Inter- and innermolecular reactions of chloro(phenyl)carbene

Article abstract of DOI:10.1021/jo026521h

Supramolecular photolyses of 3-chloro-3-phenyl-3H-diazirine (8) were performed within cyclodextrin (CyD) hosts to determine whether these toroidal inclusion compounds could alter the reactivity of the ensuing carbene reaction intermediate, chloro(phenyl)carbene (9). Remarkably, no intramolecular products stemming from carbene 9 could be detected. Instead, modified CyDs were formed via so-called innermolecular reactions. Hence, diazirine 8 was photolyzed in various conventional solvents to gauge the intermolecular reactivity of carbene 9. Relevant results were used to rationalize the CyD innermolecular reaction products.

Full text of DOI:10.1021/jo026521h

In ter - a n d In n er m olecu la r Rea ction s of Ch lor o(p h en yl)ca r ben e†
Murray G. Rosenberg‡ and Udo H. Brinker*
Institut fu¨r Organische Chemie, Universita¨t Wien, Wa¨hringer Strasse 38, A-1090 Wien, Austria, and
Department of Chemistry, State University of New York, Binghamton, New York 13902-6016
udo.brinker@univie.ac.at
Received October 3, 2002
Supramolecular photolyses of 3-chloro-3-phenyl-3H-diazirine (8) were performed within cyclodextrin
(CyD) hosts to determine whether these toroidal inclusion compounds could alter the reactivity of
the ensuing carbene reaction intermediate, chloro(phenyl)carbene (9). Remarkably, no intramo-
lecular products stemming from carbene 9 could be detected. Instead, modified CyDs were formed
via so-called innermolecular reactions. Hence, diazirine 8 was photolyzed in various conventional
solvents to gauge the intermolecular reactivity of carbene 9. Relevant results were used to rationalize
the CyD innermolecular reaction products.
In tr od u ction
Much time and effort has been spent in recent years
seeking long-lived carbenes.1 This flurry of activity has
met limited success. Tomioka carbenes,2 such as triplet
bis(10-phenylanthracen-9-yl)carbene (1) (t1/2 ) 19 min,
D/ hc ) 0.105 cm-1) (Figure 1),1a,2a,b,3 are persistent
organic reaction “intermediates” and constitute one area
of promising research. Ylide-like singlet carbenes, such
as Breslow thiazol-2-ylidenes (2),4 Wanzlick imidazolidin-
F IGURE 1. Is triplet bis(10-phenylanthracen-9-yl)carbene (1)
really a geminate diradical?
* To whom correspondence should be addressed. Phone: +43-1-
4277-52121. Fax: +43-1-4277-52140.
† Carbenes in Constrained Systems. 8. For part 7, see: Rosenberg,
M. G.; Brinker, U. H. J . Org. Chem. 2001, 66, 1517-1522. Carbene
Rearrangements. 57. For part 56, see: Knoll, W.; Bobek, M. M.; Giester,
G.; Brinker, U. H. Tetrahedron Lett. 2001, 42, 9161-9165.
‡ State University of New York.
(1) (a) Freemantle, M. Chem. Eng. News 2001, 79 (33), 11. (b)
Freemantle, M. Chem. Eng. News 1999, 77 (45), 19. (c) Freemantle,
M. Chem. Eng. News 2000, 78 (19), 57. (d) Freemantle, M. Chem. Eng.
News 2001, 79 (24), 22. (e) Dagani, R. Chem. Eng. News 1994, 72 (18),
20-22. (f) Chem. Eng. News 1991, 69 (4), 19-20. (g) Krishnamurthy,
S. S. Curr. Sci. 1991, 60, 619-620. (h) Bucher, G.; Winkler, M. Nachr.
Chem. 2002, 50, 289-293. (i) Hopkins, J . M.; Bowdridge, M.; Robertson,
K. N.; Cameron, T. S.; J enkins, H. A.; Clyburne, J . A. C. J . Org. Chem.
2001, 66, 5713-5716.
(2) (a) Tomioka, H.; Iwamoto, E.; Itakura, H.; Hirai, K. Nature 2001,
412, 626-628. (b) Tomioka, H.; Nozaki, Y.; Iwamoto, E.; Hirai, K. In
Proceedings of the Conference on Reactive Intermediates and Unusual
Molecules; Bobek, M. M., Ed.; Eigenverlag: Vienna, 2000; p 3. (c) Hirai,
K.; Tomioka, H. J . Am. Chem. Soc. 1999, 121, 10213-10214. (d)
Tomioka, H. In Advances in Carbene Chemistry; Brinker, U. H., Ed.;
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Chem. Res. 1997, 30, 315-321. (f) Tomioka, H.; Watanabe, T.; Hirai,
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6376-6377.
(3) In triplet-state ESR, the zero-field splitting parameter D rep-
resents the slight energy difference between the T( and T0 states, e.g.,
D(1) ) 3.0 × 10-4 kcal/mol, and is inversely related to the distance of
the two unpaired electrons. See: (a) Turro, N. J . Modern Molecular
Photochemistry; University Science Books: Mill Valley, CA, 1991; pp
551-552. (b) Wentrup, C. Reactive Molecules; Wiley: New York, 1984;
pp 46-48, 176-180.
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W.; Kleiner, H.-J . Angew. Chem., Int. Ed. Engl. 1964, 3, 65. (d) Olofson,
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F IGURE 2. Singlet carbene or pnictonium ylide? (a) Breslow,
(b) Wanzlick, (c) Arduengo, and (d) Bertrand carbenes.
2-ylidenes (3),5 Arduengo imidazolin-2-ylidenes (4),1f,5f,6
and Bertrand phosphinocarbenes (5),1c,7 comprise another
(Figure 2).8 However, supramolecular inclusion of more
typical carbenes within suitable hosts may offer distinct
advantages.
The rearrangement of phenylcarbene (6) to 1,2,4,6-
cycloheptatetraene (7) has been extensively studied (eq
1).9 Recently, Warmuth reported the generation of car-
(5) (a) Wanzlick, H.-W.; Kleiner, H.-J . Angew. Chem. 1961, 73, 493.
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Lemal, D. M.; Lovald, R. A.; Kawano, K. I. J . Am. Chem. Soc. 1964,
86, 2518-2519. (f) Winberg, H. E.; Carnahan, J . E.; Coffman, D. D.;
Brown, M. J . Am. Chem. Soc. 1965, 87, 2055-2056. (g) Hoffmann, R.
W. Angew. Chem., Int. Ed. Engl. 1968, 7, 754-765. (h) Wiberg, N.
Angew. Chem., Int. Ed. Engl. 1968, 7, 766-779. (i) Lemal, D. M. In
The Chemistry of the Amino Group; Patai, S., Ed.; Wiley: New York,
1968; Chapter 12. (j) Arduengo, A. J ., III; Goerlich, J . R.; Marshall,
W. J . J . Am. Chem. Soc. 1995, 117, 11027-11028.
10.1021/jo026521h CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/21/2003
J . Org. Chem. 2003, 68, 4819-4832
4819

Rosenberg and Brinker
SCHEME 1. Rin g Exp a n sion of
Ch lor o(p h en yl)ca r ben e (9)
F IGURE 3. Mesomeric forms of chloro(phenyl)carbene (9).
10) within the frozen argon matrix.14-16 However, if
7-chlorobicyclo[4.1.0]hepta-2,4,6-triene (11) were to lie in
a shallow potential energy well then it would be very
fleeting and perhaps unobservable.9d,e
Moreover, (2-chlorophenyl)carbene (iso-9) also rear-
ranges to cyclic allene 10 (Scheme 1).9c,11 Sander reported
that the two carbenes do not interconvert,11 which could
be due to the fact that halo(phenyl)carbene 9 has a singlet
ground state (GS) whereas (halophenyl)carbene iso-9
likely has a triplet GS. In contrast, Chapman and co-
workers reported that irradiation (λ > 212 nm) of cyclic
allene 10 (produced from iso-9) affords some carbene 9.9c
Finally, the 1,3-C-H insertion of carbene 9 to 1-chloro-
1H-cyclopropabenzene (13) was not observed by either
research group (eq 2).
bene 6 within a hemicarcerand (HC).10 Encapsulated
allene 7 was protected from dimerization, so even the H
2-D NOESY NMR spectrum of 7@HC could be measured.
1
Photolysis of 3-chloro-3-phenyl-3H-diazirine (8) in Ar
at 10 K generates matrix-isolated chloro(phenyl)carbene
(9) (Scheme 1),11 which completely undergoes ring expan-
sion to 1-chloro-1,2,4,6-cycloheptatetraene (10) when
exposed to short wavelength irradiation (λ > 254 nm).12
This rearrangement proceeds by either a direct or an
indirect 1,2-C shift. Indeed, neither 7-chlorobicyclo[4.1.0]-
hepta-2,4,6-triene (11) nor 2-chloro-2,4,6-cycloheptatrien-
1-ylidene (12) was observed during prolonged irradiation
(λ > 338 nm) of carbene 9.9c,13 Hence, cyclic allene 10
apparently derives from a direct “vinyl” migration (9 f
Chloro(phenyl)carbene (9) can be drawn as a reversed-
electronegativity chloronium ylide possessing a weak
C2p-Cl3p π-bond (Figure 3). Electron donation to the
divalent carbon of carbene 9 by the chlorine substituent
stabilizes the singlet electronic state relative to the
triplet. This inner covalent coordination is sufficient
enough to make the singlet state the ground state (GS).
Hence, carbene 9 shows no ESR signal and adds ste-
reospecifically to alkenes.17
To determine whether room-temperature supramo-
lecular constraint of carbene 9 could yield ring-expanded
allene 10, triplet carbene iso-9, or benzocyclopropene 13,
the carbene precursor 3-chloro-3-phenyl-3H-diazirine (8)
was prepared,18 and then included within cyclodextrins
prior to photolysis. Indeed, recent advances in carbene
chemistry19 demonstrate that constrictive hosts, like
cyclodextrins,20 are able to modify the selectivity of the
(6) (a) Arduengo, A. J ., III; Harlow, R. L.; Kline, M. J . Am. Chem.
Soc. 1991, 113, 361-363. (b) Arduengo, A. J ., III; Dias, H. V. R.; Dixon,
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1994, 116, 6812-6822. (c) Olofson, R. A.; Thompson, W. R.; Michelman,
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Irngartinger, H.; Mannschreck, A.; Wu, M.-T. J ustus Liebigs Ann.
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Bertrand, G. Heteroat. Chem. 1991, 2, 29-38. (d) Igau, A.; Baceiredo,
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(8) (a) Chen, P. In Advances in Carbene Chemistry; Brinker, U. H.,
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(13) Singlet 2-chloro-2,4,6-cycloheptatrien-1-ylidene (12) is expected
to lie at the transition state (TS) between (R)-1-chloro-1,2,4,6-cyclo-
heptatetraene ((R)-10) and (S)-1-chloro-1,2,4,6-cycloheptatetraene ((S)-
10). For an account of the related enantiomerization of DL-7, see ref
10c, p 432.
(9) (a) J ones, W. M.; Brinker, U. H. In Pericyclic Reactions; Marc-
hand, A. P., Lehr, R. E., Eds.; Academic: New York, 1977; Vol. 1,
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4820 J . Org. Chem., Vol. 68, No. 12, 2003

