Halogenation of cubane under phase-transfer conditions: Single and double C - H-bond substitution with conservation of the cage structure

Article abstract of DOI:10.1021/ja0032677

The first highly selective C - H chlorination, bromination, and iodination of cubane (1) utilizing polyhalomethanes as halogen sources under phase-transfer (PT) conditions is described. Isomeric dihalocubanes with all possible combinations of chlorine, bromine, and iodine in ortho, meta, and para positions were also prepared by this method; m-dihalo products form preferentially. Ab initio and density functional theory (DFT) computations were used to rationalize the pronounced differences in the reactions of 1 with halogen (Hal·) vs carbon-centered trihalomethyl (Hal₃C·) radicals (Hal = Cl, Br), For Hal₃C radicals the C - H abstraction pathway is less unfavorable (ΔG?₂₉₈ = 21.6 kcal/mol for C₃C· and 19.4 kcal/mol for Br₃C· at B3LYP/6-311+G**//B3LYP/6-31G**) than the fragmentation of the cubane skeleton via S_H2-attack on one of the carbon atoms of 1 (ΔG?₂₉₈ = 33.8 and 35.1 kcal/mol, respectively). In stark contrast, the reaction of 1 with halogen atoms preferentially follows the fragmentation pathway (ΔG?₂₉₈ = 2.1 and 7.5 kcal/mol) and C - H abstraction is more unfavorable (ΔG?₂₉₈ = 4.6 and 12.0 kcal/mol). Our computational results nicely agree with the behavior of 1 under PT halogenation conditions (where Hal₃C· is involved in the activation step) and under free-radical photohalogenation with Hal₂ (Della E. W., et al. J. Am. Chem. Soc. 1992, 114, 10730). The incorporation of a second halogen atom preferentially in the meta position of halocubanes demonstrates the control of the regioselectivity by molecular orbital symmetry.

Full text of DOI:10.1021/ja0032677

1842
J. Am. Chem. Soc. 2001, 123, 1842-1847
Halogenation of Cubane under Phase-Transfer Conditions: Single and
Double C-H-Bond Substitution with Conservation of the Cage
Structure
Andrey A. Fokin,*,† Oliver Lauenstein,‡ Pavel A. Gunchenko,† and Peter R. Schreiner*,‡,§
Contribution from the Department of Organic Chemistry, KieV Polytechnic Institute, pr. Pobedy 37,
02056 KieV, Ukraine, Georg-August UniVersity Go¨ttingen, Institute of Organic Chemistry,
Tammannstrasse 2, D-37077 Go¨ttingen, Germany, and Department of Chemistry, UniVersity of Georgia,
Athens, Georgia 30602-2556
ReceiVed September 5, 2000. ReVised Manuscript ReceiVed December 1, 2000
Abstract: The first highly selective C-H chlorination, bromination, and iodination of cubane (1) utilizing
polyhalomethanes as halogen sources under phase-transfer (PT) conditions is described. Isomeric dihalocubanes
with all possible combinations of chlorine, bromine, and iodine in ortho, meta, and para positions were also
prepared by this method; m-dihalo products form preferentially. Ab initio and density functional theory (DFT)
computations were used to rationalize the pronounced differences in the reactions of 1 with halogen (Hal•) vs
carbon-centered trihalomethyl (Hal3C•) radicals (Hal ) Cl, Br). For Hal3C radicals the C-H abstraction pathway
is less unfavorable (∆G‡ ) 21.6 kcal/mol for Cl3C• and 19.4 kcal/mol for Br3C• at B3LYP/6-311+G**//
298
B3LYP/6-31G**) than the fragmentation of the cubane skeleton via SH2-attack on one of the carbon atoms of
1 (∆G‡ ) 33.8 and 35.1 kcal/mol, respectively). In stark contrast, the reaction of 1 with halogen atoms
298
preferentially follows the fragmentation pathway (∆G‡ ) 2.1 and 7.5 kcal/mol) and C-H abstraction is
298
more unfavorable (∆G‡298 ) 4.6 and 12.0 kcal/mol). Our computational results nicely agree with the behavior
of 1 under PT halogenation conditions (where Hal3C• is involved in the activation step) and under free-radical
photohalogenation with Hal2 (Della, E. W., et al. J. Am. Chem. Soc. 1992, 114, 10730). The incorporation of
a second halogen atom preferentially in the meta position of halocubanes demonstrates the control of the
regioselectivity by molecular orbital symmetry.
