, R. A.; Terpinski, J.; Cox, D. P.; Denney, D. Z.; Krogh-
Jespersen, K. J. Am. Chem. Soc. 1985, 107, 2743.
(13) See Supporting Information for experimental details and spectra.
(14) Similar observations of PhCF (λmax ) 550 nm at 13 K in a nitrogen
matrix) have been reported: Zuev, P. S.; Sheridan, R. S. J. Am. Chem. Soc.
1994, 116, 9381.
Org. Lett., Vol. 11, No. 17, 2009
3867

Each of the possible innermolecular reaction products will
show a few unique NMR-spectroscopic features that may
be used to uncover its identity and to exclude other
possibilities. We employed the following observations in this
analysis: (1) The 1H and 13C NMR spectra of 6 are consistent
with a C1 symmetric product. (2) In the 19F NMR, the
fluorine of 6 resonates at δF ) -150.55 ppm as a doublet of
doublets (2JHF ) 57.4, 51.7 Hz) and couples to two
diastereomeric methylene protons, H1 and H2. The latter give
cross correlations to each other in the TOCSY of 6 but not
to other host protons (see Supporting Information). This
automatically excludes C-H insertions (A, D, E), Caryl-O
insertions (B, F), and linker CR-O insertion (G) as possible
reaction modes of incarcerated PhCF. (3) The 13C NMR
spectrum shows a uniquely downfield shifted signal at δC )
190.27 ppm, which we assign to the tropone carbonyl of 6
and which cannot be rationalized with a linker CR-O insertion
product. This leaves cyclopropanation (H in Figure 1) as
the only reaction channel for PhCF, consistent with the
observed reactivity of p-tolylcarbene inside the same
hemicarcerand.4d Cylopropanation by PhCF is then followed
by rearrangement to 6, as detailed in Scheme 1.
Precedent for this sequence can be found in the dichlo-
rocarbene-induced transformations of methoxy-aromatics to
chlorotropones.16 Moreover, in a model reaction, photolysis
of diazirine 5 in anisole at 77 K, followed by warming to
25 °C, gave 17% of 2-phenyltropone (10),17 as well as
carbene dimers 11 (4%) and 12 (6%), and azine 13 (6%,
from attack of PhCF on diazirine 5); cf. eq 1.
Figure 1. Partial structures of all possible primary reaction products
between incarcerated PhCF and hemicarcerand 2: C-H insertions
(A, D, E), C-O insertions (B, C, F, G), and aryl cyclopropanation
(H). The carbene fragment and the reactive functional group of 2
are highlighted in red and blue, respectively.
The conversion of anisole to 2-phenyltropone upon reac-
tion with photogenerated PhCF can be rationalized by a
mechanism analogous to that of Scheme 1. As expected, the
carbene dimers and azine 13 were the only products obtained
when diazirine 5 was photolyzed in CH2Cl2 or pentane in
the absence of anisole.
The attack of incarcerated PhCF on its hemicarcerand host,
which proceeds rapidly even at very low temperatures, stands
in dramatic contrast to the stability of similarly incarcerated
PhOCF, which persists for days at ambient temperature.10
Clearly, the 14 kcal/mol reduction in substituent stabilization
of PhCF relative to PhOCF has a major impact. PhCF is too
reactive to persist within hemicarcerand 2, whose walls are
constructed of alkoxy-activated aryl units.18 Combined with
the results of an earlier investigation of the innermolecular
tion affords the tropylium ion derivative 9 and fluoride ion
as a tight ion pair. Subsequent SN2 attack of the fluoride at
an adjacent dioxymethylene unit furnishes the tropone
hemicarcerand derivative 6, which also bears a fluo-
romethoxy substituent. Alternatively, there may be a more
or less concerted process that does not involve complete
ionization.
To elucidate the structure of 6 and its mode of formation,
we first note that PhCF can react with 2 in only eight different
ways (see Figure 1), of which several have been observed
in other carbene hemicarceplexes.4a,b,d These are insertions
into C-H (A), Caryl-O (B), or Cacetal-O (C) bonds of the
spanners; insertions into CR-H (D), Cꢀ-H (E), Caryl-O (F), or
CR-O (G) bonds of the linkers; or cyclopropanation of an
aryl unit (H), which as one of us has shown earlier4d is only
possible at the C1-C2 or C1-C6 bond. Other reactions are
impossible due to the rigidity of the host.
(16) (a) Parham, W. E.; Bolon, D. A.; Schweizer, E. E. J. Am. Chem.
Soc. 1961, 83, 603. (b) Sato, M.; Uchida, A.; Tsunetsugu, J.; Ebine, S.
Tetrahedron Lett. 1977, 25, 2151.
(17) Doering, W. v. E.; Hiskey, C. F. J. Am. Chem. Soc. 1952, 74, 5688.
3868
Org. Lett., Vol. 11, No. 17, 2009

chemistry of tolylcarbenes, our work suggests that singlet
carbenes prefer addition to the aryl units of hemicarcerand
2, whereas triplet carbenes preferentially attack the inward
pointing C-H bonds.4a,b,d Perhaps an “umpolung” of the
electronic properties of the cavitands, e.g., through metalation
of the outer arene faces,19 might afford carcerands with
greater resistance to attack by singlet carbenes.
From the viewpoint of effective carbene incarceration, the
substituent change of PhO to Ph, which converts PhOCF to
PhCF, results in an excessive decrease in carbenic stability
and an unacceptable increase in carbenic reactivity. An
alternative substituent change for PhOCF would be F to Cl,
i.e., PhOCF to PhOCCl. The stabilization energy of PhOCCl
relative to CH2 can be calculated11 as 53.6 kcal/mol, only
∼6 kcal/mol less than the stabilization energy of PhOCF.
The possible persistence of PhOCCl inside hemicarcerand
2 thus becomes a matter of future experimental interest.
In conclusion, photolysis of fluorophenyldiazirine, incar-
cerated in hemicarcerand 2, affords fluorophenylcarbene,
which attacks an aryl unit of the host, leading (after
rearrangement) to a fluoromethoxy/phenyltropone derivative
of the hemicarcerand. From our NMR studies, the incarcer-
ated carbene 2.3 is definitely unstable at temperatures above
-80 °C, while the color bleaching experiment reported above
suggests that 2.3 is probably unstable at temperatures
above 100 K.
Acknowledgment. We are grateful to the National Science
Foundation and the Petroleum Research Fund for financial
support.
Supporting Information Available: Preparative details
for hemicarceplex 2.5, photolysis experiments and product
studies, enthalpy scheme and computational studies, and
NMR spectra. This material is available free of charge via
the Internet at http://pubs.acs.org.
(18) Not surprisingly, the even less stabilized phenylcarbene (PhCH)
also attacks the hemicarcerand; cf. ref 4.
(19) (a) Steed, J. W.; Holman, K. T.; Atwood, J. L. Chem. Commun.
1996, 1401. (b) Fairchild, R. M.; Holman, K. T. J. Am. Chem. Soc. 2005,
127, 16364.
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