Inter- and Innermolecular Reactions of Chloro(phenyl)carbene
SCHEME 2. F or m a tion of Gr a h a m ’s Dia zir in e
3-Ch lor o-3-p h en yl-3H-d ia zir in e (8)
constant (K)24 that may be measured in a variety of
different ways, e.g., spectrofluorometric methods based
on competition experiments.25 Recently, induced circular
dichroism (ICD) has also been used to assess the binding
constants of carbene-forming 3H-diazirine@CyD inclusion
complexes (ICs).26
F IGURE 4. Structure of cyclodextrin (CyD) depicting the O1-
C4 R-linkage of D-glucopyranose monomers. Note the inward
pointing H3 and H5 atoms.
Resu lts a n d Discu ssion
3-Chloro-3-phenyl-3H-diazirine (8) was prepared from
benzamidine hydrochloride (14‚HCl) and sodium hy-
pochlorite (NaOCl) in ca. 70% yield.18a,27 In addition to
diazirine 8, other more polar compounds were formed in
the following relative yields: benzaldehyde (PhCHO, 9%),
benzonitrile (PhCN, 16%), x-(1-chloro-1-phenylmethyl)-
pentanes (20i, 4%),28,29 benzyl benzoate (BzOBn, 54%),30
1,2-dichloro-1,2-diphenylethene (17, 3%),31 2,5-diphenyl-
1,3,4-oxadiazole (PPD, trace),32 and bis(1-chloro-1-phe-
nylmethylidene)hydrazine (18, 14%).33 However, most of
these byproducts can be attributed to the decomposition
of diazirine 8.
high-energy reaction intermediate.21 Thus, we hypoth-
esized that the confinement of carbene 9 within the
nanoscopic cavities of cyclodextrins (Figure 4) would alter
its reactivity.
A cyclodextrin (CyD) is a nonreducing, cyclic oligosac-
charide molecule composed of R-D-glucopyranose (R-D-
Glcp) monomers linked at the 1 and 4 glycosidic positions.
The general structure of CyDs is shown in Figure 4. Their
prefixes depend on the number of pyranose units
present: six (R-CyD), seven (â-CyD), eight (γ-CyD), and
nine (δ-CyD).22
These torus-shaped23 hosts can accommodate many
sorts of organic molecules that can reside within the
nonpolar cavity. The strength of this noncovalent inter-
action is directly related to the position of the equilibrium
for complex formation. This is evaluated by a binding
The original mechanism for diazirine 8 formation,
proposed by Graham,18a was contested in 1980 when
3-chloro-3-phenyl-3H-diaziridine (N,N′-dihydro-8) was
suggested as a reaction intermediate (Scheme 2).34
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J . Org. Chem, Vol. 68, No. 12, 2003 4821

Rosenberg and Brinker
SCHEME 3. Gen er a tion of Ch lor o(p h en yl)ca r ben e (9) a n d Its Su bsequ en t Rea ction sa
a
RH ) (a) R-CyD, (b) â-CyD, (c) γ-CyD, (d) MeOH, (e) i-PrOH, (f) t-BuOH, (g) H2O, (h) HCl, (i) C5H12 (j) c-C6H12, (k) PhH, (l) THF, (m)
CHCl3, (n) PhCH(OH)CH(OH)Ph (24).
TABLE 1. Rela tive Yield s (%) of P r od u cts F or m ed u p on
P h otolysis of 3-Ch lor o-3-p h en yl-3H-d ia zir in e (8) in
Differ en t Rea ction Med ia
3-Chloro-3-phenyl-3H-diazirine (8) was photolyzed in
various solvents and within CyDs. The solution results
are summarized in Table 1. The conventional solvents
were used to gauge whatever effects the CyD hosts had
on chloro(phenyl)carbene (9). Hydrocarbon solvents, like
pentane (n-C5H12) and cyclohexane (c-C6H12), were used
to mimic the inner cavities of CyDs, which are also
nonpolar, hydrophobic environments. Tetrahydrofuran
(THF) was employed because the cyclic ether resembles
the D-glucopyranose (D-Glcp) monomer units of the CyDs.
Moreover, since CyDs also possess many hydroxyl (OH)
groups, it seemed appropriate to perform control experi-
ments upon alcoholic solutions of diazirine 8. Finally,
chloroform (CHCl3) was used to assess the spin-state of
carbene 9.
P h otolysis in Solu tion P h a se. The photolysis of
3-chloro-3-phenyl-3H-diazirine (8) in chloroform and
chloroform-d resulted in moderate amounts of (1,2,2,2-
tetrachloroethyl)benzene (20m )37 and (1,2,2,2-tetrachlo-
roethyl-1-d)benzene (20m -d), respectively (Table 1). Both
of these isotopomers stem from carbene 9 insertions into
the C-H(D) bonds of chloroform(-d), rather than the
expected C-Cl insertions (eq 3; cf. Scheme 7).
medium
(RH)
neat
n-C5H12
(0.01 M)
n-C5H12
(0.5 M)
c-C6H12
(0.1 M)
c-C6H12
(0.5 M)
κa PhCHO 17
1.8
18
20
20h
21 other
100
trace trace 32
68b
trace
1.8
2.0
2.0
trace 23
trace trace 20
61
77b
80c
traced
39c
benzene
CHCl3
(wet)
CDCl3
THF
i-PrOH
(0.1 M)
i-PrOH
(0.5 M)
MeOH
2.3
4.7
2
21
5
4
83
trace
8
46
2e
3h
trace 33f
3
4
57
22g
11
15
7.3
18.3
100i
100j
18.3
32.7
81j
100k
a
Dielectric constant. b x-(1-Chloro-1-phenylmethyl)pentanes (20i).
c [Chloro(cyclohexyl)methyl]benzene (20j). PPD. e Biphenyl (25).
d
f (1,2,2,2-Tetrachloroethyl)benzene (20m ). (1,2,2,2-Tetrachloro-
g
ethyl-1-d)benzene (20m -d). PhCN. i 2-(1-Chloro-1-phenylmethyl)-
h
oxolane (20l). j [Di(1-methylethoxy)methyl]benzene (21e). k (Dimeth-
oxymethyl)benzene (21d ).
However, this notion was later shown to be incorrect.35
Note that the ring closure leading to the diazirine
parallels that for the classical Neber rearrangement.36
The photolysis of diazirine 8 is expected to form rela-
tively “long-lived” chloro(phenyl)carbene (9), which usu-
ally decomposes via intermolecular reactions (Scheme 3).
The photolysis results for diazirine 8 in pentane (Table
1)38 are similar to those already reported for a 19.7 mM
solution, i.e., 28% of 18 and 71% of 20i.28 Further analysis
of the C-H insertion products, i.e., x-(1-chloro-1-phenyl-
(35) (a) Moss, R. A.; Włostowska, J .; Guo, W.; Fedorynski, M.;
Springer, J . P.; Hirshfield, J . M. J . Org. Chem. 1981, 46, 5048-5050.
(b) Moss, R. A. In Chemistry of Diazirines; Liu, M. T. H., Ed.; CRC:
Boca Raton, FL, 1987; Vol. 1, pp 99-109.
(36) (a) Neber, P. W.; Burgard, A. J ustus Liebigs Ann. Chem. 1932,
493, 281-294. (b) O’Brien, C. Chem. Rev. 1964, 64, 81-89. (c) Advanced
Organic Chemistry, 4th ed.; March, J ., Ed.; Wiley: New York, 1992;
pp 1089-1090. (d) Hassner, A.; Stumer, C. Organic Syntheses Based
on Name Reactions and Unnamed Reactions; Pergamon: Tarrytown,
NY, 1994; p 271.
(37) (a) Ettel, V.; Weichet, J . Collect. Czech. Chem. Commun. 1950,
15, 520-527. (b) Naidan, V. M.; Dombrovskii, A. V. J . Org. Chem.
USSR (Transl.Zh. Org. Khim.) 1965, 1, 2037-2040. (c) Grishchuk, B.
D.; Sinchenko, V. G.; Kudrik, E. Y.; Gorbovoi, P. M.; Shandruk, R. N.;
Kulaga, O. E. Pharm. Chem. J . (Transl. Khim.-Farm. Zh.) 1995, 29,
406-408.
(38) Since azine 18 precipitated from the pentane solutions, the
samples were rotary evaporated, and then the residues were dissolved
in CHCl3 (0.1 M) for GC analysis.
4822 J . Org. Chem., Vol. 68, No. 12, 2003

