Reaction mechanism for the LiCl-mediated directed zinc insertion: A computational and experimental study

Article abstract of DOI:10.1002/chem.200902957

An experimental/computational study on the LiCI-mediated zinc insertion, and the questions of the generation mechanism of Li ion ZnRCIHal, the role of LiCI, and the origin of the regioselectivity in the reaction has been demonstrated. The acceleration of Zn insertion by LiC1 was thermodynamically and kinetically confirmed. The exchange of electrons occurs exclusively among the three atoms, and the charges of the Li and the Cl atoms remain essentially constant during the reaction, indicating that LiCI does not participate in any oxidation/reduction process. The origin of the LiCI effect was investigated by natural bond orbital (NBO) analysis. Origin of the directed oct/to selectivity of the zinc insertion reaction. The theoretical analysis delineated above further advances the understanding of recent zinc insertion chemistry and should contribute to rational design for efficient preparation of functionalized aryl zinc reagents and its application to useful synthetic transformations.

Full text of DOI:10.1002/chem.200902957

DOI: 10.1002/chem.200902957
Reaction Mechanism for the LiCl-Mediated Directed Zinc Insertion:
A Computational and Experimental Study
[
a, b]
[a]
[a]
[a, b]
Ching-Yuan Liu,*
Xuan Wang, Taniyuki Furuyama, Shuji Yasuike,
a] [c] [a, b]
[
Atsuya Muranaka, Keiji Morokuma,* and Masanobu Uchiyama*
In situ generation of organozinc reagents and their inte-
Firstly, DoI reactions of 1-functionalized 2,4-dibromoaryls
1a–c in the absence/presence of LiCl were examined under
various (kinetic and thermodynamic) conditions in order to
elucidate the influence of functional groups and the effect of
LiCl on the activation energy and regioselectivity (Table 1).
Some important aspects of the reactivity and regioselec-
tivity of this Zn insertion can be drawn from the data in the
Table 1.
gration into CÀC bond-forming processes are of continuing
interest because of the characteristically high chemo- and
[1]
stereoselectivity. In 2006, Knochel and co-workers discov-
ered that the oxidative insertion of zinc dust into aryl hal-
ides is drastically accelerated in the presence of LiCl, there-
by opening up a practical and efficient preparation method
[2]
for aryl- and alkylzinc reagents. This protocol was success-
[3]
fully used for chemo- and regioselective Zn insertion (also
termed directed ortho insertion (DoI)), and is now widely
Table 1. DoI reaction of zinc into functionalized dibromoaryls.
+
À
employed. Koszinowski et al. detected Li ZnRClHal
Hal=halide), which had been proposed by Knochel as the
(
[
2]
active species for the LiCl-mediated zinc insertion, in the
reaction mixture by using ESI-MS.
[
4,1f]
However, the reac-
+
À
tion pathway and mechanism of Li ZnRClHal formation
are still far from being settled. Herein, we report an experi-
mental/computational study on the LiCl-mediated zinc inser-
tion, and we address the questions of the generation mecha-
nism of Li ZnRClHal , the role of LiCl, and the origin of
the regioselectivity in the reaction.
[a]
[a]
Zn
58C, 12 h RT, 12 h
Zn+LiCl
558C, 12 h
5
558C, 48 h
FG=CO
2
Me (1a) 79:21 (2%) 98:2 (94%) 96:4 (95%) 95:5 (96%)
+
À
FG=OMe (1b)
FG=CN (1c)
– (<0.1%) – (<0.1%) 92:8 (3%)
– (<0.1%) – (<0.1%) 75:25 (1%) 72:28 (1%)
89:11 (4%)
[
a] Ratio (2:3)/Yield (2+3, values in parentheses) determined by gas
chromatography (GC).
[
a] Dr. C.-Y. Liu, X. Wang, T. Furuyama, Prof. Dr. S. Yasuike,
Dr. A. Muranaka, Prof. Dr. M. Uchiyama
Advanced Elements Chemistry Laboratory
Advanced Science Institute, RIKEN
1
) Reactivity: In all cases, acceleration of Zn insertion by
LiCl was thermodynamically and kinetically confirmed.
