Leaving group dependence of the rates of halogen-magnesium exchange reactions

Article abstract of DOI:10.1021/ol300906a

Relative reactivities and absolute rate constants of the reactions of haloarenes with i-PrMgCl?LiCl were investigated in THF at 0 °C. The rate of the halogen-magnesium exchange decreases in the series ArI > ArBr > ArCl (relative reactivities: 10¹¹:10⁶:1). Preliminary experiments show that the p-tolylsulfinyl group is exchanged slightly faster than iodide, while a tosyl group is exchanged at least 10⁴ times more slowly than a bromide.

Full text of DOI:10.1021/ol300906a

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Leaving Group Dependence of the Rates
of HalogenꢀMagnesium Exchange
Reactions
Lei Shi,*,† Yuanyuan Chu,† Paul Knochel,‡ and Herbert Mayr‡
The Academy of Fundamental and Interdisciplinary Sciences, Harbin Institute of
Technology, Harbin 150080, China, and Department Chemie der Ludwig-Maximilians-
€
Universitat Munchen, Butenandtstrasse 5-13 (Haus F), Munchen 81377, Germany
€
€
lshi@hit.edu.cn
Received April 9, 2012
ABSTRACT
Relative reactivities and absolute rate constants of the reactions of haloarenes with i-PrMgCl LiCl were investigated in THF at 0 °C. The rate of the
3
halogenꢀmagnesium exchange decreases in the series ArI > ArBr > ArCl (relative reactivities: 1011:106:1). Preliminary experiments show that the
p-tolylsulfinyl group is exchanged slightly faster than iodide, while a tosyl group is exchanged at least 104 times more slowly than a bromide.
Since Grignard’s discovery that organometallics of the
generalformula RMgXcan be preparedbythe reactions of
alkyl halides with magnesium in Et2O,1 organomagnesium
reagents have become important reagents for the forma-
tion of CꢀC and carbon heteroatom bonds.2 Currently,
the most important methods for the preparation of organo-
magnesium compounds are (1) direct metalation of organic
halides with metallic magnesium;3 (2) deprotonation of CH-
groups with strong Mg-bases;4 (3) transmetalation of other
organometallics;5 and (4) halogenꢀmagnesium exchange,
e.g., by reactions of aryl halides with alkylmagnesium
halides.6ꢀ8
Althoughhalogenꢀmagnesium exchangereactionshave
already been observed in the early 1930s,6 they have not
ꢀ
(6) (a) Prevost, C. Bull. Soc. Chim. Fr. 1931, 49, 1372. (b) Urion, E.
