Formation of benzynes from 2,6-dihaloaryllithiums: Mechanistic basis of the regioselectivity

Article abstract of DOI:10.1021/ja044899m

The key elimination step for the formation of 3-chloro- and 3-fluorobenzyne from 2-chloro-6-fluorophenyllithium displays a pronounced solvent-dependent regioselectivity. ⁶Li and ¹³C NMR spectroscopic studies on 2-chloro-6-fluorophenyllithium reveal a single monomeric aryllithium, suggested by DFT computational studies to be a trisolvate. Rate studies indicate that the elimination of LiCl and LiF proceeds via trisolvated and disolvated monomers, respectively. Copyright

Full text of DOI:10.1021/ja044899m

Published on Web 10/23/2004
Formation of Benzynes from 2,6-Dihaloaryllithiums: Mechanistic Basis of the
Regioselectivity
Antonio Ram´ırez,† John Candler,‡ Crystal G. Bashore,‡ Michael C. Wirtz,‡ Jotham W. Coe,*,‡ and
David B. Collum*,†
Baker Laboratory, Department of Chemistry and Chemical Biology, Cornell UniVersity,
Ithaca, New York 14853-1301, and Pfizer Global Research and DeVelopment, Groton Laboratories, Pfizer, Inc.,
Groton, Connecticut 06340
Received August 24, 2004; E-mail: coejw@groton.pfizer.com; dbc6@cornell.edu
Benzyne was first discussed over a century ago by Stoermer and
Kahlert.1 Fifty years later, Roberts and co-workers reported their
landmark isotopic labeling studies on the KNH2-mediated reaction
of chlorobenzene that left little doubt about the existence of benzyne
as a highly reactive intermediate.2 Since then, the generation,
structure, and reactivity of benzynes have been studied by synthetic
organic and physical organic chemists.3 Although ortholithiated
haloarenes are often used to generate benzynes,4 the understanding
of coordinating solvents in the key elimination step is based largely
on empirical observations.5 Moreover, evidence supporting or
refuting a central importance of aggregation is nonexistent.6
As part of a program to identify nicotinic receptor agonists as
potential aids for smoking cessation and other neurochemically
mediated conditions,7 we observed that the reaction of 1-chloro-
3-fluorobenzene (1) with n-BuLi affords intermediate benzynes 2
and 3 (eq 1) that can be trapped to form bicycloadducts 4 and 5.8
Unexpectedly, the key elimination step displays a pronounced
solvent-dependent regioselectivity.9 A combination of structural and
rate studies described herein provides the first detailed view of how
the mechanism influences the rates and regioselectivity of the key
elimination step.
6
Figure 1. (a) Li NMR spectrum of 0.2 M [6Li]2-chloro-6-fluorophenyl-
lithium (6) in THF (10.3 M) with toluene cosolvent at -100 °C. (b) 13C
NMR spectrum of 0.4 M [6Li]-6 in neat THF at -100 °C.
combination of inductive stabilization of the charge and steric
inhibition of aggregation.15,16
Rate studies were carried out by treating THF/toluene solutions
of 1 and spiro[2.4]hepta-4,6-diene with n-BuLi at -25 °C. Under
these conditions, aryllithium 6 is generated instantaneously. The
initial rates17 for the formation of intermediate benzynes 2 and 3
are monitored by following the loss of 1 and formation of
bicycloadducts 4 and 5 via GC analysis. Arene 1 was maintained
in 0.2 M excess to aryllithium concentrations. The initial rates were
independent of the concentration of spiro[2.4]hepta-4,6-diene
(maintained at >20% molar excess), indicating that the halide
elimination is irreversible.3a There was no evidence of downward
curvature that would indicate autocatalysis by the lithium halide.
The rate constant for the loss of 6 (kobsd(6)) corresponds to the sum
6Li and 13C NMR spectra recorded on [6Li]2-chloro-6-fluorophen-
yllithium (6) prepared from 1 and recrystallized [6Li]n-BuLi at -100
°C10 show a single species in both neat THF and THF/toluene
mixtures (Figure 1). The 6Li-13C, 6Li-19F, and 19F-13C couplings
and multiplicities11 are consistent with aryllithium monomer 6. The
2JF-C(ipso) coupling constant of 130.3 Hz is substantially larger than
the analogous 19.8 Hz coupling in 1,3-dihaloarene 1.12 On a
practical note, the 19F in the arene serves as an excellent surrogate
for an inaccessible 13C label at the 6Li-bearing (ipso) carbon.