Introduction
strained10 hydrocarbons ever prepared, does not react selectively
with halogen radicals.11 Bromination with elementary bromine
under photoinitiation12 induces homolytic cleavage of two C-C
bonds and gives 30% of tetrabromide 2 (Scheme 1). The free
radical chlorination of 1 is even less selective, forming complex
mixtures of oligochlorocubanes and tetrachloride 3 in 3% yield.12
The only example for a direct radical C-H substitution of the
cubane skeleton with halogen radicals was reported for the
oxidation of 1 with tert-butyl hypoiodite: Irradiation in Freon-
113 gave a mixture of polyiodinated cubanes as well as some
iodocubane.13
Recently, we demonstrated that a wide range of alkanes, from
linear or branched to polycyclic, can be halogenated selectively
and conveniently in high yields under phase-transfer (PT)
conditions. Bromination14 and even iodination15 of secondary
and tertiary C-H bonds occurs readily utilizing polyhalo-
methanes under phase-transfer conditions. The initiation step
involves the reduction of the tetrahalomethane with the OH-
anion (Scheme 2) via single electron transfer (SET); further
Haloalkanes, some of the most important starting materials
in preparative chemistry, are produced industrially via the free-
radical halogenations of alkanes;1-3 the higher homologues
generally react with low selectivities. Only some moderately
strained hydrocarbons can be halogenated selectively under free-
radical conditions because of strain relief which singles out
certain bonds or molecular moieties. Typical examples are
hydrocarbons with relatively reactive C-C bonds, such as small-
ring propellanes,4,5 bicyclobutanes,6 and bicyclohexanes.7 Highly
strained hydrocarbons generally do not undergo C-H bond
substitution with halogen atoms because C-C bond breaking
and fragmentation reactions are typically more favorable. For
instance, highly symmetrical cubane (1),8,9 one of the most
† Kiev Polytechnic Institute.
‡ Georg-August University Go¨ttingen.
§ University of Georgia. prs@chem.uga.edu.
(1) Crabtree, R. H. Chem. ReV. 1995, 95, 987-1007.
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Chem., Int. Ed. Engl. 1999, 38, 2786-2788.
10.1021/ja0032677 CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/13/2001

Halogenation of Cubane under Phase-Transfer Conditions
J. Am. Chem. Soc., Vol. 123, No. 9, 2001 1843
Scheme 1. Photoinitiated Free Radical Halogenation of
Cubane with Br2 and Cl2
our case with CBr4) without skeletal rearrangements. Iodination
takes place in a similar manner: CI4 is generated in situ through
a base-catalyzed exchange reaction (2HCI3 f CI4 + CH2I2).15
Hence, PT iodination of cubane in the presence of HCI3 affords
iodocubane 5 in 67% preparative yield (Scheme 3).
Herein we also report a new method for chlorination under
PT conditions. Chlorocubane 6 was prepared from 1 in 81%
preparative yield in the CCl4/50% aqueous NaOH PT system.
Since CCl4 can be removed easily, this method is convenient
for the selective chorination of hydrocarbons;22 it is highly
probable that the initiation step for the chlorination (Scheme 2,
Hal ) Cl) also involves SET from the OH- anion to CCl4. This
peculiar reduction (eq 1), first suggested by Sawyer and
Roberts,23 is -30.3 kcal/mol exothermic at B3LYP, in reason-
able agreement with the experimental value (-24.6 ( 7.9 kcal/
mol) calculated from the heats of formation.24,25
Scheme 2. Halogenation of Alkanes (R-H) with
Tetrahalomethanes under Phase-Transfer Conditions
In marked contrast to free-radical halogenations with Hal2,
which cause fragmentation of the cubane skeleton, PT halogena-
tions do give the desired halocubanes without rearrangement.
This must be due to the differences in the nature of the
abstracting radicals (abstraction is rate determining,16 i.e., Hal•
vs. Hal3C•), as also found for the reactions of other strained
alkanes such as cyclopropane with halogen and carbon-centered
radicals.26-30 To rationalize these findings, we studied these
reactions computationally (Scheme 4, see Computational Meth-
ods below).31 Labels A1 and A2 refer to the hydrogen abstraction
reaction with the halogen and trihalomethyl radicals, respec-
tively; direct attack of these radicals at the carbon atom of
cubane is presented by fragmentation pathways B1 and B2.
Cubane exergonically forms initial η1-complexes with the
halogen radicals (MIN1); these complexes are considered as
the ground states for the H-abstraction reactions with Hal• (for
optimized geometries see Figures 4 and 5 in the Supporting
Information). Although enthalpically favored, carbon-centered
(Hal3C•) radicals do not form initial complexes when thermal
and entropic effects are included.
Scheme 3. Monohalogenation of Cubane under
Phase-Transfer Conditions
decomposition of the tetrahalomethane radical anion leads to
the trihalomethyl radical (eq 1) which is involved in C-H
activation and propagation steps (eqs 2 and 3).16
Since PT halogenations do not involve halogen radicals, we
hoped that our method would allow clean and efficient C-H
halogenations of cubane without loss of the cubane structure.
Here we present combined experimental and computational data
that 1 and its monohalo derivatives can be halogenated in high
yields under PT conditions. These protocols are also useful for
the preparation of polysubstituted cubane derivatives,17 which
are very high-energy materials or can be used en route to
multiply substituted cubanes.
C-H bond activation proceeds through TS1 and TS2
(pathways A1 and A2) and is mildly endergonic due to the
relative instability of the resulting cubane radical 1•. In contrast,
the ring-opening pathways B1 and B2 are highly exergonic due
to strain relief in the fragmentation products MIN2 and MIN3.
This double fragmentation of the cubane cage proceeds as a
stepwise process via TS3-TS6 and intermediates MIN4 and
MIN5.