Inter- and Innermolecular Reactions of Chloro(phenyl)carbene
SCHEME 4. Selective F or m a tion of
x-(1-Ch lor o-1-p h en ylm eth yl)P en ta n es (20i)
80% relative yield) and three other undisclosed products
(eq 6).42 However, an unusual mechanism involving
chloro(phenyl)carbene (9) was formulated to explain
BzOBn formation.
methyl)pentanes (20i), revealed that carbene 9 did not
react with the terminal methyl groups of pentane (Scheme
4). This is in stark contrast with the results reported for
(methoxycarbonyl)carbene, which gave methyl hep-
tanoate via C-H insertions of the -CH3 groups of
pentane.29
Similarly, C-H insertion was observed with THF as
solvent, but only with the R-C-H bonds of the cyclic
ether,39 giving 2-(1-chloro-1-phenylmethyl)oxolane (20l)
exclusively (eq 4; Table 1).
It should be noted, however, that t-BuOK is hygro-
scopic (eq 7). So, any resulting KOH impurities would
transform benzal chloride 20h into benzaldehyde (Ph-
CHO) (eq 8). Therefore, it is more likely that the benzyl
ester BzOBn was formed by the action of the alkoxide
base upon adventitious PhCHO according to the Tish-
chenko reaction, i.e., 2PhCHO f BzOBn.30,43,44
The photolysis of diazirine 8 in anhydrous methyl
alcohol (MeOH) yielded (dimethoxymethyl)benzene (21d )
(Table 1) and HCl (Scheme 5). Since the product mixture
was very sensitive to moisture,40 it was necessary to
quench the photolyzed MeOH solution with anhydrous
NH3(g) to inhibit subsequent HCl acid-catalyzed hydroly-
sis of the benzaldehyde dimethyl acetal 21d to benzal-
dehyde (PhCHO). Ammonium chloride (NH4Cl) mist and
heat were observed upon quenching. To gauge the effect
of ammonia on carbene 9, anhydrous NH3(g) was intro-
duced prior to photolysis of the methanolic solution of
diazirine 8. Again, only acetal 21d was produced. Indeed,
It should also be mentioned that base-induced R-elim-
ination of HCl from (dichloromethyl)benzene (20h ) does
not even necessarily afford chloro(phenyl)carbene (9).45
A carbenoid intermediate 9‚KCl is likely formed. How-
ever, this condition could be remedied by using crown
ethers, which appear to promote the formation of free
carbene 9, as compared with results obtained from the
nitrogenous precursor 3-chloro-3-phenyl-3H-diazirine (8).45
addition of anhydrous potassium carbonate (K2CO3(s)
)
before photolysis also made no difference and was most
convenient.
Photolysis of a 0.1 M solution of 3-chloro-3-phenyl-3H-
diazirine (8) in anhydrous isopropyl alcohol (i-PrOH),
followed by NH3(g) quenching, afforded [di(1-methyl-
ethoxy)methyl]benzene (21e)46 as the sole product (Table
1). Photolysis of a 0.5 M solution of diazirine 8 in
anhydrous i-PrOH, followed by NH3(g) quenching, af-
forded benzaldehyde diisopropyl acetal 21e, (dichloro-
methyl)benzene (20h ), and benzaldehyde (PhCHO) in
81%, 15%, and 4% yields, respectively (Table 1, eq 9). The
formation of benzal chloride 20h within the concentrated,
i.e., 0.5 M, solution of diazirine 8 may be a consequence
Next, the reaction of 3-chloro-3-phenyl-3H-diazirine (8)
with the primary reaction product (dimethoxymethyl)-
benzene (21d ) was investigated to determine whether the
acetal was inert toward chloro(phenyl)carbene (9). It was
found that photolysis of diazirine 8 in neat benzaldehyde
dimethyl acetal 21d gave (1-chloro-2,2-dimethoxy-2-
phenylethyl)benzene (28) in low yield (eq 5). Desyl
chloride dimethyl acetal 28 likely derives from ben-
zylidene C-H insertion of acetal 21d by carbene 9.41
In a prior and seemingly conflicting report about this
reaction (eq 5), heating (dimethoxymethyl)benzene (21d )
with (dichloromethyl)benzene (20h ) and t-BuOK, followed
by aqueous workup, gave benzyl benzoate (BzOBn, ca.
(42) Dement’eva, L. P.; Kostikov, R. R. J . Org. Chem. USSR (Transl.
Zh. Org. Khim.) 1990, 26, 117-118.
(43) (a) Advanced Organic Chemistry, 4th ed.; March, J ., Ed.;
Wiley: New York, 1992; p 1235. (b) Hassner, A.; Stumer, C. Organic
Syntheses Based on Name Reactions and Unnamed Reactions; Perga-
mon: Tarrytown, NY, 1994; p 384.
(39) For similar examples, see: Lin, G. Diss. Abstr. Int. B 1995, 56
(6), 3203; Chem. Abstr. 1996, 124, 175117.
(40) Appreciable amounts of benzaldehyde (PhCHO) were formed
even within 1 min of exposure to air, as detected via GC.
(41) For a similar example, see: Moss, R. A.; Yan, S. Tetrahedron
Lett. 1998, 39, 9381-9384.
(44) Rosenberg, M. G. Ph.D. Dissertation, State University of New
York at Binghamton, 2002.
(45) Moss, R. A.; Pilkiewicz, F. G. J . Am. Chem. Soc. 1974, 96, 5632-
5633.
(46) Roelofsen, D. P.; van Bekkum, H. Synthesis 1972, 419-420.
J . Org. Chem, Vol. 68, No. 12, 2003 4823

Rosenberg and Brinker
SCHEME 5. P h otolysis of 3-Ch lor o-3-p h en yl-3H-d ia zir in e (8) in MeOH
of the relatively low acidity of i-PrOH.47 The subdued
reactivity of i-PrOH with carbene 9 decreases the usually
diffusion-limited rate of carbene O-H insertion and
concomitantly fosters HCl insertion. However, the exist-
ence of benzal chloride 20h within the product solution
may also reflect a diminished ability of the bulkier alcohol
to solvolyze the gem-dichloride byproduct.
SCHEME 6. Mech a n istic P a th w a ys Lea d in g to th e
F or m a tion of Azin e 18 a n d Ca r ben e Dim er 17
Further analysis of the reactions of chloro(phenyl)-
carbene (8) with relevant oxygen-containing functional
groups (alcohols, such as t-BuOH, MeOH, and DL-hy-
drobenzoin (DL-24), aldehydes, and ethers) can be found
elsewhere.48
Condensed-phase carbenes will often react with the
surrounding solvent medium, but they can also combine
with other solute molecules. Indeed, these intermolecular
reactions commonly occur at rates that are limited only
by diffusion. Consequently, such carbenes are just short-
lived intermediates. Nevertheless, arylhalocarbenes tend
to have much longer lifetimes than typical alkylhalocar-
benes, e.g., 3 orders of magnitude longer, because the
latter also undergo rapid 1,2-H shift to form alkenes.49,50
Indeed, the lifetime (τ) of singlet chloro(phenyl)carbene
(9) (λmax ) 310 nm)51 in 2,2,4-trimethylpentane (isooctane)
is reported to be ca. 3.6 µs, as determined via laser flash
photolysis (LFP) of 3-chloro-3-phenyl-3H-diazirine (8).52
Under thermal conditions, diazirine 8 decomposes
unimolecularly to give N2 and carbene 9.53 The free
carbene can subsequently react with the ubiquitous
solvent to form insertion products (Table 1). Moreover,
carbene 9 appears to react with its nitrogenous precursor-
(s). Indeed, the thermolysis of diazirine 8 in benzene, an
“inert” solvent,54 yields bis(1-chloro-1-phenylmethylidene)-
hydrazine (18).28 It was observed during this study that
the photolysis of neat diazirine 8 at room temperature
afforded azine 18 in high yield and purity. Therefore, the
diazirine route to 18 could become the leading alternative
to Stolle´’s classical reaction involving chlorination of
benzaldehyde azine (29).28,33
It has been suggested that intermolecular reaction of
chloro(phenyl)carbene (9) with 3-chloro-3-phenyl-3H-
diazirine (8) yields the azine bis(1-chloro-1-phenylmeth-
ylidene)hydrazine (18) (Scheme 3).28 2,4-Dichloro-2,4-
diphenyl-1,3-diazabicyclobutane (31) was postulated as
an intermediate in the formation of azine 18 (Scheme 6).28
It would stem from π-attack of diazirine precursor 8 by
carbene 9. Recently though, the carbene-diazirine ylide
(CDY) was postulated as an intermediate in the forma-
tion of azine 18.55 It would stem from n-attack (of a N
atom) of diazirine precursor 8 by carbene 9. However,
the 9-8 CDY could not be observed. Therefore, it was
concluded that if the 9-8 CDY did form then it rapidly
rearranged to azine 18, which is photostable.55
(47) The pKa of i-PrOH is 17.1, whereas that for MeOH is 15.5.
See: Miller, A.; Solomon, P. H. Writing Reaction Mechanisms in
Organic Chemistry, 2nd ed.; Academic: San Diego, 2000; pp 461-462.
(48) See the Supporting Information.
(49) Liu, M. T. H. Acc. Chem. Res. 1994, 27, 287-294.
(50) (a) Bonneau, R.; Liu, M. T. H. In Advances in Carbene
Chemistry; Brinker, U. H., Ed.; J AI: Stamford, CT, 1998; Vol. 2, pp
1-28. (b) Liu, M. T. H.; Bonneau, R. J . Am. Chem. Soc. 1996, 118,
8098-8101.
(51) For the π f π* transition. For the σ f p transition (λmax ) 750
nm), see: (a) Zuev, P. S.; Sheridan, R. S. J . Org. Chem. 1994, 59, 2267-
2269. (b) Sheridan, R. S. Inter-Am. Photochem. Soc. News. 2000, 23
(1), 39-48.
(54) Benzene may not be totally inert since it may form a charge-
transfer complex with arylhalocarbenes. See: C¸ elebi, S.; Platz, M. S.
In Proceedings of the Conference on Reactive Intermediates and
Unusual Molecules; Bobek, M. M., Ed.; Eigenverlag: Vienna, 2000; p
31.
(55) Bonneau, R.; Liu, M. T. H. J . Phys. Chem. A 2000, 104, 4115-
4120.
(52) (a) Turro, N. J .; Butcher, J . A., J r.; Moss, R. A.; Guo, W.; Munjal,
R. C.; Fedorynski, M. J . Am. Chem. Soc. 1980, 102, 7576-7578. (b)
Naito, I.; Oku, A.; Otani, N.; Fujiwara, Y.; Tanimoto, Y. J . Chem. Soc.,
Perkin Trans. 2 1996, 725-729.
(53) Liu, M. T. H.; Toriyama, K. J . Phys. Chem. 1972, 76, 797-801.
4824 J . Org. Chem., Vol. 68, No. 12, 2003

