Buttressing effects on haloarene deprotonation: A merely kinetic or also thermodynamic phenomenon?

Article abstract of DOI:10.1021/ol0480022

(Chemical equation presented) (2,6-Dichlorophenyl)- and (2,6-dibromophenyl)trialkylsilanes undergo hydrogen/metal interconversion preferentially at the 4- rather than 3-position. However, the organometallic species generated by such a meta metalation are thermodynamically less stable (i.e., more basic) than those that would result from an ordinary ortho metalation . This was demonstrated by equilibration experiments based on permutational halogen/ metal interconversion. A new buttressing effect can explain the unprecedented regioselectivity. It is supported by X-ray structures that reveal marked deformations of the benzene ring in halophenylsilanes.

Full text of DOI:10.1021/ol0480022

ORGANIC
LETTERS
2004
Vol. 6, No. 24
4591-4593
Buttressing Effects on Haloarene
Deprotonation: A Merely Kinetic or Also
Thermodynamic Phenomenon?
Joanna Gorecka, Christophe Heiss, Rosario Scopelliti, and Manfred Schlosser*
Institute of Chemical Sciences and Engineering (ISIC), Ecole Polytechnique Fe´de´rale,
(BCh), CH-1015 Lausanne, Switzerland
manfred.schlosser@epfl.ch
Received September 30, 2004
ABSTRACT
(2,6-Dichlorophenyl)- and (2,6-dibromophenyl)trialkylsilanes undergo hydrogen/metal interconversion preferentially at the 4- rather than 3-position.
However, the organometallic species generated by such a "meta metalation" are thermodynamically less stable (i.e., more basic) than those
that would result from an ordinary "ortho metalation". This was demonstrated by equilibration experiments based on permutational halogen/
metal interconversion. A new buttressing effect can explain the unprecedented regioselectivity. It is supported by X-ray structures that reveal
marked deformations of the benzene ring in halophenylsilanes.
Buttressing effects1-5 have so far been invoked only in
relation to molecular mobility. For example, the introduction
of bulky groups R into the meta positions of biphenyls,
carrying ortho substituents X and X′, compromises the
flexibility of the latter and, by increasing the repulsive forces
at the coplanar transition state, raises the torsional barrier.1
Similar arguments were put forward to rationalize the
unusually high (approximately 32 kcal/mol) inversion barrier
of the 1,2,3,4-tetramethylcyclooctatetraene ring.5,6 At the
planar transition state, each methyl group is squeezed in
by its neighbors and thus has been confined to rigidity
(Scheme 1).
lithium 2,2,6,6-tetramethylpiperidide (LITMP) or sec-butyl-
lithium, were unprecedented until a short while ago. Al-
though 1,3,5-tribromobenzene readily undergoes hydrogen/
metal permutation at the 2-position,9 (2,4,6-tribromo-
phenyl)trimethylsilane proved to be completely inert toward
LITMP, even when in the presence of N,N,N′,N′′,N′′-
pentamethyldiethylenetriamine (PMDTA) and potassium tert-
butoxide.7 (2,6-Dibromophenyl)triethylsilane and its 2,6-
dichloro analogue do experience deprotonation when treated
with strong bases, but mainly, if not exclusively, at the
Buttressing effects on acid-base reactions,7,8 in particular
the proton transfer from haloarenes to strong bases such as
Scheme 1. Typical Buttressing Effects Restraining the Internal
Molecular Mobility
(1) Adams, R.; Yuan, H. C. Chem. ReV. 1933, 12, 261-338.
(2) Chien, S. L.; Adams, R. J. Am. Chem. Soc. 1934, 56, 1787-1792.
(3) Westheimer, F. H. In Steric Effects in Organic Chemistry; Newman,
M. S., Ed.; Wiley: New York, 1956; pp 523-555 (spec. 552-554).
(4) Theilacker, W.; Hopp, R. Chem. Ber. 1959, 92, 2293-2301.
(5) Paquette, L. A.; Gardlik, J. M. J. Am. Chem. Soc. 1980, 102, 5033-
5035.
(6) Paquette, L. A.; Gardlik, J. M.; Johnson, L. K.; McCullough, K. J.
J. Am. Chem. Soc. 1980, 102, 5026-5032.
(7) Mongin, F.; Marzi, E.; Schlosser, M. Eur. J. Org. Chem. 2001, 2771-
2777.
(8) Heiss, C.; Marzi, E.; Schlosser, M. Eur. J. Org. Chem. 2003, 4625-
4629.
10.1021/ol0480022 CCC: $27.50
© 2004 American Chemical Society
Published on Web 11/02/2004