Results and Discussion
The H-abstraction (A1) and carbon-bond-breaking (B1)
pathways have relatively low barriers in the case of Hal•; the
fragmentation pathway B1 via MIN4 is favored for the Br
Halogenation of Cubane under PT Conditions. Utilizing
the tetrabromoethane/50% aqueous sodium hydroxide/CH2Cl2
PT system with 10 mol % (relative to hydrocarbon) of
Bu4N+Br- (Scheme 3),14 1 selectively gives bromocubane (4)
in 75% yield; no detectable side reactions occur (GC/MS). It is
reasonable to suggest that this reaction also involves the cubane
radical in accord with Scheme 2 (R ) cubyl and Hal ) Br).
This radical was previously generated18 in solution through
thermolysis of tert-butyl cubanepercarboxylate,19 the Huns-
diecker reaction,20 or hydrogen abstraction from cubane with
tert-butoxy radicals.13 Although the cubyl radical21 is relatively
unstable compared to other tertiary cage radicals, apparently it
can be effectively trapped in solution with halomethanes19 (in
(22) Adamantane and cyclohexane can be chlorinated under identical
conditions.
(23) Sawyer, D. T.; Roberts, J. L. Acc. Chem. Res. 1988, 21, 469-476.
(24) Chase, M. W. J. J. Phys. Chem. Ref. Data 1998, 9, 1-1951.
(25) Staneke, P. O.; Groothuis, G.; Ingemann, S.; Nibbering, N. M. J.
Mass Spectrom. 1995, 142, 83-93.
(26) Russell, G. A. In The Chemistry of Alkanes and Cycloalkanes; Patai,
S., Rappoport, Z., Eds.; John Wiley & Sons: Chichester, 1992; p 983.
(27) Roberts, J. D.; Dirstine, P. H. J. Am. Chem. Soc. 1945, 67, 1281-
1283.
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3331.
(29) Tanko, J. M.; Suleman, N. K. J. Am. Chem. Soc. 1994, 116, 5162-
5166.
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112, 5557-5562.
(16) Lauenstein, O.; Fokin, A. A.; Schreiner, P. R. Org. Lett. 2000, 2,
2201-2204.
(17) Zhang, M.-X.; Philip, E.; Eaton, P. E.; Gilardi, R. Angew. Chem.
2000, 112, 422-426.
(18) Tsanaktsidis, J.; Eaton, P. E. Tetrahedron Lett. 1989, 6967-6968.
(19) Luh, T.-Y.; Stock, L. M. J. Org. Chem. 1978, 43, 3271-3273.
(20) Cristol, S. J.; Firth, W. C., Jr. J. Org. Chem. 1961, 26, 280-282.
(21) Schubert, W.; Yoshimine, M.; Pacansky, J. J. Phys. Chem. 1981,
85, 1340-1342.
(31) The transformations shown in Scheme 4 were computed also at the
MP2/6-31G**. The geometries (see Supporting Information) are very similar
((0.02 Å) to those obtained at DFT. As some structures (e.g., TS3-TS6)
show substantial spin contamination at MP2 ( S2 ) 0.8-1.0), the projected
energies were used in energetic evaluations; the PMP2 ∆E values are very
similar to those obtained at DFT.

1844 J. Am. Chem. Soc., Vol. 123, No. 9, 2001
Fokin et al.
Scheme 4. Computed H-Abstraction (A1 and A2) and Bond Fragmentation (B1 and B2) Pathways for the Reaction of Cubane
with Halogen and Trihalomethyl Radicals (Hal ) Cl, first line, and Hal ) Br, second line, ∆G298 values in kcal/mol at B3LYP/
6-311+G**//B3LYP/6-31G**)
radical both kinetically and thermodynamically. H-abstraction
has a much lower barrier for chlorine than for bromine radicals
(4.6 vs 12.0 kcal/mol, respectively). This is consistent with the
free-radical chlorination of cubane, where chlorocubanes as well
as open-cage products form (vide supra), while free-radical
bromination exclusively leads to ring-opened fragmentation
products.12
fragment (in the cubyl radical the nonbonding 1,4-distance is
2.64 Å at B3LYP/6-31G**). A halogen substituent destabilizes
the radical in the para position (Figure 1) by about 1 kcal/mol,
due to antibonding MO interactions of the collinear bonds. This
finding is in agreement with the interpretation that a cross-
diagonal 1,4-bond through the cubane cage cannot be
realized.35-37 However, as we have noted for the C-H substitu-
tion reactions of adamantane (the secondary radical is 2.5 kcal/
mol more stable, but tertiary products predominate) under
identical conditions, the radical stabilities do not necessarily
reflect the product distributions.14-16,38 Furthermore, there is very
little orbital interaction between the radical site and the halogen
bonds or orbitals in the singly occupied orbitals (SOMOs).
Although the relative energies of the radical intermediates agree
nicely with our product distributions (Figure 1), is clear that
this cannot be the only factor. Orbital symmetries and polar
effects must be considered.39
The hydrogen abstraction pathway A2 with the Hal3C• radicals
(via TS2) has substantially lower barriers (21.6 kcal/mol for
Cl3C• and 19.4 kcal/mol for Br3C•) than the direct attack on
carbon through TS5 (B2, the barriers are 33.8 and 35.1 kcal/
mol, respectively). Hence, the computations demonstrate that
although cage fragmentation with the Hal3C• radicals is favored
thermodynamically, the cubane radical 1• may form under
kinetic control.