For instance, 1a reacted very slowly with zinc powder at
558C over 12 h to afford 2+3 in only 2% yield, whereas
in the presence of LiCl (2.0 equiv), zinc insertion pro-
ceeded rapidly at 558C (also even at room temperature)
furnishing the products in excellent total yield. In con-
trast, the MeO (1b) or CN (1c) derivatives fail to
behave likewise and the zinc insertions occurred in low
yields even with LiCl, and required a longer reaction
time (48 h).
2
-1 Hirosawa, Wako-shi, Saitama 351-0198 (Japan)
Fax : (+81)48-467-2879
E-mail: liu@riken.jp
uchiyama@riken.jp
[
b] Dr. C.-Y. Liu, Prof. Dr. S. Yasuike, Prof. Dr. M. Uchiyama
Department of Pharmaceutical Sciences
Hokuriku University, Ho-3, Kanagawa-machi
Kanazawa, Ishikawa 920-1181 (Japan)
[
c] Prof. Dr. K. Morokuma
Cherry L. Emerson Center for Scientific Computation and
Department of Chemistry, Emory University
Atlanta, Georgia, 30322 (USA)
Fax : (+1)404-727-7412
E-mail: morokuma@euch4e.chem.emory.edu
2
) Regioselectivity: the COOMe and OMe groups exhibit-
ed high ortho-selectivities. As evidenced by 1a, with the
assistance of the LiCl, ortho-selectivity was enhanced.
Surprisingly, 1c underwent the zinc insertion with LiCl
to give the products in low yield with poor selectivity.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200902957.
1780
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 1780 – 1784

COMMUNICATION
Figure 1. Plausible reaction pathways of zinc insertion into bromobenzene: a) without LiCl; b) with LiCl. Energy changes at the B3LYP/631SVP level
À1
are shown in kcalmol on the arrows and bond lengths are shown in angstrom.
Since the CN group is classified as an electron-withdraw-
ing group (EWG), one would expect it to facilitate oxi-
dative metal insertion and DoI reactions. Thus, it is of
interest to seek the reason for the origin of the accelera-
tion of Zn insertion by LiCl and the DoI selectivity.
As judged from the degree of elongation of the CÀBr
bond, as well as the forming ZnÀC bond in the TSs, we con-
sider TS2 to be significantly earlier in the reaction pathway
than TS1. This was also confirmed by natural population
analysis (NPA) and natural resonance theory (NRT)
[2]
[7]
(
Figure 2 and Supporting Information); the positive charge
[5]
DFT calculations (B3LYP/631SVP) were performed to
investigate the reaction pathway of the LiCl-mediated zinc
insertion using bromobenzene
of the Zn atom increases monotonously from CP2 to PD2,
while the negative charge of the phenyl carbon and Br
(
Figure 1). In the absence of
LiCl, we could not find any en-
ergetically plausible initial com-
plex and zinc insertion takes
place directly from the reac-
tants RT1 through the distorted
“
triangular TS” TS1 with an
À1
energy loss of 44.4 kcalmol .
This large energy loss is a result
of the cleavage of the stable CÀ
Br bond and of the rather small
energy gain to form the triangle
bond.
Figure 2. Charge changes (left) and NBO donor–acceptor interactions (right) of TS2 (energy shown in kcal
mol ).
In the presence of LiCl, reac-
tants RT2 form an association
complex CP2 first with an
À1
À1
energy gain (8.0 kcalmol ).
The Zn atom can migrate very smoothly from CP2, along
atoms decreased monotonously toward À1 in the product.
The exchange of electrons occurs exclusively among the
three atoms, and the charges of the Li and the Cl atoms
remain essentially constant during the reaction, indicating
that LiCl does not participate in any oxidation/reduction
process.
[6]
the intrinsic reaction coordinate, to the phenyl carbon
À1
atom with a small activation energy (22.2 kcalmol ) to
afford a five-membered ring in TS2. Zn metal then inserts
into the PhÀBr bond to produce the adduct PD2. The stabi-
À1
lization energy is very large (À81.3 kcalmol ) because of
the formation of the stable halogen ate complex, and this
provides a driving force for the insertion reaction and
energy for successive reaction of the intermediate PD2.
These computational results are in good agreement with the
experimental facts that the additive LiCl substantially facili-
The origin of the LiCl effect was then investigated by nat-
[7]
ural bond orbital (NBO) analysis. Second-order perturba-
tion analysis of TS2 indicates two large stabilization energies
À1
due to the push–pull interactions of LiCl (9.9 kcalmol
À1
(push)/13.6 kcalmol (pull)), corresponding to the secon-
+
À
tates the zinc insertion and that Li ZnRClHal is generated
dary orbital interactions between the lone pair of Cl (donor
NBO) and the vacant 5s* orbital of Zn (acceptor NBO),
[2–4]
as the active species in the reaction system.