Scheme 2. Predominant or Exclusive “meta Metalation”
Rather Than “ortho Metalation”
Scheme 3. Equilibration between Two
Dichloro(triethylsilyl)phenyllithiums and the Corresponding
Iodoarenes by Permutational Halogen/Metal Interconversion
remote 5-position ("meta position") rather than at the
halogen-adjacent position ("ortho position"; Scheme 2).8
To gain insight we embarked on a systematic investigation.
One of the key questions to be asked was whether the
preference for meta rather than ortho lithiation is a kinetic
or thermodynamic phenomenon. To this end, we have
determined the relative stabilities of our metalation products
by heavy halogen/metal permutational equilibration. This
method has been first applied to probe the basicity of
4-tolyllithium relative to phenyllithium by allowing one
organolithium Li-R to react with the other bromoarene Br-
R′ in diethyl ether at 0 °C until the proportions of the four
components did not change any more and by repeating the
experiment starting from the counterpart combination of
reagents Br-R and Li-R′.10 The carbon-halogen bond
strengths being tacitly assumed to depend little or not at all
on the nature of the organic parts R and R′, the equilibrium
positions must mirror the relative thermodynamic stabilities
(or, in other words, basicities) of the organolithium species
involved. Later, the relative basicities of two more aryllithi-
ums were assessed in this way.11,12
observed one. The 14:86 proportions correspond to a basicity
difference of 1.25 kcal/mol. This is the amount of energy
gained when one moves a chloro substituent in an aryllithium
from a meta to an ortho position and simultaneously another
one from a meta to the para position. The quantitative
agreement with model studies is remarkably good. The
iodoarene-mediated equilibration between 3- and 2-chlo-
rophenyllithium produces a 5:95 mixture at -100 °C and
between 2- and 4-chlorophenyllithium a 70:30 mixture at
-75 °C (Scheme 4). This corresponds to basicity increments
Scheme 4. Equilibration between 2,4- and
3,5-Dichlorophenyllithium and the Corresponding
Dichloroiodobenzenes
R′-I + Li-R {K
\} Li-R′ + R-I
When applying this technique to the couples (2,6-dichloro-
3-iodophenyl)triethylsilane/3,5-dichloro-4-(triethylsilyl)phe-
nyllithium (1) and (2,6-dichloro-4-iodophenyl)triethylsilane/
2,4-dichloro-3-(triethylsilyl)phenyllithium (2), the equilibrium,
approached from both sides, was attained in tetrahydrofuran
at -100 °C after a few minutes (Scheme 3). The aryllithium
species were converted with elemental bromine into (4-
bromo-2,6-dichlorophenyl)triethylsilane and (3-bromo-2,6-
dichlorophenyl)triethylsilane, which were quantified together
with the corresponding iodo compounds by gas chromato-
graphic analysis. The monitored 13:87 equilibrium composi-
tion in favor of the kinetically disadvantaged aryllithium
species 2 translates into a difference in thermodynamic
stability, ∆G1eq73, of 1.31 kcal/mol.
of -2.03 and +0.67 kcal/mol, the sum of -1.36 being an
excellent approximation to the previously found number of
-1.25 kcal/mol.
The conclusion is clear. The buttressing effect encountered
with the metalation of (2,6-dichlorophenyl)- or (2,6-dibro-
mophenyl)trialkylsilane does not manifest itself at the ground
state level but represents a merely kinetic and hence transition
state phenomenon. To elucidate all details associated with
it, more scrutinity will be required. All that we can do at the
moment is to present a working hypothesis that can be
subjected to accordingly devised tests in the future.
Our deductions proceeded stepwise. We ruled out repulsive
interactions between lithium and any halogen on the basis
of their opposite polarities (which hardly will create attractive
forces) and the distance (approximately 2.3 Å in the case of
bromine). Moreover, the "meta-orienting" effect was found
to be particularly pronounced when the deprotonation was
Most instructive was also the comparison with the non-
silylated analogues. The couples 2,4-dichloro-1-iodobenzene/
3,5-dichlorophenyllithium (3) and 1,3-dichloro-5-iodobenzene/
2,4-dichlorophenyllithium (4) converged to an equilibrium
position that was virtually the same as the previously
(9) Mongin, F.; Schlosser, M. Tetrahedron Lett. 1997, 38, 1559-1562.
(10) Gilman, H.; Jones, R. G. J. Am. Chem. Soc. 1941, 63, 1441-1443.
(11) Winkler, H. J. S.; Winkler, H. J. Am. Chem. Soc. 1966, 88, 964-
969.
(12) Winkler, H. J. S.; Winkler, H. J. Am. Chem. Soc. 1966, 88, 969-
974.
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Org. Lett., Vol. 6, No. 24, 2004