The Halogenation of Halocubanes. The effects of halogen
substitution on the reactivity of cubane C-H bonds are expected
to be high due to its unique shape and structural rigidity.32,33
A
When considering orbital interactions we first have to decide
whether the CHal3 radicals are electrophilic or nucleophilic, i.e.,
if they interact more with the HOMO or the LUMO of the
hydrocarbon. Matching the orbital energies does not help much
in this respect as the interactions with filled shells may be
attractive or repulsive, depending on the overall energy change.
The reactivity toward the positively charged hydrogens of
cubane (natural bond orbital (NBO) charge on H: +0.20 e,
Figure 2) indicates that the trihalomethyl radicals are probably
peculiarity are cross-cage34 para (or through bond) inter-
actions,35-37 where the SOMO is collinear to the C-Hal
(32) Honegger, E.; Heilbronner, E.; Urbanek, T.; Martin, H.-D. HelV.
Chim. Acta 1985, 68, 23-38.
(33) Irngartinger, H.; Strack, S.; Gredel, F.; Dreuw, A.; Della, E. W.
Eur. J. Org. Chem. 1999, 1253, 3-1257.
(34) Adcock, W.; Binmore, G. T.; Krstic, A. R.; Walton, J. C.; Wilkie,
J. J. Am. Chem. Soc. 1995, 117, 2758-2766.
(35) Eaton, P. E.; Tsanaktsidis, J. J. Am. Chem. Soc. 1990, 112, 876-
878.
(36) Hassenru¨ck, K.; Radziszewski, J. G.; Balaji, V.; Murthy, G. S.;
McKinley, A. J.; David, D. E.; Lynch, V. M.; Martin, H.-D.; Michl, J. J.
Am. Chem. Soc. 1990, 112, 873-874.
(37) Hrovat, D. A.; Borden, W. T. J. Am. Chem. Soc. 1990, 112, 875-
876.
(38) Aubry, C.; Holmes, J. L.; Walton, J. C. J. Phys. Chem. A 1998,
102, 1389-1393.
(39) Hrovat, D. A.; Borden, W. T. J. Am. Chem. Soc. 1994, 116, 6459-
6460.

Halogenation of Cubane under Phase-Transfer Conditions
J. Am. Chem. Soc., Vol. 123, No. 9, 2001 1845
Figure 1. The relative stabilities (kcal/mol) of isomeric halocubyl
radicals from B3LYP/6-31G** data. SOMOs of the radicals for Hal )
Cl.
Figure 3. The activation enthalpies (∆H‡298 K, kcal/mol) for hydrogen
abstraction from cubane and halocubanes with trihalomethyl radicals
at B3LYP/6-311+G** (H, C, Cl, Br), 3-21G* (I)//B3LYP/6-31G**
(H, C, Cl, Br), and 3-21G* (I).
in TS2 (Hal ) Cl, Figure 2), where the chlorine atoms of the
trichloromethyl moiety are essentially neutral due to π-back-
bonding to help bind the migrating positively polarized hydrogen
atom. The polarization in the product chlorocubane is, apart
from the almost neutral C-Cl bond, almost unchanged relative
to 1.
The reaction enthalpies for hydrogen abstraction from 1 and
halocubanes 4-6 were computed at the B3LYP level (Figure
3). The computed activation energies are very similar for Cl3C•
and Br3C• (∆H‡298, 11-15 kcal/mol) but are much lower for
I3C• (∆G‡ ) 6-8 kcal/mol), also due to substantial polarization
of the TSs for H-abstraction.39 The developing negative charge
on the trihalomethyl carbon atom in the course of H-abstraction
is much higher for Hal ) I (δ ) -0.37, due to its high
polarizability) than for the other halogens (Hal ) Br, δ ) -0.19;
Hal ) Cl, δ ) +0.07). This is in line with the increase of the
relative stabilities of the trihalomethyl anions (Cl3C- < Br3C-
< I3C-): The isodesmic equation Br3CH + Cl3C- f Br3C- +
Cl3CH is only slightly exothermic (∆E ) -6.3 kcal/mol at
B3LYP, -14 ( 9 experimental, based on the heats of forma-
tion24,45,46); I3CH + Cl3C- f I3C- + Cl3CH gives ∆E ) -8.3
kcal/mol. As a consequence, the hydrogen abstraction barriers
are the lowest for CI3 and the highest for CCl3 (Figure 3).