Chem. Eur. J. 2010, 16, 1780 – 1784
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1781

C.-Y. Liu, K. Morokuma, M. Uchiyama et al.
and between the lone pair of Br
donor NBO) and the unoccu-
(
pied s orbital of Li atom (ac-
ceptor NBO), respectively.
These results strongly suggest
that the LiCl stabilizes the zinc
insertion TS sterically and elec-
tronically.
Finally, we focused on the
origin of the regioselectivity.
The B3LYP/631SVP-optimized
TSs for zinc insertions of ortho/
para-functionalized bromoben-
zenes are shown in Supporting
Information (Figure S1 for no
LiCl TSs) and Figure 3 (for
LiCl-assisted TSs).
1
) Reactivity: All activation
energies with LiCl are con-
siderably lower than those
without LiCl (ca. 19–
À1
2
2 kcalmol ), in accordance
with
facts.
the
experimental
[8]
Figure 3. TS structures and activation energies of LiCl-mediated zinc insertion reactions of ortho/para func-
[9]
2
) DoI selectivity:
ortho- tionalized bromobenzenes at the B3LYP/631SVP level.
Functional groups such as
ester, alkoxy, and CF3
groups can facilitate DoI reactions through an active in-
teraction/contribution to the five-membered “push–pull”
TSs. Among them, the ortho-substituted ester (o-
CO Me) is proved to be the most efficient as a directing
2
and activation group mainly due to the best interaction/
combination between ester and the five-membered zinc
insertion TS. In order to obtain spectroscopic informa-
tion about the metalation process and the regioselectivi-
ty, an in situ FT-IR study was then performed with ethyl
ortho/para-iodobenzoates as model substrates. The zinc
insertion of the para-derivative with Zn/LiCl scarcely
proceeded at room temperature for 30 min (Supporting
Information, Figure S2), whereas the metalation process
of the ortho isomer under the same reaction conditions
was rapid and efficient (Figure 4). An IR band at
Figure 4. In situ FT-IR monitoring of the LiCl-mediated zinc insertion of
ethyl ortho-iodobenzoate.
À1
1
733 cm in the spectrum of ethyl ortho-iodobenzoate
quickly diminished in intensity as the reaction proceeded
and the newly generated red-shifted absorption at
À1
around 1675 cm increased during the course of the
cyano bromobenzene is depicted in detail in Figure 5.
metalation. These observations are in good agreement
The reactants initially form an association complex CP17
with a reasonable stabilization energy (17.1 kcalmol ).
À1
with the computed C=O stretching frequencies of the
À1
ortho-substrate (1786 cm ) and the metalated intermedi-
The Zn atom then reaches the ipso-phenyl carbon, while
À1
…
ate (1680 cm ) (Supporting Information). However, in
maintaining the CN Li coordination; thus, the ortho-Br
the absence of LiCl, zinc insertion scarcely proceeds and
no band shift was observed (Supporting Information,
Figure S3).
atom cannot coordinate to the Li atom. Lack of coordi-
nation of the Br atom to the Li atom in TS17 causes an
À1
overall energy loss of 18.7 kcalmol (this would be
3
1
) CN group: Interestingly, TS17 shows a completely differ-
ent form from those of others (TS5, TS9, and TS13). The
reaction pathway of LiCl-mediated zinc insertion of 2-
greater for EWG-containing substrates). Therefore, the
activation energies of TS17 and TS18 stay about the
same. The unique cylindrical symmetry of the CN group
782
www.chemeurj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 1780 – 1784

Reaction Mechanisms
COMMUNICATION
other argon-flushed flask followed by
the addition of saturated aqueous
NH
phase was extracted with ether (2ꢁ
0 mL) and the combined organic
phases were washed with brine
20 mL), dried over MgSO and con-
centrated in vacuo. The crude mixture
2+3) was then submitted to GC/MS
analyses.
4
Cl solution (5 mL). The aqueous
1
(
4
(
Figure 5. Plausible reaction pathways of zinc insertion into 2-cyanobromobenzene with LiCl. Energy changes
at the B3LYP/631SVP level are shown in kcalmol on the arrows and bond lengths are shown in angstrom.