Figure 1. Postulated transition state of the (disfavored) metalation
of (2,6-dichlorophenyl)- or (2,6-dibromophenyl)trialkylsilanes at the
3-position (ortho-metalation).
accomplished with potassium rather than lithium bases. On
the other hand, we had recognized a marked increase in
deprotonation-related buttressing effects when the transmitter
halogen was varied from fluorine through chlorine and
bromine to iodine. The heavier the halogen, the longer is its
atomic distance but also its van der Waals radius and the
looseness of its nonbonding electrons. One of these non-
bonding doublets collides with the two delocalized electrons
confined in the molecular orbital (m) within which the proton
is transferred from the aromatic carbon to the base, i.e. from
its former to its future binding partner, in an almost linear
C‚‚‚H‚‚‚Bs array (Figure 1). The in-plane proximity of two
times two loosely bound electrons must give rise to repulsive
forces.
Figure 2. X-ray crystallographic structures of 3,5-dichloro- and
3,5-dibromo-4-triethylsilylbenzoic acids (5 and 6) revealing marked
deformations of the C(2)C(1)C(6), (C(1)C(2)X, and C(1)C(6)X
angles (X ) Cl or Br).
But why then do other 2-substituted 1,3-dihalobenzenes
such as 1,3-dichloro-2-fluorobenzene undergo lithiation at
the 4-position rapidly and cleanly? The halogen n-electrons
overlap with the proton-transfer-mediating m-electrons only
when the C(2),C(3),X valence angle is widened beyond the
standard 120°. If there is no bulky substituent attached to
the 2-position, the X,H distance is presumable large enough
to avoid any repulsive orbital interference. Moreover, if not
impeded by buttressing, the halogen X may swing to the
other side and thus facilitate the protophilic attack of the
base. In other words, the key argument for explaining the
different behavior of 1,3-dichloro-2-fluorobenzene and (2,3-
dichlorophenyl)trialkylsilanes centers around the facile in-
plane deformability of the bond angles established between
chlorine, bromine, or iodine atoms and the carbon skeleton.
This deformability is illustrated impressively by the X-ray
structures of the 3,5-dichloro- and 3,5-dibromo-4-(triethyl-
silyl)benzoic acid (5 and 6, respectively; Figure 2).8
Acknowledgment. This work was supported by the
Schweizerische Nationalfonds zur Fo¨rderung der wissen-
schaftlichen Forschung, Bern (grant 20-100′336-02).
Supporting Information Available: Experimental pro-
cedures and characterization data for the new compounds
1-11. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL0480022
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