All halocubanes react more slowly under PT conditions
relative to 1; iodocubane 5 is the most reactive among the three
halocubanes studied. As demonstrated in Figure 3, the hydrogen
abstraction from the m-C-H positions of halocubanes is
associated with the lowest barriers for all Hal3C radicals and
the regioselectivity is meta > ortho > para. This parallels the
Figure 2. Selected molecular orbitals of cubane (1), chlorocubane (6),
and the transition structure for H-abstraction (TS2); natural bond orbital
(NBO) charges (right); constant electrostatic potential around the
chlorine substituent in 6 (gray, bottom right).
very slightly nucleophilic in this reaction.40 This also agrees
with the experimental findings that electrophilic halogen radicals
(Cl• and Br•) attack the slightly negatively charged (-0.20 e)
carbons of 1, leading to cage opening (vide supra); note that
the HOMO coefficients on the carbon-carbon bonds in 6 are
large but negligible on the hydrogens. Hence, the interaction
of •CHal3 with the LUMO of 6 should be important (Figure 2)
for determining the selectivity of the second hydrogen abstrac-
tion. Due to the inherent C3V symmetry of monohalogenated
cubanes, there is a negligible LUMO coefficient on the hydrogen
in the para position and products derived from this mode of
attack should be a minor component (irrespective of statistical
factors). The ortho and meta coefficients are of similar
magnitude.
•
•
(42) Klenke, K.; Metzger, J. O. Angew. Chem., Int. Ed. Engl. 1988, 27,
1168-1170.
(43) Wu, J. Q.; Beranek, I.; Fischer, H. HelV. Chim. Acta 1995, 78, 194-
214.
(44) Quiclet-Sire, B.; Zard, S. Z. J. Am. Chem. Soc. 1996, 118, 9190-
9191.
Polarization also is important in the transition states for
hydrogen abstraction.41-44 This is evident from the NBO charges
(45) Page, F. M.; Goode, G. C. NegatiVe Ions and the Magnetron;
Wiley: New York, 1969.
(40) Heberger, K.; Lopata, A. J. Org. Chem. 1998, 63, 8646-8653.
(41) Giese, B.; Hartung, J. Chem. Ber. 1992, 125, 1777-1779.
(46) Paulino, J. A.; Squires, R. R. J. Am. Chem. Soc. 1991, 113, 5573-
5580.

1846 J. Am. Chem. Soc., Vol. 123, No. 9, 2001
Fokin et al.
Scheme 5. Halogenation of Halocubanes under PT
Conditions
pronounced meta selectivity due to molecular orbital symmetry
control and polarization in the transition structures.
Computations also reveal substantial differences in the
interactions of cubane with halogen (Hal•) and carbon-centered
(Hal3C•) radicals. For the Hal3C radicals the C-H abstraction
pathway is much more favorable than the fragmentation of the
cubane skeleton via SR2-attack on a carbon atom. In contrast,
the reaction of 1 with Hal• preferentially leads to ring-opening
and fragmentation.
In summary, we demonstrate that our newly developed phase-
transfer protocol for the activation of secondary and tertiary
aliphatic C-H bonds is a mild and hence selective method
applicable also to highly strained alkanes such as cubane. The
original protocol for bromination and iodination can also be
adopted for aliphatic chlorination reactions which can be
conducted with unparalleled selectivities.
Computational Methods
All computations were performed with the Gaussian98 program.48
Geometries were fully optimized at the density functional three-
parameter hybrid B3LYP functional49,50 and at the Møller-Plesset51,52
(MP2, not reported here, included in the Supporting Information) levels
of theory; we used the 3-21G(d) basis set for iodine and 6-31G(d,p)
for all other atoms. The ∆H‡298 values computed at our level of theory
for the H-abstractions with Cl3C• from cyclohexane (14.8 kcal/mol)
and (CH3)3CH (9.9 kcal/mol) are in good agreement with experimental
values (13.2 and 10.2 kcal/mol, respectively53,54). Thus, DFT appears
suitable for such types of reactions.16,55 As MP2 sometimes suffers from
spin contamination (we found S2 values of 0.75-0.99 for doublets),
we used spin-projected PMP2 energies. Harmonic vibrational frequen-
cies were computed at the B3LYP level to ascertain the nature of all
stationary points (NIMAG ) 0 for minima and 1 for transition
structures). Zero-point vibrational energies (ZPVE, unscaled), thermal
corrections to enthalpies, and free energies were used to improve our
energy evaluations. MP2 vibrational frequencies were not computed
due to the large size of the molecules. Unless noted otherwise, the
energies discussed in this paper refer to B3LYP/6-311+G** (C, H,
Cl, Br); 3-21G* (I)//B3LYP/6-31G** (C, H, Cl, Br); and 3-21G* (I).
Absolute DFT and MP2 energies (not discussed) as well as xyz-
coordinates for optimized species are collected in the Supporting
Information.
above-mentioned relative stabilities of the halocubyl radicals
(m-halocubyl• > o-halocubyl• > p-halocubyl•).
These computational predictions were verified with the
preparation of dihalocubanes from monohalocubanes (Scheme
5). The second halogenation requires much longer reaction times
due to the deactivation of the halocubanes (cf. Figure 3); all
possible isomeric dihalocubanes (7-15) were found in variable
proportions (Scheme 5). The ortho:meta:para ratios determined
from GC/MS and NMR data are 0.63-0.70:1.00:0.09-0.10.47
The preference for meta substitution agrees nicely with our
computational assessment (Figure 3).