Inter- and Innermolecular Reactions of Chloro(phenyl)carbene
SCHEME 7. Exp ected Rea ction of Ch lor o(p h en yl)ca r ben e (9) w ith Ch lor ofor m
In contrast, the formation of ∆1-1,2-diazetines from
σ-attack of 3H-diazirines appears to have never been
considered. If formed, 3,4-dichloro-3,4-diphenyl-∆1-1,2-
diazetine (iso-31) might be expected to yield (irreversibly)
both the azine 18, via C-C cleavage, and the alkene 1,2-
dichloro-1,2-diphenylethene (17), via N2 extrusion.56,57
The formation of alkene 17 from the direct dimerization
of two short-lived carbenes 9 in dilute solution is highly
improbable. Therefore, the presence of trace amounts of
dimer 17 found after the photolysis of a 0.01 M pentane
solution of diazirine 8 (Table 1) suggests that either diazo
compound 19 or ∆1-1,2-diazetine iso-31 may have been
involved. Indeed, much of the electron density within the
highest occupied n-orbital of diazirines is coincident with
the C-N σ-orbital.58 Hence, the formation of ∆1-1,2-
diazetine iso-31, via formal carbene C-N insertion, is not
implausible.
The reaction of chloro(phenyl)carbene (9) with ethers
F IGURE 5. Structure of 6A,6B-O-(benzylidene)â-cyclodextrin
has already been examined.48 However, the reactions of
carbenes with aldehydes has been studied only to a
limited extent.59,60 Therefore. the reactivity of carbene 9
within benzaldehyde (PhCHO) was investigated in order
to learn more about the reaction mechanism and its
intermediates.48
(21b).
the NMR and MS data indicate the formation of (1,2,2,2-
tetrachloroethyl)benzene (20m ) and (1,2,2,2-tetrachloro-
ethyl-1-d)benzene (20m -d),61 respectively. However, the
unanticipated C-H(D) insertion products 20m and 20m -d
most likely derive from a concerted C-H(D) insertion by
singlet carbene 9 because the preponderance of other
evidence (vide supra) challenges the existence of triplet
chloro(phenyl)carbene (39).
Finally, the spin-state results from the photolyses of
3-chloro-3-phenyl-3H-diazirine (8) in both chloroform and
chloroform-d, reported herein (eq 3; Table 1), are not
consistent with those expected from singlet chloro-
(phenyl)carbene (19) (Scheme 7).
P h otolysis in th e Su p r a m olecu la r P h a se. The
addition of benzaldehyde (PhCHO) and acetic acid (AcOH)
to an aqueous solution of â-CyD allegedly gives 6A,6B-O-
(benzylidene)â-cyclodextrin (21b) in 45% yield (Figure
5).62 However, that result could not be reproduced in this
study. Moreover, the microanalysis, mass spectrometry,
and NMR spectroscopy data that were used to character-
ize acetal 21b were not made available in the patent.62
Therefore, its formation should be regarded with skepti-
cism. Surely, the OH groups of the hydroxylic solvent,
i.e., water, would compete with those of â-CyD for
PhCHO. Indeed, acidified water is typically used to
catabolize acetals.63 Moreover, the preparation of ben-
zylidene acetals from nonreducing glucopyranosides typi-
cally gives the 4,6-O-benzylidene isomers.64 Only 2,3-O-
benzylidenation of intact cyclodextrins should occur since
they are 1,4-linked.
Insertions by singlet carbene 9 into the C-Cl bonds of
chloroform and chloroform-d, yielding (1,1,2,2-tetrachlo-
roethyl)benzene (33) and (1,1,2,2-tetrachloroethyl-2-d)-
benzene (33-d), respectively, were expected. In contrast,
(56) (a) Timberlake, J . W.; Elder, E. S. In Comprehensive Hetero-
cyclic Chemistry; Lwowski, W., Ed.; Pergamon: Oxford, 1984; Vol. 7;
pp 456-457, 483. (b) White, D. K.; Greene, F. D. J . Am. Chem. Soc.
1978, 100, 6760-6761. (c) Wildi, E. A.; Carpenter, B. K. Tetrahedron
Lett. 1978, 2469-2472. (d) Vereshchinskii, I. V.; Podkhalyuzin, A. T.
Dokl. Chem. (Transl. Dokl. Akad. Nauk SSSR, Ser. Khim.) 1965, 165,
1065-1067. (e) Ebsworth, E. A. V.; Hurst, G. L. J . Chem. Soc. 1962,
4840-4843.
(57) Compare to cyclobutene electrocyclic ring opening vs cyclor-
eversion: (a) Cook, B. H.; Leigh, W. J .; Michael, C. L.; Squillacote, M.
Abstr. Pap. Am. Chem. Soc. 1997, 214, CHED 121. (b) Leigh, W. J .;
Postigo, J . A. J . Am. Chem. Soc. 1995, 117, 1688-1694.
(58) (a) Baird, N. C. In Chemistry of Diazirines; Liu, M. T. H., Ed.;
CRC: Boca Raton, FL, 1987; Vol. 1, pp 1-17. (b) J orgensen, W. L.;
Salem, L. The Organic Chemist’s Book of Orbitals; Academic: New
York, 1973; pp 40-42, 135-136. (c) Shustov, G. V.; Varlamov, S. V.;
Rauk, A.; Kostyanovsky, R. G. J . Am. Chem. Soc. 1990, 112, 3403-
3408. (d) Bobek, M. M.; Krois, D.; Brehmer, T. H.; Giester, G.; Wiberg,
K. B.; Brinker, U. H. J . Org. Chem. 2003, 68, 2129-2134.
(59) Gutsche, C. D. Org. React. N.Y. 1954, 8, 364-429.
(60) (a) L’Esperance, R. P.; Ford, T. M.; J ones, M., J r. J . Am. Chem.
Soc. 1988, 110, 209-213. (b) de March, P.; Huisgen, R. J . Am. Chem.
Soc. 1982, 104, 4952. (c) Huisgen, R.; de March, P. J . Am. Chem. Soc.
1982, 104, 4953-4954.
(61) See the Supporting Information, Scheme S9.
(62) Yoshinaga, M. J pn. Patent 05 32 704, 1993; Chem. Abstr. 1993,
119, 10738.
(63) Meskens, F. A. J . Synthesis 1981, 501-522.
(64) (a) Evans, M. E. Carbohydr. Res. 1972, 21, 473-475. (b) Horton,
D.; Weckerle, W. Carbohydr. Res. 1975, 44, 227-240.
J . Org. Chem, Vol. 68, No. 12, 2003 4825

Rosenberg and Brinker
ROESY spectrum for the 8@(R-CyD)2 inclusion complex
(IC), no cross-peaks were observed for the (8@â-CyD)2 IC.
The induced circular dichroism (ICD) spectrum of
aqueous 8@(R-CyD)2 was also obtained.68 Asymmetric
induction by chiral R-CyD upon the chromophore of
achiral diazirine 8 was made evident by the weak
negative circular dichroism exhibited at λmax ) 372 nm.
In contrast, an ICD spectrum for the (8@â-CyD)2 complex
could not be observed. However, this absence is not
unexpected after considering the lack of cross-peaks in
its 2-D ROESY spectrum.
Photolysis of 3-chloro-3-phenyl-3H-diazirine (8) in-
cluded within the cavities of CyDs presumably formed
chloro(phenyl)carbene (9) CyD ICs, i.e., 9@CyD (eq 10).
The lifetime (τ) of carbene 9 was expected to be prolonged
due to the preclusion of intermolecular reactions (Scheme
3), such as azine 18 formation and solvent insertion, i.e.,
9 f 20. However, interfering innermolecular reactions10c,69
between the host and guest were indicated (vide infra).
Therefore, the latent intramolecular rearrangement of
carbene 9 to cyclic allene 10, a rare transformation seen
under the forbidding, low-temperature conditions of
argon matrixes,9c,11 was not observed.
F IGURE 6. 250 MHz 2-D ROESY spectrum of the diazirine
CyD IC 8@(R-CyD)2.
Cyclodextrin inclusion complexes (CyD ICs) of 3-chloro-
3-phenyl-3H-diazirine (8) were prepared to determine the
effect of supramolecular inclusion upon chloro(phenyl)-
carbene (9). The R-cyclodextrin (R-CyD) and â-cyclodex-
1
trin (â-CyD) ICs were analyzed using H NMR,65 includ-
ing 2-D ROESY,66 induced circular dichroism (ICD),26 and
microanalysis. The integral structures of the CyD ICs
were concluded to be 8@(R-CyD)2 and (8@â-CyD)2, based
on their physical and chemical characteristics (vide infra).
These stoichiometries denote that diazirine 8 is sand-
wiched between two R-CyD units, but that it forms a
2-fold 1:1 complex with â-CyD.67 It has been demon-
strated that a guest must have a substituent capable of
hydrogen bonding, like -F or -OH,66,67 to effect an
opposite inclusion orientation within cyclodextrins in the
aqueous versus solid phase. Hence, it is likely that
hydrophobic diazirine 8 adopted the same orientation
within its CyD host during photolyses in both phases that
were employed.
The 2-D ROESY spectrum of 8@(R-CyD)2 showed cross-
peaks between the phenyl ring protons of diazirine 8 with
only the H3 protons of one R-CyD (Figure 6). The absence
of cross-peaks with the H5 protons of R-CyD suggests
that diazirine 8 does not fit entirely within one R-CyD
and, therefore, requires two hosts to ensnare it. Moreover,
a tight fit between the diazirine 8 guest and either R-CyD
host is not indicated since neither H3 nor H5 are shifted
upfield to any considerable degree, with deference to the
spectrum of empty R-CyD.65f In contrast to the 2-D
The 8@CyD ICs were photolyzed initially in the solid
state under inert atmosphere. Principally, carbene 9
appears to have reacted with adventitious H2O, which
likely resides near the perimeters of the CyDs, to give
PhCHO and HCl (eq 11; cf. Scheme 3). Of course, these
hydrolysis products may also stem from 9‚CyDs, which
are daughter isomers of 9@CyDs, that derive from
innermolecular reactions (eq 12). Therefore, such descen-
dants were sought. Indeed, fast atom bombardment
(FAB) mass spectrometry of the products revealed the
presence of new signals with masses greater than those
of the unfilled CyD hosts.70 However, the main [M - H]-
signals are not attributable to 9‚CyDs, but rather to CyD
hydrochlorides that could be either noncovalently bound
HCl@CyD ICs or their covalently bound, constitutional
isomers CyD‚HCl.
9 + H2O f PhCHO + HCl
(11)
(65) (a) Casu, B.; Reggiani, M.; Gallo, G. G.; Vigevani, A. Tetrahe-
dron 1966, 22, 3061-3083. (b) Demarco, P. V.; Thakkar, A. L. J . Chem.
Soc. D 1970, 2-4. (c) MacNicol, D. D. Tetrahedron Lett. 1975, 3325-
3326. (d) Chung, W.-S.; Turro, N. J .; Silver, J .; le Noble, W. J . J . Am.
Chem. Soc. 1990, 112, 1202-1205. (e) Qi, Z. H.; Mak, V.; Diaz, L.;
Grant, D. M.; Chang, C.-j. J . Org. Chem. 1991, 56, 1537-1542. (f)
Salvatierra, D.; J aime, C.; Virgili, A.; Sa´nchez-Ferrando, F. J . Org.
Chem. 1996, 61, 9578-9581.
9‚CyD + H2O f PhCHO + HCl + CyD (12)
Since H2O molecules appear to remain chemisorbed
onto the “dried” CyD ICs, it was decided that photolyzing
(66) (a) Alderfer, J . L.; Eliseev, A. V. J . Org. Chem. 1997, 62, 8225-
8226. (b) Ivanov, P. M.; Salvatierra, D.; J aime, C. J . Org. Chem. 1996,
61, 7012-7017.
(68) See the Supporting Information, Figure S5.
(69) Warmuth, R. Angew. Chem., Int. Ed. Engl. 1997, 36, 1347-
1350. (b) Warmuth, R. Chem. Commun. (Cambridge) 1998, 59-60. (c)
Bradley, D. Chem. Br. 1998, 34 (3), 16. (d) Warmuth, R. J . Inclusion
Phenom. Macrocycl. Chem. 2000, 37, 1-38.
(67) For
a related example employing X-ray diffraction upon a
crystalline diazirine@CyD IC, see: Bobek, M. M.; Giester, G.; Ka¨hlig,
H.; Brinker, U. H. Tetrahedron Lett. 2000, 41, 5663-5667.
(70) See the Supporting Information, Figure S7.
4826 J . Org. Chem., Vol. 68, No. 12, 2003