À1
prohibits DoI selectivity and efficient activation of Zn in-
sertion by LiCl.
Acknowledgements
We gratefully acknowledge financial support from Hoansha, the Naito
foundation, Mochida memorial foundation and KAKENHI (Young Sci-
entist (A), Houga, and Priority Area No. 459) (to M.U.), the Frontier Or-
ganization of Hokuriku University (to M.U., S.Y., and C-Y.L.), and a
JSPS Research Fellowship for Young Scientists (to T.F.). The calculations
were partially performed on the RIKEN Super Combined Cluster
In summary, DFT calculations, kinetic/thermodynamic
competitive experiments, and an in situ FT-IR study of
LiCl-mediated directed zinc insertion have been performed.
The following aspects were addressed:
(
RSCC).
1
) Reaction pathways of zinc insertion reactions in the pres-
ence of LiCl with (functionalized) halobenzenes, includ-
ing the formation mechanism of Li ZnRClHal , which
Koszinowski et al. recently detected in the reaction
medium.
+
À
Keywords: density functional calculations · insertion ·
lithium chloride · reaction mechanisms · regioselectivity ·
zinc
2
) Role of LiCl in the oxidative insertion of zinc metal into
aryl halides and the reason why LiCl facilitates the reac-
tion, including some unprecedented findings, such as the
[
1] a) Handbook of Functionalized Organometallics, Vol. 1 (Ed.: P. Kno-
chel), Wiley-VCH, Weinheim, 2005, p 251; b) Organozinc Reagents
5
-membered ring TS including LiCl, and secondary orbi-
(
Eds.: P. Knochel, P. Jones), Oxford University Press, New York,
1999; c) H. Ren, G. Dunet, P. Mayer, P. Knochel, J. Am. Chem. Soc.
007, 129, 5376–5377; d) A. Metzger, M. Schade, P. Knochel, Org.
tal interaction among phenyl halide substrates, Zn atom,
and LiCl.
) Origin of the directed ortho selectivity of the zinc inser-
tion reaction.
) General requirements for functionalized phenyl halide
compounds to accept zinc insertion smoothly and regio-
selectively.
2
Lett. 2008, 10, 1107–1110; e) A. Metzger, M. Schade, G. Manoli-
kakes, P. Knochel, Chem. Asian J. 2008, 3, 1678–1691; f) R. E.
Mulvey, F. Mongin, M. Uchiyama, Y. Kondo, Angew. Chem. 2007,
119, 3876–3899; Angew. Chem. Int. Ed. 2007, 46, 3802–3824.
3
4
[2] A. Krasovskiy, V. Malakhov, A. Gavryushin, P. Knochel, Angew.
Chem. 2006, 118, 6186–6190; Angew. Chem. Int. Ed. 2006, 45, 6040–
6
044.
[
3] N. Boudet, S. Sase, P. Sinha, C.-Y. Liu, A. Krasovskiy, P. Knochel, J.
Am. Chem. Soc. 2007, 129, 12358–12359.
The theoretical analysis delineated above further advan-
ces the understanding of recent zinc insertion chemistry
and should contribute to rational design for efficient prepa-
ration of functionalized arylzinc reagents and its application
to useful synthetic transformations. Further extensions of
this work are currently under way in our laboratory.
[1–3]
[4] a) K. Koszinowski, P. Bçhrer, Organometallics 2009, 28, 771–779;
b) K. Koszinowski, P. Bçhrer, Organometallics 2009, 28, 100–110;
c) R. Bilow, S. Deuerlein, T. Stey, R. Herbst-Irmer, H. Gornitzka, D.
Stalke, Z. Naturforsch. B 2004, 59, 1471–1479.
[
5] The basis set denoted 631SVP consists of Ahlrichsꢂ SVP all-electron
basis set for the zinc and bromine atoms and 6-31+G* for the other
atoms. For details of theoretical methods and chemical models, see:
a) F. E. Hæffner, C. Sun, P. G. Williard, J. Am. Chem. Soc. 2000, 122,
1
2542–12546; b) M. Uchiyama, S. Nakamura, T. Ohwada, M. Naka-
Experimental Section
mura, E. Nakamura, J. Am. Chem. Soc. 2004, 126, 10897–10903;
c) M. Uchiyama, Y. Matsumoto, S. Usui, Y. Hashimoto, K. Moroku-
ma, Angew. Chem. 2007, 119, 944–947; Angew. Chem. Int. Ed. 2007,
46, 926–929.