It seemed feasible to extend our PT approach to the first
preparation of mixed halocubanes (heterohalocubanes, Scheme
5) because halogen exchange does not occur under these
conditions. The dihalocubanes (16-24) containing all possible
combinations of chlorine, bromine, and iodine in the ortho, meta,
and para positions of cubane were prepared and characterized
spectroscopically. The regioselectivities for the halogenations
follow the above pattern, i.e., meta substitution prevails, while
the para isomers form in less than 7% yield on average.
Conclusions
Experimental Section
Cubane could be selectively halogenated under PT conditions
involving Hal3C radicals in the C-H activation step; cubane
radical intermediates are trapped effectively by halomethanes.
These results are distinctly different from the reactions of cubane
with elementary halogens under photoinitiation, where products
form from cage-opening. The introduction of a second halogen
atom under PT conditions is also preparatively useful, leading
to homo or hetero dihalocubanes without halogen exchange
reactions. Introducing a second halogen atom into cubane shows
NMR spectra were recorded on a Varian VXR-300 spectrometer at
300 (1H NMR) and 75 MHz (13C NMR) in CDCl3. The chemical shifts
are given on the δ scale in ppm; the internal standard was HMDS. The
GC/MS analyses were performed on an HP5890 with an H5971A
detector (HP GC-MS capillary column 50 m-0.2 mm, Ultra1, Silicone,
80-250 °C). The compounds gave satisfactory elemental analysis and
showed adequate IR and DEPT 13C NMR spectra. The yields for the
dihalocubanes were determined as follows: o-Dihalocubanes could be
separated preparatively (column chromatography, see text) from m- and
p-dihalocubanes which could be identified unambiguously by their 1H
and 13C NMR spectra. Their relative proportions were determined by
GC/MS.
A. Bromination of Cubane (1). A mixture of 208 mg (2 mmol) of
1, 1.28 g (4 mmol) of CBr4, 5 mL of CH2Cl2, 3 mL of 50% aqueous
NaOH, and 25 mg of tetrabutylammonium bromide was stirred at room
temperature for 24 h,56 then diluted with 10 mL of water and extracted
with CH2Cl2 (3 × 5 mL). The extracts were washed with water and
(47) These values were not corrected by calibration of the relative
abundances of the components. The signals of ortho and para isomers are
not fully separated in the GC; the ratio of these isomers was obtained from
the integration of NMR spectra of the mixture of ortho and para isomers,
obtained by preparative LC. Reddy, D.; Sivakumar, S. G. P.; Eaton, P. E.
J. Org. Chem. 1989, 54, 722-723.
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Stratmann, R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels, A.
D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.; Barone, V.; Cossi,
M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford, S.;
Ochterski, J.; Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.; Malick,
D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Cioslowski, J.;
Ortiz, J. V.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi,
I.; Gomperts, R.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.;
Peng, C. Y.; Nanayakkara, A.; Gonzalez, C.; Challacombe, M.; Gill, P. M.
W.; Johnson, B.; Chen, W.; Wong, M. W.; Andres, J. L.; Gonzalez, C.;
Head-Gordon, M.; Replogle, E. S.; Pople, J. A. Gaussian 98, ReVision A.7;
Pittsburgh, PA, 1998.
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pedia of Computational Chemistry; Schleyer, P. v. R., Allinger, N. L., Clark,
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Halogenation of Cubane under Phase-Transfer Conditions
J. Am. Chem. Soc., Vol. 123, No. 9, 2001 1847
dried over Na2SO4; excess CH2Cl2 was removed at atmospheric
pressure. Column chromatography (silica/pentane) gave 20 mg of 1
and 274 mg (75%) of bromocubane (4) identical to the material
described earlier by NMR57,58 and MS59 data.
B. Iodination of Cubane (1). A mixture of 208 mg (2 mmol) of 1,
1.6 g (4 mmol) of HCI3, 5 mL of CH2Cl2, and 3 g of solid NaOH was
stirred at room temperature for 36 h, then diluted with 10 mL of CH2-
Cl2 and filtered; the solid was washed with CH2Cl2 and the solvent
removed at atmospheric pressure. The residue was separated by column
chromatography (silica/pentane): 25 mg of cubane 1 were recovered;
308 mg (67%) of iodocubane 5 were isolated. The material was identical
to that described earlier by NMR60 data. MS m/z (%) 230 (1), 204 (4),
127 (22), 103 (40), 77 (100), 51 (33).
C. Chlorination of Cubane (1). A mixture of 208 mg (2 mmol) of
1, 15 mL of CCl4, 5 mL of 50% aqueous NaOH, and 25 mg of
tetrabutylammonium bromide was stirred under reflux for 5 days,
diluted with 10 mL of water, and extracted with CCl4 (3 × 5 mL). The
extracts were washed with water and dried over Na2SO4, and excess
CCl4 was removed at atmospheric pressure with use of a Vigreux
column. Separating by column chromatography (silica/pentane) gave
10 mg of 1 and 227 mg (81%) of chlorocubane 6, which was identical
to the material described earlier by MS12 data. 1H NMR: 4.18 (m, 3H),
4.03 (m, 4H). 13C NMR: 72.76, 56.69, 48.22, 43.87. Mp ) 28-29
°C.