Inter- and Innermolecular Reactions of Chloro(phenyl)carbene
signal.72 Indeed, only signals from the empty CyD hosts
were observed.73 Evidently, loosely bound PhCHO is
expelled from the PhCHO@CyD ICs during FAB MS
analyses, leaving behind the empty CyDs.74 This result
lends support to the notion that covalently bound CyD‚
HCl species, rather than loosely bound HCl@CyD ICs,
are responsible for the signals that were observed after
unbuffered, solid-state photolyses.70
The FAB MS spectra of the alkaline buffer photolysis
products indicated that innermolecular reactions took
place between the carbene 9 guest and the CyD hosts
(Figure 7). Such supramolecular processes might entail
carbene 9 insertions into the C-H bonds of the CyDs,
but more likely they involve insertions into the host’s
O-H bonds (Scheme 8). However, no 9‚CyD primary
insertion products, e.g., 35, were detected. Instead, such
daughter isomers appear to have reacted further by
conceptual replacement of an HCl formula unit by H2O.
To clarify the FAB MS results, a summary of exact mass
calculations is given in Table 2.
Carbene C-H insertion products within CyDs have
never been observed.21,75 Instead, formal O-H insertion
appears to be preferred and can even be chemospecific.76
Therefore, one could envision an insertion into the O2-H
bond by carbene 9 (Scheme 8), because the -OH groups
on the C2 atoms of the smaller CyDs also point toward
the apolar cavities. The resulting O-H insertion product
35 is an R-chloroether that could undergo CyD ring
expansion to 38 or scission to seco-38. Cyclic 38 and
acyclic seco-38 might account for the observed FAB MS
signal (Figure 7, Table 2).
F IGURE 7. FAB MS spectra of the innermolecular products
formed by photolysis of diazirine 8 within (a) R-CyD and (b)
â-CyD in the presence of alkaline buffer.
In summary, chloro(phenyl)carbene (9) was generated
within the supramolecular phase and control experiments
were conducted in several organic solvents, so that the
supramolecular effects upon carbene 9 could be ascer-
tained. The question to be answered was whether CyD
hosts modify the guest or vice versa? The latter process
appears to be true for chloro(phenyl)carbene (9). The true
structure of the innermolecular product that was formed
in alkaline buffer, and then observed via FAB MS and
RP HPLC, has not yet been determined. But the co-
valently bound, modified cyclodextrin is definitely not the
acetal 6A,6B-O-(benzylidene)â-cyclodextrin (21b) (Figure
5).62 The ability of the basic medium to preserve the
innermolecular product and reduce the amount of Ph-
CHO formed seems to indicate that the latter stems from
the former, e.g., O-H insertion product 38. However, the
an aqueous suspension of 8@CyD could do no further
harm and might even present an advantage. In deference
to the instructive MeOH and i-PrOH results (eq 9;
Scheme 5), the 8@CyD ICs were suspended in an alkaline
buffer (to neutralize the HCl byproduct)71 during subse-
quent photolysis experiments. Hence, the HCl acid-
catalyzed hydrolysis of any CyD benzylidene acetals, e.g.,
21b (Figure 5),62 that may have formed would be thwarted.
Indeed, such detrimental effects were remedied by con-
ducting the photolyses in aqueous alkaline buffer (vide
infra).
The ability of the CyDs to insulate carbene 9 from the
bulk aqueous medium while still allowing HCl neutral-
ization appears to have been realized to some extent,
according to the FAB MS spectra of the 8@CyD alkaline
buffer photolysis products (Figure 7). Still, the main [M
- H]- signals are not attributable to 9‚CyDs. Instead,
the spectra clearly show appreciable amounts of PhCHO‚
CyD (not PhCHO@CyD) and only traces of HCl@CyD (or
CyD‚HCl) byproducts. Note that the covalently bound
character of each modified PhCHO‚CyD was confirmed
by control experiments and reversed-phase high-pressure
liquid chromatography (RP HPLC).
(72) PhCHO@CyDs have been studied in the solid state using 13C
CP/MAS NMR: (a) Ripmeester, J . A. J . Inclusion Phenom. 1988, 6,
31-40. (b) Garces, F. O.; Rao, V. P.; Garcia-Garibay, M. A.; Turro, N.
J . Supramol. Chem. 1992, 1, 65-72.
(73) See the Supporting Information, Figure S9.
(74) The association constants (K) for PhCHO@CyDs have been
determined: K(PhCHO@R-CyD) ) 1.02(4) × 102 M-1 and K(PhCHO@â-
CyD) ) 1.50(7) × 102 M-1. See: Guo, Q.-X.; Luo, S.-H.; Liu, Y.-C. J .
Inclusion Phenom. Mol. Recognit. Chem. 1998, 30, 173-182; Chem.
Abstr. 1998, 128, 270367.
(75) (a) Abelt, C. J .; Pleier, J . M. J . Org. Chem. 1988, 53, 2159-
2162. (b) Abelt, C. J .; Lokey, J . S.; Smith, S. H. Carbohydr. Res. 1989,
192, 119-130. (c) Smith, S. H.; Forrest, S. M.; Williams, D. C., J r.;
Cabell, M. F.; Acquavella, M. F.; Abelt, C. J . Carbohydr. Res. 1992,
230, 289-297. (d) Abelt, C. J . Insertion Reactions of Cyclodextrin-Bound
Carbenes; final report to the Petroleum Research Fund on Grant 22092-
B4; College of William and Mary; Williamsburg, VA, 1992. (e) Abelt,
C. J . Minutes Int. Symp. Cyclodextrins, 6th 1992, 649-654; Chem.
Abstr. 1994, 121, 83794.
Control FAB MS spectra of the independently pre-
pared PhCHO@(R-CyD)2 and (PhCHO@â-CyD)2 ICs were
obtained to verify that these noncovalently bound
PhCHO@CyD ICs do not register a supramolecular
(71) Photolyses of the 8@CyD ICs under an atmosphere of NH3(g) or
within a vacuum line equipped with a trap containing NaH(s) were also
considered. However, both of these strategies were rejected in favor of
using an aqueous alkaline buffer to neutralize the HCl byproduct.
(76) Krois, D.; Bobek, M. M.; Werner, A.; Ka¨hlig, H.; Brinker, U. H.
Org. Lett. 2000, 2, 315-318.
J . Org. Chem, Vol. 68, No. 12, 2003 4827

Rosenberg and Brinker
SCHEME 8. Hyd r olysis of O2-H In ser ted -CyD 35 Sh ou ld Give F AB MS Ca n d id a tes 38 a n d /or seco-38
TABLE 2. Ca lcu la ted Exa ct Ma sses for CyD In n er m olecu la r P r od u ctsa
n )
6 (R-CyD)
7 (â-CyD)b
8 (γ-CyD)
[C6(H2O)5]n
C36H60O30
972.3169
C42H70O35
1134.3698
C49H75ClO35
1258.3777
C49H76O36
1240.4116
C42H71ClO35
1170.3464
C48H80O40
1296.4226
C55H85ClO40
1420.4306
C55H86O41
1402.4645
C48H81ClO40
1332.3993
9@[C6(H2O)5]n, 9‚[C6(H2O)5]n, 35
PhCHO@[C6(H2O)5]n, 38, seco-38
HCl@[C6(H2O)5]n, [C6(H2O)5]n‚HCl
C43H65ClO30
1096.3249
C43H66O31
1078.3588
C36H61ClO30
1008.2936
a
b
(a) 12C ) 12 amu; (b) 1H ) 1.007825035 amu; (c) 35Cl ) 34.96885272 amu; (d) 16O ) 15.99491463 amu. For comparison, the exact
mass of 21b is 1222.4011 Da.
to the literature.78 1,2-Diphenylethyne (tolan) [501-65-5] was
recrystallized (3 mL of EtOH/1 g of tolan) prior to use.79 Desyl
chloride (DsCl)80 [447-31-4], benzil (39) [134-81-6], benzoin
(DsOH) [579-44-2], LiCl [7447-41-8], i-PrOH [67-63-0], ben-
zaldehyde dimethyl acetal (21d ) [1125-88-8], and (()-hy-
drobenzoin (DL-24) [655-48-1] were used without further
purification. Chlorine [7782-50-5] was dried by bubbling the
gas through a trap containing concentrated H2SO4 [7664-93-
9]. An aqueous “scrubber” was attached to the outlet of the
reaction vessel. Methanol (MeOH) [67-56-1] was dried over
magnesium and then stored over active 3 Å molecular sieves.81
R-CyD [10016-20-3] and â-CyD [7585-39-9] were recrystallized
from H2O and found to be 90.0% (w/w) and 86.5% (w/w),
respectively, by microanalysis. Centrifugation was necessary
exact mechanism of PhCHO formation within the CyD
ICs could not be pinpointed.
Exp er im en ta l Section
Gen er a l In for m a tion . 3-Chloro-3-phenyl-3H-diazirine (8)
[CAS Registry No. 4460-46-2 (registry numbers supplied by
author)] was prepared according to the literature,18a with slight
variations. Common household chlorine bleach solutions were
used as sources of sodium hypochlorite (NaOCl).27 The con-
centration (C) of NaOCl was determined via redox titration
and was unchanged after several weeks of refrigeration (ca. 2
°C). Benzaldehyde (PhCHO) was purified prior to use by
washing an Et2O solution of the aldehyde with 10% aqueous
Na2CO3 and then H2O. After predrying with saturated NaCl,
the PhCHO solution was fully dried over anhydrous MgSO4.
After suction filtration, the Et2O was removed via rotary
evaporation and the residue was vacuum distilled using a
diaphragm pump (ca. 15 mmHg) and a hot water bath.77
Benzaldehyde azine (29) [28867-76-7] was prepared according
(78) (a) Furniss, B. S.; Hannaford, A. J .; Smith, P. W. G.; Tatchell,
A. R.; Vogel, A. I. Vogel’s Textbook of Practical Organic Chemistry, 5th
ed.; Longman: Essex, 1989; p 1260. (b) Hatt, H. H. Organic Syntheses;
Wiley: New York, 1943; Collect. Vol. II, pp 395-397.
(79) Smith, L. I.; Falkof, M. M. Organic Syntheses; Wiley: New York,
1955; Collect. Vol. III, pp 350-351.
(80) Ward, A. M. Organic Syntheses; Wiley: New York, 1943; Collect.
Vol. II, pp 159-160.
(81) See ref 77, p 64.
(77) Leonard, J .; Lygo, B.; Procter, G. Advanced Practical Organic
Chemistry, 2nd ed.; Chapman & Hall: London, 1995; p 73.
4828 J . Org. Chem., Vol. 68, No. 12, 2003