Typical procedure for the directed zinc insertion of 1a–1c (Table 1): Lith-
ium chloride (258 mg, 6 mmol) was placed in an argon-flushed flask and
dried for 10 min at 2008C (heat gun) under vacuum (1 mbar). Zinc
powder (390 mg, 6 mmol) was added under argon and the mixture was
dried again for 10 min at 2008C under vacuum (1 mbar). The reaction
flask was evacuated and refilled with argon twice. THF (2.5 mL) was
[6] a) K. Fukui, Acc. Chem. Res. 1981, 14, 363–368; b) K. Ishida, K. Mo-
rokuma, A. Komornicki, J. Chem. Phys. 1977, 66, 2153–2156.
[7] NPA, NRT and NBO analysis were carried out by using NBO 3.0
program on Gaussian 03. NBO analysis was performed using
“CHOOSE” keywords in order to standardize the resonance struc-
ture representations of each TS. The details are given in the Support-
ing Information; Gaussian 03 (Revision E.01), M. J. Frisch, G. W.
Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman,
added and the zinc was activated with BrCH
2 2
CH Br (5 mol%) and
Me SiCl (5 mol%). Compounds 1a, 1b, or 1c (3 mmol) was added neat
3
at room temperature and the reaction mixture was then heated at room
temperature or 558C for 12–48 h. After cooled to room temperature, the
solution of the corresponding arylzinc bromide was carefully separated
from the remaining zinc powder by using a syringe and transferred to an-
J. A. Montgom
ACHTUNGTRENNGNUe ry Jr., T. Vreven, K. N. Kudin, J. C. Burant, J. M.
Millam, S. S. Iyengar, J. Tomasi, V. Barone, B. Mennucci, M. Cossi, G.
Chem. Eur. J. 2010, 16, 1780 – 1784
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1783

C.-Y. Liu, K. Morokuma, M. Uchiyama et al.
Scalmani, N. Rega, G. A. Petersson, H. Nakatsuji, M. Hada, M.
Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima,
Y. Honda, O. Kitao, H. Nakai, M. Klene, X. Li, J. E. Knox, H. P.
Hratchian, J. B. Cross, C. Adamo, J. Jaramillo, R. Gomperts, R. E.
Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J. W. Och-
terski, P. Y. Ayala, K. Morokuma, G. A. Voth, P. Salvador, J. J. Dan-
nenberg, V. G. Zakrzewski, S. Dapprich, A. D. Daniels, M. C. Strain,
O. Farkas, D. K. Malick, A. D. Rabuck, K. Raghavachari, J. B. Fores-
man, J. V. Ortiz, Q. Cui, A. G. Baboul, S. Clifford, J. Cioslowski, B. B.
Stefanov, G. Liu, A. Liashenko, P. Piskorz, I. Komaromi, R. L.
Martin, D. J. Fox, T. Keith, M. A. Al-Laham, C. Y. Peng, A. Nanayak-
kara, M. Challacombe, P. M. W. Gill, B. Johnson, W. Chen, M. W.
Wong, C. Gonzalez, J. A. Pople, Gaussian, Inc., Pittsburgh, PA, 2004.
[8] Direct zinc insertion reactions into ortho-, or para-substituted
(ÀCO
Me, ÀOMe, ÀCF , ÀCN) bromobenzenes were also carried out
2
3
to study the influence of different functional groups and the effect of
LiCl on the substrate reactivity and regioselectivity (see the Support-
ing Information, TP2, Table S2, for details).
[9] B3LYP/6-31++G**(TZVP for Zn and Br) and MP2/6-31++
G**(TZVP for Zn and Br) single point energies of activation
À1
(298.15 K, kcalmol ) are as follows: TS5, 15.1, 13.6; TS6, 21.0, 20.4;
TS9, 22.1, 20.0; TS10, 24.2, 25.0; TS13, 18.7, 17.6; TS14, 21.4, 20.2, re-
spectively. These calculations do not change the conclusions of the
above analysis.
Received: October 26, 2009
Published online: January 11, 2010
1784
www.chemeurj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 1780 – 1784