D. Bromination of Bromocubane (4). A mixture of 183 mg (1
mmol) of 4, 640 mg (2 mmol) of CBr4, 3 mL of CH2Cl2, 1.5 mL of
50% aqueous NaOH, and 10 mg of tetrabutylammonium bromide was
allowed to react following procedure A (5 days); after column
chromatography, 25 mg of 4 was recovered and 183 mg (65%) of a
mixture of 1,2- (7), 1,3- (8), and 1,4- (9) dibromocubanes was obtained
in a ratio of 7:8:9 ) 0.63:1.00:0.09 according to GC/MS and NMR
data. 1,2-Dibromocubane (7): 1H NMR δ 4.34 (m, 4H), 4.19 (m, 2H);
13C NMR δ 67.9, 55.11, 46.19; MS m/z (%) 262 (0.5%), 236 (1%),
182 (2%), 156 (5%), 102 (100%), 76 (10%), 50 (8%). 1,3-Dibromocu-
bane (8): 1H NMR δ 4.47 (m, 2H), 4.11 (m, 2H), 4.18 (m, 2H); 13C
NMR δ 65.25, 58.27, 57.41, 43.18; MS m/z (%) 262 (0.4%), 236 (2%),
182 (2%), 156 (5%), 102 (100%), 76 (8%), 50 (6%). 1,4-Dibromocu-
bane was identical to the material described earlier by NMR data.32,58
E. Iodination of Iodocubane (5). A mixture of 115 mg (0.5 mmol)
of iodocubane 5, 0.79 g (2 mmol) of HCI3, 5 mL of CH2Cl2, and 1.5
g of solid NaOH was stirred at room temperature for 3 days; then the
reaction mixture was filtered and an additional amount of 0.79 g (2
mmol) of HCI3, 3 mL of CH2Cl2, and 1.5 g of solid NaOH was added
to the reaction mixture. After another 5 days of stirring, the reaction
mixture was worked up as in B; 16 mg of 5 were recovered and 123
mg (69%) of a mixture of 1,2- (10), 1,3- (11), and 1,4- (12)
diodocubanes was obtained in a ratio of 10:11:12 ) 0.70:1.00:0.08
according to GC/MS and NMR data. 1,2-Diiodocubane (10):61 1H NMR
δ 4.43 (m); 13C NMR δ 57.45, 48,72, 45.94; MS m/z (%) 228 (0.3%),
204 (3%), 127 (2%), 102 (100%), 76 (14%), 50 (9%). 1,3-Diiodocubane
(11): 1H NMR δ 4.46 (m, 4H), 4.33 (m, 2H); 13C NMR δ 65.80, 57.69,
48.76, 32.21; MS m/z (%) 228 (0.5%), 204 (4%), 127 (6%), 102 (100%),
76 (16%), 50 (12%). 1,4-Diiodocubane (12) was identical to the material
described earlier by NMR and MS data.58,62
chromatography, was obtained 35 mg of unreacted 6 and 95 mg (55%)
of a mixture of 1,2- (13), 1,3- (14), and 1,4- (15) dichlorocubanes in
a ratio of 13:14:15 ) 0.70:1.00:0.09 identified according to GC/MS
and NMR data. 1,2-Dichlorocubane (13): 1H NMR δ 4.17 (m, 4H),
4.03 (m, 2H); 13C NMR δ 69.94, 53.35, 44.53; MS m/z (%) 172 (0.3%,
137 (12%), 112 (19%), 102 (100%), 75 (21%), 50 (14%). 1,3-
Dichlorocubane (14): 1H NMR δ 4.32 (m, 2H), 4.17 (m, 2H), 4.03
(m, 2H); 13C NMR δ 67.53, 64.59, 56.93, 39.67; MS m/z (%) 172
(0.7%), 146 (18%), 136 (21%), 112 (27%), 102 (100%), 75 (38%), 51
(23%). 1,4-Dichlorocubane (15) was identical to NMR and MS literature
data.32
G. Iodination of Bromocubane (4). From 183 mg (1 mmol) of
bromocubane 4, following procedure E (4 days), 53 mg of unreacted
4 and 151 mg (49%) of a mixture of 1,2- (16), 1,3- (17), and 1,4- (18)
iodobromocubanes was obtained in a ratio of 16:17:18 ) 0.68:1.00:
0.09 according to GC/MS and NMR data. 1-Iodo-2-bromocubane
(16): 1H NMR δ 4.42 (m, 2H), 4.35 (m, 2H), 4.30 (m, 2H); 13C NMR
δ 57.25, 54.94, 53.10, 48.64, 45.99, 45.22; MS m/z (%) 310 (0.3%),
282 (1%), 228 (2%), 204 (4%), 156 (5%), 127 (8%), 102 (100%), 76
(10%), 50 (7%). 1-Iodo-3-bromocubane (17): 1H NMR δ 4.48 (m, 2H),
4.27 (m, 2H), 4.22 (m, 2H); 13C NMR δ 65.59, 60.55, 57.72, 57.24,
46.01, 30.09; MS m/z (%) 282 (0.8%), 228 (0.5%), 204 (2%), 156 (3%),
127 (6%), 102 (100%), 76 (9%), 50 (4%). 1-Iodo-4-bromocubane (18)
was described previously:63 13C NMR δ 63.37, 57.00, 54.81, 31.12;
MS m/z (%) 282 (0.8%), 228 (0.5%), 204 (2%), 156 (3%), 127 (6%),
102 (100%), 76 (9%), 50 (4%).