Inter- and Innermolecular Reactions of Chloro(phenyl)carbene
TABLE 3. F TNMR Sp ectr om eter s Used in Th is Stu d y
gram were used: Toven,i ) 50 °C (5 min), ramp ) +10 °C/min,
Toven,f ) 230 °C (7 min), and Tinjector ) 185 °C. Preparative GC
was performed using a Varian Aerograph model 920 instru-
ment equipped with a 3.05-m poly(methyltrifluoropropylsi-
loxane) packed (aluminum) column (Alltech, 20 wt % of silicone
DC-QF1 (50% trifluoropropyl and 50% methyl) on Chromosorb
(80-100 mesh, NAW, 6.4-mm i.d.), and a thermal conductivity
detector (TTCD ) 200 °C). The following isothermal conditions
were used: Toven ) 100 °C, Tinjector ) 200 °C, and carrier flow
) 76 (mL of He)/min. The effluent was condensed using a
CO2(s)/i-PrOH trap. GC-MS analyses were conducted using a
Hewlett-Packard 6890 series GC outfitted with a 30-m poly-
(methylphenylsiloxane) capillary column (HP-5MS (95% dim-
ethyl and 5% diphenyl), 0.25-mm i.d., and 0.25-µm film-
thickness), a Hewlett-Packard 5973 mass selective detector
(TMSD ) 280 °C), and an auto split-injection system (splitter-
vent flow ) 8.0 (mL of He)/min). The following GC conditions
and temperature programs were used: Toven, i ) 80 °C (7 min),
1H Larmor 13C Larmor
frequency
frequency
Bruker
magnetic field
νo(1H)
νo(13C)
spectrometer
strength B0 (T)
(MHz)
(MHz)
AVANCE DPX-250
AC-300
AM-360
5.875
7.049
8.458
9.398
250.1
300.1
360.1
400.1
62.9
75.5
90.6
AVANCE DRX-400
100.6
when precipitates, e.g., CyD ICs, were too fine to collect via
suction filtration with a sintered funnel (Porosity 4 frit); turbid
solutions were centrifuged. The pH of aqueous solutions, e.g.,
NaHCO3/Na2CO3 buffer, were measured using a pH meter that
was calibrated using pH 7.00 buffer. Photolyses were per-
formed using a Hanovia 450-W medium-pressure Hg-arc lamp.
Both solid and liquid samples were agitated using a vortexer
and cooled by an electric fan. Photolyses were also performed
using a Heraeus TQ 718 Z4 700-W medium-pressure Hg-arc
lamp doped with FeI2 (λmax ) 370 nm) at Tsample ) ca. 15 °C
(water bath). Although made from quartz, i.e., SiO2, the lamps
were placed in water-cooled jackets that were made of boro-
silicate glass, which essentially filtered out light below λ )
300 nm. Precautions must be taken to prevent exposure to the
skin and eyes.82 Solution photolyses of 3H-diazirine 8 (concn
) 0.01-0.50 M) were performed in Schlenk tubes after three
freeze-pump-thaw cycles with argon purging.83 Sometimes,
however, samples were placed in sealed test tubes and
submerged in a water bath, and argon was slowly bubbled in
for 10 min with the aid of a second vent needle. The solid
samples were placed in either Schlenk tubes or round-bottom
flasks, sealed with rubber septa, and alternately evacuated
and purged with argon three times. Larger samples were
partially submerged in a continuously cooled water bath and
slowly spun at an angle using a modified mechanical stirrer.
The times required for complete photolysis of the 3H-diazirine
guest were occasionally short, e.g., 2 h, but usually exceeded
1 day of exposure. The CyD ICs of 3-chloro-3-phenyl-3H-
diazirine (8) were also suspended in an alkaline buffer solution.
FTNMR spectra were recorded on various spectrometers
(Table 3). J values are reported in Hz. 2-D ROESY spectra of
the dilute D2O solutions of 8@(R-CyD)2 and (8@â-CyD)2 were
obtained using a mixing time of 0.60 s, with solvent peak
presaturation.
ramp ) +10 °C/min, Toven,f ) 270 °C (5 min), and Tinjector
200 °C; Toven,i ) 140 °C (10 min), ramp ) +30 °C/min, Toven,f
)
)
220 °C (20 min), and Tinjector ) 180 °C. Microanalysis and a
manual fitting procedure using a spreadsheet program were
employed to determine the guest@host stoichiometry of the
CyD ICs as well as their crystal-water content. Microanalyses
were performed by the Mikroanalytisches Laboratorium am
Institut fu¨r Physikalische Chemie der Universita¨t Wien,
Vienna, Austria. Analytical RP HPLC was performed using a
Hewlett-Packard HP 1090 Liquid Chromatograph, with a
Hewlett-Packard 35900E interface, equipped with a Nucleosil
300-5 C8 5-µm column (290 × 4 mm, FZ Seibersdorf, Austria).
Isocratic elution giving a 70% H2O and 30% MeOH mixture
was employed at 0.5 mL/min. Product signals were observed
using an UV detector (λ ) 211 and 281 nm) and a HP 1047A
RI detector, consecutively, and compared with those from
R-CyD and â-CyD standards. FAB MS assays were performed
on a Finnigan MAT 900 spectrometer by bombarding the
photolyzed CyD ICs, in either a 1-thioglycerol (3-mercapto-
1,2-propanediol) or a diethanolamine (2,2′-iminodiethanol)
matrix, with a 20 keV beam of Cs atoms at 70 °C.
3-Ch lor o-3-p h en yl-3H-d ia zir in e (8) [4460-46-2]. CAU-
TION! (Perform behind a safety shield under dim lighting.) A
solution of LiCl (5.30 g, 0.125 mol) in DMSO (87 mL) was
rapidly stirred within a 1-L Erlenmeyer flask bearing a ground
joint. Meanwhile, NaCl (31.7 g, 0.542 mol) was dissolved in
cold 0.56 M NaOCl (296 mL, 0.166 mol) in another 1-L
Erlenmeyer flask. The salty chlorine bleach solution was
transferred to a 500-mL dropping funnel equipped with an
equilibrating sidearm and ground joints. Benzamidine hydro-
chloride hydrate (14‚HCl‚H2O, 4.365 g,84 ca. 23.7 mmol) was
added to the 1-L Erlenmeyer reaction flask, and then pentane
(50 mL) was poured in. The reaction flask was submerged into
an ice-salt bath, and rapid stirring was continued. The
NaOCl/NaCl solution was dripped in within 15 min. The
reaction mixture was stirred for an additional 30 min in the
ice-salt bath. The pentane layer was collected using a 1-L
separatory funnel. Next, the aqueous DMSO layer was ex-
tracted with Et2O (4 × 25 mL). The combined organic extracts
were washed with H2O (5 × 20 mL) and then predried with
saturated aqueous NaCl (20 mL). The organic layer was dried
over anhydrous MgSO4 and then suction-filtered through a
sintered funnel (Porosity 4 frit) into a tared 250-mL round-
bottom flask. A diluted aliquot was analyzed via GC and GC-
MS. The entire sample was carefully rotary-evaporated af-
fording 3.117 g of an odorous yellow oil. The residual oil was
chromatographed (15 g of silica gel 60, 230-400 mesh) using
pentane as eluant. The nonpolar diazirine eluted first giving
2.496 g, 69% yield of a yellow, odorous liquid after 30 min of
careful rotary evaporation.1H NMR integration showed only
traces of pentane eluant. The neat diazirine 8 could be stored
for up to four months in the freezer (-22 °C) without
For IR absorption spectroscopy, solid samples were analyzed
by pressing dilute, e.g., 1-4% (w/w), KBr pellets or by applying
a concentrated solution onto a silicon wafer and evaporating
the volatile solvent; liquid samples were analyzed as dilute
CCl4 solutions or by applying neat, viscous samples onto a
silicon wafer. UV/vis absorption spectra were recorded using
quartz cuvettes. CD spectra of aqueous solutions were obtained
using an I. S. A. J obin Yvon CD 6 circular dichrograph
spectrometer and quartz cuvettes. Analytical GC assays were
conducted using a Sichromat 1-4 series GC instrument
outfitted with a 26-m poly(dimethylsiloxane) capillary (glass)
column (silicone OV-101), a flame-ionization detector (TFID
)
250 °C), and a split-injector system (splitter-vent flow ) 1.5
(mL of He)/min). The following conditions and temperature
program were used: Toven,i ) 100 °C (16 min), ramp ) +30
°C/min, Toven,f ) 220 °C (40 min), and Tinjector ) 150 °C.
Analytical GC assays were also conducted using a Fisons 8000
series GC instrument outfitted with a 30-m poly(dimethylsi-
loxane) capillary (copper) column (PE-1, 0.32-mm i.d., and
0.25-µm film-thickness), a flame-ionization detector (TFID ) 260
°C), and a split injection system (splitter-vent flow ) 2.1 (mL
of He)/min). The following conditions and temperature pro-
(82) Note that UV-A (λ ) 320-400 nm) penetrates more deeply into
the skin than UV-B (λ ) 280-320 nm); see: Reisch, M. Chem. Eng.
News 2002, 80 (25), 38.
(83) CAUTION! Take care not to condense Ar(g) in N2(l) trap!
(84) Calculated from 3.71 g anhydrous basis.
J . Org. Chem, Vol. 68, No. 12, 2003 4829