C. R. Hebd. Seances Acad. Sci. Ser. 1934, 198, 1244.
€
(7) (a) Rottlander, M.; Boymond, L.; Berillon, L.; Lepretre, A.;
Varchi, G.; Avolio, S. L.; Laaziri, H.; Queguiner, G.; Ricci, A.; Cahiez,
ꢀ
^
ꢀ
G.; Knochel, P. Chem.;Eur. J. 2000, 6, 767. (b) Jensen, A. E.; Dohle,
W.; Sapountzis, I.; Lindsay, D. M.; Vu, V. A.; Knochel, P. Synthesis
2002, 56. (c) Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel, F. F.;
Kopp, F.; Korn, T.; Sapountzis, I.; Vu, V. A. Angew. Chem., Int. Ed.
2003, 42, 4302. (d) Ila, H.; Baron, O.; Wagner, A. J.; Knochel, P. Chem.
Lett. 2006, 35, 1. (e) Ila, H.; Baron, O.; Wagner, A. J.; Knochel, P. Chem.
Commun. 2006, 583.
† Harbin Institute of Technology.
‡
€
Ludwig-Maximilians-Universitat M€unchen.
(1) Grignard, V. C. R. Hebd. Seances Acad. Sci. Ser. 1900, 130, 1322.
(2) (a) Silverman, G. S.; Rakita, P. Handbook of Grignard Reagents;
Marcel Dekker: New York, 1996. (b) Richey, H. G., Jr. Grignard Reagents:
New Developments; Wiley & Sons: New York, 1999. (c) Yamamoto, H.;
Oshima, K. Main Group Metals in Organic Synthesis; Wiley & Sons: New
York, 2004. (d) Seyferth, D. Organometallics 2009, 28, 1598. For the
reviews on Grignard reagent/organic halide cross-coupling and aryl
Grignard reagent homocoupling, see: (e) Frisch, A. C.; Beller, M.
Angew. Chem., Int. Ed. 2005, 44, 674. (f) Acc. Chem. Res. 2008, 41,
No. 11, special issue.
(3) Lai, Y.-H. Synthesis 1981, 585.
(4) Snieckus, V. Chem. Rev. 1990, 90, 879.
(5) Knochel, P. Handbook of Functionalized Organometallics; Wiley &
Sons: Weinheim, 2005.
(8) (a) Krasovskiy, A.; Knochel, P. Angew. Chem., Int. Ed. 2004, 43,
3333. (b) Krasovskiy, A.; Straub, B. F.; Knochel, P. Angew. Chem., Int.
Ed. 2006, 45, 159. (c) Hauk, D.; Lang, S.; Murso, A. Org. Process Res.
Dev. 2006, 10, 733. (d) Li, F.; Castle, S. L. Org. Lett. 2007, 9, 4033. (e)
Hirner, S.; Panknin, O.; Edefuhr, M.; Somfai, P. Angew. Chem., Int. Ed.
2008, 47, 1907. (f) Huang, L.; Wu, S.; Qu, Y.; Geng, Y.; Wang, F.
Macromolecules 2008, 41, 8944. (g) Rauhut, C. B.; Melzig, L.; Knochel,
P. Org. Lett. 2008, 10, 3891. (h) Duan, X.-F.; Ma, Z.-Q.; Zhang, F.;
Zhang, Z.-B. J. Org. Chem. 2009, 74, 939. For iodineꢀmagnesium
exchange reactions using i-PrMgCl LiCl, see: (i) Martin, R.; Buchwald,
3
S. L. J. Am. Chem. Soc. 2007, 129, 3844.
r
10.1021/ol300906a
XXXX American Chemical Society