H. Bromination of Chlorocubane (6). From 137 mg (1 mmol) of
chlorocubane 6, following procedure D (4 days), 17 mg of unreacted
6 and 154 mg (71%) of a mixture of 1,2- (19), 1,3- (20), and 1,4- (21)
bromochlorocubanes was obtained. The ratio of 19:20:21 ) 0.67:1.00:
0.09 according to GC/MS and NMR data. 1-Bromo-2-chlorocubane
(19): 1H NMR δ 4.26 (m, 4H), 4.12 (m, 2H); 13C NMR δ 67.94, 54.99,
53.60, 53.43, 46.47, 44.42; MS m/z (%) 216 (0.3%), 192 (3%), 156
(5%), 136 (7%), 112 (9%), 102 (100%), 75 (18%), 51 (11%). 1-Bromo-
3-chlorocubane (20): 1H NMR δ 4.01 (m, 2H), 4.23 (m, 2H), 4.10 (m.
2H); 13C NMR δ 68.77, 64.99, 57.56, 57.48, 56.74, 41.49; MS m/z
(%) 216 (0.2%), 192 (4%), 156 (6%), 136 (5%), 112 (8%), 102 (100%),
75 (15%), 51 (10%). 1-Bromo-4-chlorocubane (21) was identical to
NMR and MS spectra described previously.12
M. Iodination of Chlorocubane (6). From 137 mg (1 mmol) of
chlorocubane 6, following procedure E, 50 mg of unreacted 6 and 143
mg (54%) of a mixture of 1,2- (22), 1,3- (23), and 1,4- (24)
iodochlorocubanes was obtained in a ratio of 22:23:24 ) 0.65:1.00:
0.09 according to GC/MS and NMR data. 1-Iodo-2-clorocubane (22):
1H NMR δ 4.33 (2H), 4.23 (m, 2H), 4.18 (m, 2H); 13C NMR δ 74.82,
57.12, 53.23, 48.85, 45.04, 44.87; MS m/z (%) 264 (0.3%), 228 (0.7%),
204 (2%), 127 (7%), 102 (100%), 75 (21%), 51 (12%). 1-Iodo-3-
chlorocubane (23): 1H NMR δ 4.41 (m, 2H), 4.29 (m, 2H), 4.14 (m,
2H); 13C NMR δ 70.68, 65.27, 57.96, 56.72, 44.25, 29.07; MS m/z
(%) 238 (1%), 204 (3%), 127 (5%), 112 (6%), 102 (100%), 75 (21%),
51 (12%). 1-Iodo-4-chlorocubane (24) was prepared previously:18 13
C
NMR δ 70.62, 56.58, 53.15, 29.18; MS m/z (%) 238 (1%), 204 (3%),
127 (5%), 112 (6%), 102 (100%), 75 (21%), 51 (12%).
F. Chlorination of Chlorocubane (6). From 137 mg (1 mmol) of
chlorocubane 6, following procedure C (10 days) after column
Acknowledgment. This work was supported by the Volk-
swagenstiftung (Grant I/74614). We are grateful to the HRLS
(Stuttgart) for generous allotments of computer time. P.R.S.
thanks the Deutsche Forschungsgemeinschaft and the Fonds der
Chemischen Industrie as well as Prof. Dr. A. de Meijere for
continuing support.
(56) The reaction conditions were not optimized. A substantial shortening
of the reaction times for the bromination and iodination of cubanes was
observed at higher temperatures.
(57) Edward, J. T.; Farrell, P. G.; Langford, G. E. J. Am. Chem. Soc.
1976, 98, 3075-3085.
(58) Axenrod, T.; Liang, B.; Bashir-Hashemi, A.; Dave, P. R.; Reddy,
D. S. Magn. Reson. Chem. 1991, 29, 88-91.
Supporting Information Available: Tables with absolute
energies, including ZPVEs, as well as thermal corrections to
enthalpies and xyz-coordinate energies of all computed species
and Figures 4S and 5S depicting ground and transition structures
for different halogenation reactions described in the present work
(PDF). This material is available free of charge via the Internet
at http://pubs.acs.org.
(59) Luh, S. J. Org. Chem. 1977, 42, 2790.
(60) Abeywickrema, R. S.; Della, E. W. J. Org. Chem. 1980, 45, 4226-
4229.
(61) 1,2-Diiodocubane was first prepared by Eaton et al. (Eaton, P. E.;
Maggini, M. J. Am. Chem. Soc. 1988, 110, 7230-7232), but was not
separated from byproducts.
(62) Reddy, D. S.; Sollot, G. P.; Eaton, P. E. J. Org. Chem. 1989, 54,
722-723.
(63) Moriarty, R. M.; Khosrowshahi, J. S.; Dalecki, T. M. Chem.
Commun. 1987, 675-676.
JA0032677