Rosenberg and Brinker
decomposition: δH/ppm (360.1 MHz, CDCl3) 7.08-7.15 (2 H,
m), 7.35-7.41 (3 H, m); δC/ppm (90.6 MHz, CDCl3) 47.1, 126.0,
128.5, 129.3, 135.8; νjmax/cm-1 (pentane) 1570; λmax/nm (pen-
tane) 368 (ꢀ ) 2.3 × 102 M-1 cm-1); λmax/nm (EtOH) 371 (ꢀ )
2.1 × 102 M-1 cm-1).
1,2-Dich lor o-1,2-d ip h en ylet h en e (17) [13700-82-8].31
CAUTION! (Perform within a well-ventilated fume hood.) Dry
Cl2(g) was bubbled through a solution of 1,2-diphenylethyne
(tolan) (10.0 g, 56.1 mmol) in CCl4 (100 mL) for 5 min until no
more heat was evolved. The green solution was stirred
overnight whereupon a white precipitate had formed. The
mixture was refrigerated to induce more precipitation and then
suction-filtered through a sintered funnel. (A second crop of
oily material could be obtained after rotary evaporation of the
CCl4 filtrate.) Analysis by GC showed a 3:1 ratio of the tolan
dichlorides 17 in addition to tolan tetrachloride (40) and traces
of tolan. A portion of the first crop was chromatographed (silica
gel 60, 230-400 mesh) using pentane as eluant yielding
fractions of various purity, Rf 0.32 (UV; pentane). It was found
that impure samples of dichloride 17 could be separated from
tetrachloride 40 via preparative GC or via vacuum sublima-
tion. νjmax/cm-1 (KBr) 866.
F IGURE 8. Newman projection of desyl chloride dimethyl
acetal 28 showing diastereotopic methyl groups.
F IGURE 9. Newman projection of benzaldehyde diisopropyl
acetal 21e showing diastereotopic methyl groups.
(360.1 MHz, CDCl3) 7.44-7.63 (3 H, m), 8.10-8.17 (2 H, m);
δC/ppm (90.6 MHz, CDCl3) 124.0, 126.9, 129.1, 131.7, 164.6;
m/z (EI) 222 (M+, 100), 165 (99), 105 (86), 89 (8), 77 (73), 63
(12), 51 (17).
Ben zyl Ben zoa te (BzOBn ) [120-51-4]. A 50-mL three-
necked round-bottom flask, equipped with a dropping funnel,
Dimroth condenser, and drying tube, was charged with benzyl
alcohol (BnOH) (2.163 g, 20 mmol), pyridine (1.582 g, 20
mmol), and Et2O (25 mL). Benzoyl chloride (BzCl) (2.811 g,
20 mmol) was slowly dripped into the stirred reaction flask,
which was then refluxed for 2 h. After cooling, H2O (10 mL)
was added to dissolve the pyridinium chloride salts, and the
mixture was transferred to a separatory funnel. After the
aqueous layer was discarded, the ether layer was washed with
H2O (5 × 10 mL) and predried with saturated NaCl (10 mL).
The ether layer was dried over anhydrous MgSO4 overnight.
The product mixture was suction-filtered through a sintered
funnel, and the filtrate was collected and rotary-evaporated.
Analysis of the product residue by GC showed it to contain
BzOBn (84%), BzOH (7%), and BnOH (9%). Column chroma-
tography (silica gel 60, 230-400 mesh), using pentane/Et2O
(19:1) as eluant, was employed after 2-D TLC confirmed that
the BzOBn ester (Rf 0.40 (UV, I2)) did not decompose to BzOH
(Z)-17 (76%) [5216-32-0]: mp 58 °C; δH/ppm (360.1 MHz,
CDCl3) 7.13-7.23 (10 H, m); δC/ppm (90.6 MHz, CDCl3) 128.1
(CH), 128.6 (CH), 129.7 (CH), 130.8 (C), 137.3 (CCl); m/z (EI)
248 (M+, 67), 213 (41), 178 (100), 151 (17), 106 (14), 88 (24),
76 (13), 63 (5), 51 (5).
(E)-17 (24%) [951-86-0]: mp 148 °C; δH/ppm (360.1 MHz,
CDCl3) 7.36-7.46 (6 H, m), 7.61 (4 H, dm J 7.6); δC/ppm (90.6
MHz, CDCl3) 128.2 (CH), 129.0 (CH), 129.1 (CH), 129.7 (C),
137.6 (CCl); m/z (EI) 248 (M+, 40), 213 (20), 178 (100), 151
(9), 106 (7), 88 (9), 76 (7), 63 (3), 51 (3).
Bis(1-ch lor o-1-p h en ylm eth ylid en e)h yd r a zin e (18).33c-e
Meth od 1. CAUTION! (Perform within a well-ventilated fume
hood.) Dry Cl2(g) was rapidly bubbled for 3 h through a solution
of benzaldehyde azine (4.639 g, 22.3 mmol)78 in CCl4 (65 mL)
that also contained anhydrous K2CO3(s) (5.0 g, 36.2 mmol). The
product mixture was suction-filtered through a sintered funnel,
and the collected filtrate was rotary-evaporated to give a yellow
oil that solidified in the freezer (-22 °C). The product was
recrystallized from Et2O and cooled in the freezer to induce
precipitation. The crystals were suction-filtered and washed
with cold Et2O affording 0.395 g of a mixture that was
analyzed by GC: azine 18 (62%) and PPD (38%). More azine
18 was sought by analyzing the Et2O filtrate, which contained
the following compounds: PhCHO (30%), PhCN (trace), benzal
dichloride 20h (3%), (trichloromethyl)benzene (41) (33%), PPD
(31%) and azine 18 (2%).
Meth od 2. CAUTION! (Perform behind a safety shield.) A
small amount of neat diazirine 8 was photolyzed (Hanovia 450-
W) for 1-2 h. The solid product was triturated in pentane and
then suction-filtered using a Bu¨chner funnel. The off-white
residue was washed with more pentane yielding a substantial
amount of pure azine 18: mp 120-122 °C; δH/ppm (360.1 MHz,
CDCl3) 7.44-7.61 (6 H, m), 8.10-8.22 (4 H, dm J 7.7); δC/ppm
(90.6 MHz, CDCl3) 128.5, 128.6, 131.8, 133.7, 144.1; νjmax/cm-1
(KBr) 1596, 1569, 1446, 922, 761, 684; m/z (EI) 276 (M+, 46),
241 (46), 222 (17), 205 (5), 165 (17), 138 (98), 103 (52), 89 (14),
77 (100), 63 (7), 51 (19).
2,5-Dip h en yl-1,3,4-oxa d ia zole (P P D) [725-12-2].32 CAU-
TION! (Perform within a well-ventilated fume hood.) A 25-
mL round-bottom flask, equipped with a Claisen head, drop-
ping funnel, Dimroth condenser, and drying tube was charged
with hydrazine dihydrochloride (N2H4‚2HCl) (0.393 g, 3.75
mmol), pyridine (3.5 mL), and H2O (1.5 mL). Benzotrichloride
41 (1.463 g, 7.50 mmol) was slowly dripped into the stirred
reaction flask which was then refluxed for 0.5 h. After cooling,
H2O (20 mL) was added and the mixture was suction-filtered
through a Bu¨chner funnel. The brown residue was dried in a
desiccator giving 0.238 g of the crude product. The crude PPD
was cleaned via chromatography (silica gel 60, 230-400 mesh)
using Et2O as eluant, giving the orange solid PPD: δH/ppm
(Rf 0.04 (UV)) and BnOH (Rf 0.20 (UV)): mp 18-20 °C; n22
D
1.5683; δH/ppm (360.1 MHz, CDCl3) 5.39 (2 H, s), 7.32-7.49
(7 H, m), 7.56 (1 H, tt J 7.4, 1.5), 8.10 (2 H, dm J 8.0); δC/ppm
(90.6 MHz, CDCl3) 66.6, 128.1, 128.2, 128.3, 128.5, 129.7,
130.2, 132.9, 136.1, 166.3.
(1-Ch lor o-2,2-d im eth oxy-2-p h en yleth yl)ben zen e (28):
(Figure 8) δH/ppm (360.1 MHz, CDCl3) 3.15 (3 H, s), 3.56 (3
H, s), 5.31 (1 H, m), 6.93 (2 H, d J 7), 7.06 (2 H, d J 7), 7.14 (2
H, t J 7), 7.19 (4 H, t J 8), 7.28 (2 H, t J 7); δC/ppm (90.6 MHz,
CDCl3) 48.8, 50.2, 64.3, 104.0, 126.8, 127.0, 127.9, 128.2, 129.3,
129.5, 135.0, 136.8; m/z (EI) 276 (M+, trace), 245 (4), 210 (14),
178 (4), 167 (17), 165 (19), 151 (100), 125 (3), 105 (27), 91 (13),
77 (13), 59 (4), 51 (4).
(Dim eth oxym eth yl)ben zen e (21d ) [1125-88-8]: δH/ppm
(360.1 MHz, CDCl3) 3.33 (6 H, s), 5.40 (1 H, s), 7.29-7.40 (3
H, m), 7.43-7.48 (2 H, m); δC/ppm (90.6 MHz, CDCl3) 52.6,
103.2, 126.6, 128.1, 128.4, 138.1; m/z (EI) 152 (M+, 2), 121
(100), 105 (18), 91 (14), 77 (30), 51 (8).
[Di(1-m eth yleth oxy)m eth yl]ben zen e (21e) [38115-81-
0]: (Figure 9) δH/ppm (300.1 MHz, CDCl3) 1.17 (6 H, d J 6.2),
1.20 (6 H, d J 6.2), 3.90 (2 H, sept J 6.2), 5.60 (1 H, s), 7.26-
7.66 (5 H, m); δC/ppm (75.5 MHz, CDCl3) 22.5, 23.1, 67.8, 99.2,
126.7, 128.1, 128.2, 140.4.
x-(1-Ch lor o-1-p h en ylm eth yl)p en ta n es (20i). A mixture
of three diastereomers, i.e., (R*,R*)-(1-chloro-2-methylpentyl)-
benzene ((R*,R*)-20ib, 42%), (R*,S*)-(1-chloro-2-methylpen-
tyl)benzene ((R*,S*)-20ib, 42%), and (1-chloro-2-ethylbutyl)-
benzene (20ic, 16%) (Figure 10): δH/ppm (360.1 MHz, CDCl3)
0.83-2.19 (11 H, m), 4.70-4.92 (1 H, m),85 7.26-7.42 (5 H,
m); δC/ppm (90.6 MHz, CDCl3) 10.3 (20ic, CH3), 10.9 (20ic,
CH3), 14.0 (20ib, CH3), 14.2 (20ib, CH3), 15.6 (20ib, CH3), 16.6
(20ib, CH3), 19.8 (20ib, CH2), 20.0 (20ib, CH2), 21.5 (20ic,
4830 J . Org. Chem., Vol. 68, No. 12, 2003