Although we do not have a spectroscopic measure of solvation
number, DFT calculations (B3LYP/6-31G*) show that serial
solvation of the monomer is exothermic up to the trisolvate.13
Assignment of the monomer as the trisolvate 6 is also consistent
with conventional views of lithium as preferring four coordination.14
The exclusive formation of monomer 6 presumably stems from a
of the rate constants for formation of benzynes 2 and 3 (kobsd(2)
obsd(3)), which, in turn, were determined by monitoring the ratio of
cycloadducts 4 and 5 (kobsd(4)/kobsd(5)).
+
k
Loss of aryllithium 6 is first order in 6 in both 0.3 and 6.8 M
THF (kobsd(6) [6]0), which, in conjunction with NMR spectroscopic
studies, indicates a monomer-based mechanism.6 Moreover, the
independence of the [4]:[5] ratio on the initial concentration of 6
confirms that elimination of LiF and LiCl (kobsd(2) and kobsd(3)
,
respectively) both proceed via transition structures of equivalent
(monomeric) aggregation state.
The THF-concentration-dependent rates are particularly revealing
(Figure 2). The overall rate at which aryllithium 6 eliminates lithium
† Cornell University.
‡ Pfizer, Inc.
9
14700
J. AM. CHEM. SOC. 2004, 126, 14700-14701
10.1021/ja044899m CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
for indirect support. We also acknowledge the National Science
Foundation Instrumentation Program (CHE 7904825 and PCM
8018643), the National Institutes of Health (RR02002), and IBM
for support of the Cornell Nuclear Magnetic Resonance Facility.
Supporting Information Available: Spectral data, rate data, and
experimental procedures. This material is available free of charge via
the Internet at http://pubs.acs.org.
References
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Figure 2. (a) Plot of kobsd(6) vs [THF] in toluene cosolvent for the formation
of benzynes 2 and 3 from 6 (0.2 M) at -25 °C. The curve depicts the
result of an unweighted least-squares fit to kobsd(6) ) k[THF]n + k′ (k ) (4
( 0.4) × 10-5, n ) -1.12 ( 0.09, k′ ) (7.3 ( 0.3) × 10-4). (b) Plot of
kobsd(3) vs [THF]. kobsd(3) ) k[THF] + k′ (k ) -(1 ( 9) × 10-6, k′ ) (7.1
( 0.2) × 10-4). (c) Plot of kobsd(2) vs [THF]. kobsd(2) ) k[THF]n + k′ (k )
(4.2 ( 0.6) × 10-4, n ) -1.1 ( 0.1, k′ ) (1 ( 4) × 10-5).
Scheme 1
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2
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halide (kobsd(6), curve a) displays a profile that derives from the
superposition of a [THF]-independent elimination of chloride (kobsd(3)
[THF]0, curve b) and inverse-first-order dependence on fluoride
elimination (kobsd(2) 1/[THF]1.1(0.1, curve c).
The structural and rate data are fully consistent with the
mechanism outlined in Scheme 1. The solvent-dependent regiose-
lectivity clearly derives from the LiF elimination requiring THF
dissociation. Presumably, the lower solvation number enhances a
highly stabilizing Li-F interaction,14b,19 as implied in transition
structure 9. It has been suggested that the propensity of halogens
to eliminate follows the order I > Br > Cl > F.18,20 However, based
on these results, the capacity of the halide ions to function as leaving
groups clearly depends on the reaction conditions and mechanism.21
In our opinion, caution should be exercised when using categorical
rules about halide reactivities in a more general sense.
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M.; Wang, P. G.; Streitwieser, A. J. Org. Chem. 1996, 61, 3145.
(17) The initial rates (∆[6]/∆t, ∆[2]/∆t, and ∆[3]/∆t) were converted to their
corresponding observed first-order rate constants (kobsd(6), kobsd(2), and
kobsd(3)).
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We are currently studying other 1,3-dihaloaryllithiums both
experimentally and computationally. These investigations will be
described in due course.
(20) Carlqvist, P.; O¨ stmark, H.; Brinck, T. J. Org. Chem. 2004, 69, 3222.
Gohier, F.; Mortier, J. J. Org. Chem. 2003, 68, 2030. Caster, K. C.; Keck,
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Acknowledgment. D.B.C. and A.R. thank the National Science
JA044899M
Foundation for direct support of this work as well as Pfizer Inc.
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