Inter- and Innermolecular Reactions of Chloro(phenyl)carbene
H2O) and 86.5% (w/w) â-CyD (2.952 g, 2.25 mmol, 219 mL H2O)
were rapidly stirred in a room-temperature water bath under
the exclusion of light. Neat diazirine 8 (0.229 g, 1.50 mmol)
was injected into each solution and stirred overnight. Each
white suspension was separately suction-filtered through a
tared sintered funnel (Porosity 4 frit), and each residue was
washed with 3 mL of H2O. Suction was continued for 2 h to
facilitate air-drying. The loosely covered samples were placed
in a vacuum desiccator filled with anhydrous CaCl2,91 pre-
evacuated by a diaphragm pump to ca. 15 mmHg, and
evacuated by a high-vacuum oil pump to ca. 0.5 mmHg and
left overnight, giving 0.394 g of R-CyD IC (Figure 6).68,92
(Found: C, 42.96; H, 6.11; N, 1.20%, corresponding to 8@2.10R-
CyD‚6.3H2O, 11% yield) and 1.463 g of â-CyD IC93 (Found: C,
43.70; H, 6.00; N, 2.39%, corresponding to 8@0.85â-CyD‚
3.1H2O, 84% yield).94
F IGURE 10. Newman projections of (a) (1-chlorohexyl)-
benzene (20ia ),87 (b) [S-(R*,R*)]-(1-chloro-2-methylpentyl)-
benzene ([S-(R*,R*)]-20ib) and [S-(R*,S*)]-(1-chloro-2-meth-
ylpentyl)benzene ([S-(R*,S*)]-20ib), and (c) (1-chloro-2-ethyl-
butyl)benzene (20ic).88
P h otolysis of 8@(r-CyD)2 a n d (8@â-CyD)2. The CyD ICs
(0.200 g each) were transferred to round-bottom flasks, sealed
with rubber septa, and alternately evacuated and purged with
argon three times. The CyD ICs were photolyzed (Hanovia 450-
W) for 8 h. A 5-mg portion of each photolyzed CyD IC was
used for NMR (DMSO-d6) and FAB MS (-νe FAB, diethano-
lamine) analyses.70
F IGURE 11. Newman projection of [chloro(cyclohexyl)methyl]-
benzene (20j) showing diastereotopic methylidene groups.
P h otolysis of 8@(r-CyD)2 in Alk a lin e Bu ffer . The R-CyD
IC (0.150 g) was sealed via rubber septum in a 10-mL pear-
shaped flask containing a magnetic stirbar and alkaline buffer
(5 mL, pH ) 9.27).95 The white sample was photolyzed
(Heraeus 700-W) in a water bath at 12 °C for 24 h. Next, the
tan suspension was transferred to a tared centrifuge tube and
centrifuged (2.2k rpm, T ) 20 °C, 30 min), and the supernatant
was decanted and set aside. The sample tube was placed in a
vacuum desiccator filled with anhydrous CaCl2,91 preevacuated
by a diaphragm pump to ca. 15 mmHg, and evacuated by a
high-vacuum oil pump to ca. 0.02 mmHg for 2 h, giving 0.014
g of bis(1-chloro-1-phenylmethylidene)hydrazine (18) (includ-
ing traces of R-CyD), as determined by NMR (DMSO-d6). The
supernatant was diluted to 100 mL with H2O and continuously
extracted overnight with 100 mL of refluxing anhydrous CH2-
Cl2, which was subsequently concentrated and analyzed by GC,
which showed mostly benzonitrile (PhCN). Next, the extracted
aqueous layer was collected and subjected to rotary evapora-
tion (T ) 50 °C), giving residual photolyzed R-CyD IC and
buffer salts. Hence, analytical RP HPLC was also employed
to observe and quantify the modified CyD’s. Results from FAB
MS analysis revealed the presence of innermolecular prod-
ucts: m/z (-νe FAB, thioglycerol) 1077.2 ([M - H]-) (Figure
7a). Small amounts of HCl@[C6(H2O)5]n or [C6(H2O)5]n‚HCl
were also observed: m/z (-νe FAB, thioglycerol) 1007.1 ([M -
H]-) (Figure 7a).
F IGURE 12. Newman projections of [S-(R*,R*)]-2-(1-chloro-
1-phenylmethyl)oxolane ([S-(R*,R*)]-20l) and [R-(R*,S*)]-2-(1-
chloro-1-phenylmethyl)oxolane ([R-(R*,S*)]-20l).
CH2), 22.4 (20ic, CH2), 35.5 (20ib, CH2), 36.2 (20ib, CH2), 41.0
(20ib, CH), 48.4 (20ic, CH), 66.9 (20ic, CH-Cl), 69.5 (20ib,
CH-Cl),86 127.4, 127.5, 127.6, 127.7, 127.8, 127.9, 128.2, 128.3,
128.5, 140.8, 141.1, 141.2; m/z (EI) 196 (M+, 4), 161 (14), 160
(42), 131 (99), 117 (38), 91 (100), 71 (15).
[Ch lor o(cycloh exyl)m et h yl]b en zen e (20j) [28047-23-
6]:41,89 (Figure 11) Rf 0.30 (UV; pentane); δH/ppm (360.1 MHz,
CDCl3) 0.85-0.97 (1 H, qd J 12.4, J 3.7), 1.01-1.33 (4 H, m),
1.45 (1 H, dm J 12.4), 1.59-1.73 (2 H, m), 1.75-1.94 (2 H, m),
2.20 (1 H, dm J 12.4), 4.61 (1 H, d J 8.3), 7.25-7.37 (5 H, m);89
δC/ppm (90.6 MHz, CDCl3) 25.86, 25.94, 26.1, 30.3, 30.4, 45.7
(CH), 69.8 (CHCl), 127.5 (CH), 127.9 (CH), 128.3 (CH), 140.9.89
2-(1-Ch lor o-1-p h en ylm eth yl)oxola n e (20l). A 1:1 mix-
ture of two diastereomers, i.e., (R*,R*)-2-(1-chloro-1-phenyl-
methyl)oxolane ((R*,R*)-20l) and (R*,S*)-2-(1-chloro-1-phe-
nylmethyl)oxolane ((R*,S*)-20l) (Figure 12): δH/ppm (360.1
MHz, CDCl3) 1.55-2.17 (4 H, m), 3.74-3.93 (2 H, m), 4.33 (1
H, ddd J 14.0, J 7.2, J 2.5), 4.80 (1 H, dd J 4.7, J 7.2), 7.27-
7.43 (5 H, m); δC/ppm (90.6 MHz, CDCl3) 25.8, 25.9, 29.3, 29.4,
65.2, 65.8, 68.8, 69.1, 82.4, 82.8, 127.8,90 128.3, 128.4,90 128.5,
138.9, 139.1; m/z (EI) 196 (M+, 1), 161 (4), 160 (15), 125 (24),
115 (17), 104 (10), 91 (41), 77 (10), 71 (100), 63 (9), 51 (8); found
M+ 196.065(2), C11H13ClO requires 196.0655.
(1,2,2,2-Tetr a ch lor oeth yl)ben zen e (20m ) [4714-28-7]:
δH/ppm (360.1 MHz, CDCl3) 5.50 (1 H, s), 7.36-7.42 (3 H, m),
7.63-7.67 (2 H, m);37c δC/ppm (90.6 MHz, CDCl3) 74.0 (d J 156),
100.6 (s), 128.0 (d J 165), 129.9 (d J 165), 130.1 (d J 165), 134.5
(s).
(1,2,2,2-Tetr a ch lor oeth yl-1-d )ben zen e (20m -d ): m/z (EI)
243 (M+, 1), 208 (4), 173 (100), 138 (42), 126 (79), 103 (72), 75
(18), 51 (21).
P h otolysis of (8@â-CyD)2 in Alk a lin e Bu ffer . The â-CyD
IC (0.250 g) was sealed via rubber septum in a 25-mL pear-
shaped flask containing a magnetic stirbar and alkaline buffer
(10 mL, pH ) 9.27).95 The white sample was photolyzed
(Heraeus 700-W) in a water bath at 12 °C for 24 h. Next, the
tan suspension was suction-filtered through a tared sintered
funnel (Porosity 4 frit) and placed in a vacuum desiccator filled
with anhydrous CaCl2,91 preevacuated by a diaphragm pump
to ca. 15 mmHg, and evacuated by a high-vacuum oil pump to
ca. 0.02 mmHg for 2 h, giving 0.120 g of photolyzed â-CyD IC.
1
A 5-mg portion was set aside for H NMR (DMSO-d6) and FAB
MS analysis. Innermolecular products were indeed formed:
(89) Kabalka, G. W.; Wu, Z.; J u, Y. Tetrahedron 2001, 57, 1663-
1670.
(90) Two carbons.
P r ep a r a tion of 8@(r-CyD)2 a n d (8@â-CyD)2. Filtered
solutions of 90.0% (w/w) R-CyD (4.864 g, 4.50 mmol, 72 mL
(91) A rubber band was used to fasten a paper towel covering.
(92) See the Supporting Information, Figures S2 and S6.
(93) See the Supporting Information, Figure S3.
(94) The saved filtrates were analyzed separately via UV/vis (R-CyD
IC: A376 ) 0.25, d ) 1 cm; â-CyD IC: A376 ) 0.18, d ) 10 cm) and both
provided a molar absorptivity (ꢀ) value for diazirine 8 of ꢀ376 ) (14.2 (
0.5) M-1cm-1. This is 1 order of magnitude below expectation.
(95) Buffer solution was prepared by dissolving 1.060 g of Na2CO3
and 17.552 g of NaHCO3 in distilled water to afford 1 L of solution.
(85) δH/ppm ) 4.72 (0.42 H, d J 7.8), 4.83 (0.42 H, d J 6.4), and 4.90
(0.16 H, d J 7.8).
(86) In contrast to the sole 20ib signal at δc/ppm ) 41.0, two peaks
were resolved for (R*,R*)-20ib and (R*,S*)-20ib at δc/ppm ) 69.47 and
69.54.
(87) Christl, M.; Braun, M. Chem. Ber. 1989, 122, 1939-1946.
(88) Baddeley, G.; Chadwick, J .; Taylor, H. T. J . Chem. Soc. 1954,
2405-2409.
J . Org. Chem, Vol. 68, No. 12, 2003 4831

Rosenberg and Brinker
m/z (-νe FAB, thioglycerol) 1239.5 ([M - H]-) (Figure 7b). A
heavier molecule was also observed: m/z (-νe FAB, thioglyc-
erol) 1345.2 ([M - H]-) (Figure 7b). This corresponds to an
innermolecular insertion product of two carbenes 9 with one
â-CyD, which may be expected from dimeric (8@â-CyD)2. The
remaining sample, including the turbid filtrate, was dissolved
in 100 mL of H2O and continuously extracted overnight with
100 mL of refluxing anhydrous CH2Cl2, which was subse-
quently concentrated and analyzed by GC. Next, the extracted
aqueous layer was collected and subjected to rotary evapora-
tion (T ) 50 °C), giving 0.358 g of residual photolyzed â-CyD
IC and buffer salts. Hence, analytical RP HPLC was also
employed to observe and quantify the modified CyDs.
P r ep a r a tion of P h CHO@â-CyD [64691-57-2]. A filtered
solution of 86.5% (w/w) â-CyD (0.590 g, 0.45 mmol, 44 mL H2O)
was rapidly stirred in a room temperature water bath. Freshly
distilled benzaldehyde (PhCHO) (0.032 g, 0.30 mmol) was
injected into the solution and stirred for 3 days. The turbid
solution was transferred to two tared centrifuge tubes, cen-
trifuged (2.2k rpm, T ) 18 °C, 25 min), and the supernatants
were decanted. Each precipitate was triturated with 0.5 mL
of H2O and recentrifuged. After decanting the washings, the
samples were placed in
a vacuum desiccator filled with
anhydrous CaCl2,91 preevacuated by a diaphragm pump to ca.
15 mmHg, and evacuated by a high-vacuum oil pump to ca.
0.2 mmHg for 4 h, giving 0.124 g of â-CyD IC: mp 257-268
°C dec.99
P h otolysis of 8@γ-CyD in Alk a lin e Bu ffer . A sample of
the 8@γ-CyD IC96 was photolyzed in alkaline buffer,95 as above,
but using the Hanovia 450-W lamp. Analysis of a DMSO-d6
1
solution of the solid product by H NMR showed a peak at δH
Ack n ow led gm en t. Dedicated to Prof. M. Makosza
on the occasion of his 70th birthday. This work was
supported in part by the Petroleum Research Fund
(Project No. 28670-AC4), administered by the American
Chemical Society; the Fonds zur Fo¨rderung der wissen-
schaftlichen Forschung in O¨ sterreich (Project P12533-
CHE); and the Department of Chemistry, State Uni-
versity of New York at Binghamton (Graduate Fellowship
for the Summer of 1997 in support of research). The
cyclodextrins used in this study were generously pro-
vided by Cerestar USA, Inc., and Wacker Chemie,
Germany.
) 4.71 ppm (45%),97 which is consistent with a benzylidene
proton. Note that the mere inclusion of the benzylidene acetal
(dimethoxymethyl)benzene (21d ) within CyDs converted 21d
completely to PhCHO.98 Therefore, the signal is due to an
innermolecular product.
P r ep a r a tion of P h CHO@r-CyD [85888-34-2]. A filtered
solution of 90.0% (w/w) R-CyD (0.973 g, 0.90 mmol, 14.4 mL
H2O) was rapidly stirred in a room temperature water bath.
Freshly distilled benzaldehyde (0.032 g, 0.30 mmol) was
injected into the solution and stirred overnight. The white
suspension was suction-filtered through a tared sintered
funnel (Porosity 4 frit) and the residue was triturated with 3
mL of H2O. Suction was continued for 2 h to facilitate air-
drying. The loosely covered sample was placed in a vacuum
desiccator filled with anhydrous CaCl2,91 preevacuated by a
diaphragm pump to ca. 15 mmHg, and evacuated by a high-
vacuum oil pump to ca. 0.2 mmHg for 4 h, giving 0.327 g of
R-CyD IC.
Su p p or tin g In for m a tion Ava ila ble: NMR, ICD, and
FAB MS spectra of CyD ICs. This material is available free of
charge via the Internet at http://pubs.acs.org.
J O026521H
(96) See the Supporting Information, Figure S4.
(97) See the Supporting Information, Figure S8.
(98) Tee, O. S.; Fedortchenko, A. A.; Soo, P. L. J . Chem. Soc., Perkin
Trans. 2 1998, 123-128.
(99) See the Supporting Information, Figure S10.
4832 J . Org. Chem., Vol. 68, No. 12, 2003