been widely used until recently. One of us7 demonstrated
the applicability of this method for the preparation of
functionalized organomagnesium reagents that cannot
be obtained by conventional processes. In particular,
Scheme 2. Exchange Reactions between Aryl Grignard Reagent
and Aryl Bromide
i-PrMgCl LiCl was found to be a valuable reagent, as it
3
exhibits a dramatically increased reactivity in halogenꢀ
magnesium exchange reactions compared to i-PrMgCl or
(i-Pr)2Mg.8
Scheme 1. Determination of the Effect of Leaving Groups on
the Rates of HalogenꢀMagnesium Exchange Reactions
We reported9 that 2-cyanophenylmagnesium chloride,
which formed rapidly and nearly quantitatively from
2-bromobenzonitrile and i-PrMgCl LiCl, does not under-
3
go an exchange with 4-methoxybromobenzene (0 °C, 8 h),
in line with the unfavorable thermodynamics of this reac-
tion (Scheme 2). On the other hand, 4-methoxyphenyl-
magnesium chloride was observed to undergo a slow ex-
change with 2-bromobenzonitrile to yield approximately
2% of 2-cyanophenylmagnesium chloride and 4-methoxy-
bromobenzene within 8 h at 0 °C (Scheme 2).
As this reaction was slow compared with the reactions
of the bromoarenes with i-PrMgCl LiCl, we had con-
cluded that the ratios [P1]/[P2] or [P10]/[P20] reflect the
ratios k1/k2 defined in Scheme 1.
3
However, in some cases (e.g., X = I) the product ratios
[P1]/[P2] or [P10]/[P20] were found to depend on the
reaction time, indicating that the product ratios are
no longer kinetically controlled. Thus, the ratio k1/k2
(Scheme 1) cannot simply be derived from the prod-
uct ratios when aryl derivatives ArꢀX are treated with
i-PrMgCl LiCl.
3
Figure 1 shows that 4-methoxyphenylmagnesium chlo-
ride reacts slowly with 1-iodo-2-methylbenzene in THF at
0 °C reaching an equilibrium mixture of arylmagnesium
reagents and aryl iodides within 1 h. An analogous ob-
servation was made when 2-tolylmagnesium chloride was
treated with 1-iodo-4-methoxybenzene under the same
conditions (Figure 2).
Both figures show that the exchange reaction between
the corresponding arylmagnesium reagents and iodoar-
enes require about ∼1 h for completion, and the degree of
conversion is low within 5 min. In line with this observa-
tion, the ratio of arylmagnesium halides obtained by the
fast reaction of a mixture of two competing iodoarenes
Recently, we investigated the kinetics of the reactions of
substituted bromoarenes toward i-PrMgCl LiCl in THF
3
at 0 °C9 and demonstrated that the rates of the bromineꢀ
magnesium exchangereactionsare accelerated byelectron-
withdrawing substituents in the aromatic ring. The sub-
stituent effects decrease with increasing distance between
bromine and the substituent under consideration (para <
meta , ortho). We now report how the rates of the
halogenꢀmagnesium exchange reactions depend on the
nature of the halogens and how these data can be used for
predicting the regioselectivities of halogenꢀmagnesium
exchange reactions of arene derivatives bearing different
leaving groups.
with a substoichiometric amount of i-PrMgCl LiCl was
3
The relative rates of halogenꢀmagnesium exchange
almost the same after 1 and 5 min.
reactions were determined by competition experiments,
where substoichiometric amounts of i-PrMgCl LiCl
If the exchange between an aryl iodide and an aryl-
magnesium halide is slow compared with the initial
reaction, the relative reactivities of R1 and R2 toward
3
(typically 0.33 to 0.5 equiv) were added to mixtures of
two different haloarenes in THF at 0 °C. At various times,
the composition of the reaction mixture was analyzed by
gas chromatographic determination of the product ratios
obtained by quenching either with iodine ([P10]/[P20]) or
with methanol ([P1]/[P2]) (Scheme 1).
i-PrMgCl LiCl can be expressed by eq 1,10 as reported
3
previously.9
K1
K2
log([R1]0=[R1]t)
log([R2]0=[R2]t)
K ¼
¼
ð1Þ
Substitution of [R1]0 and [R2]0 by the expressions [R1]0
= [R1]t þ [P1]t and [R2]0 = [R2]t þ [P2]t (mass balance)
(9) (a) Shi, L.; Chu, Y.; Knochel, P.; Mayr, H. Angew. Chem., Int. Ed.
2008, 47, 202. (b) Shi, L.; Chu, Y.; Knochel, P.; Mayr, H. J. Org. Chem.
2009, 74, 2760. (c) Shi, L.; Chu, Y.; Knochel, P.; Mayr, H. Org. Lett.
2009, 11, 3502.
(10) Huisgen, R. Angew. Chem., Int. Ed. 1970, 9, 751.
Org. Lett., Vol. XX, No. XX, XXXX
B

Figure 1. Time-dependent concentrations of 4-methoxyphenyl-
magnesium chloride (O) and 2-tolylmagnesium chloride (Δ)
obtained by treatment of 4-methoxyphenylmagnesium chloride
(starting concentration = 0.257 M) with 1-iodo-2-methylben-
zene (starting concentration = 0.418 M) in THF at 0 °C.
Figure 3. Relative reactivities of haloarenes toward i-PrMgCl LiCl
3
in THF at 0 °C and τ1/2 for 1 M solutions (PhBr = 1.0).
other aryl halides, to give the 10 competition constants κ11
illustrated in Figure 3. The combination with the pre-
viously reported relative reactivities of differently sub-
stituted bromoarenes9 and solving the resulting overde-
termined set of linear equations (eq 3) by least-squares
minimization yielded the krel values listed in the left
column of Figure 3.
log K ¼ log ka ꢀ log kb
ð3Þ
As shown in previous work,9b second-order rate con-
stants for several bromineꢀmagnesium exchange reactions
have been measured directly, which allows us to estimate
absolute rate constants for other aryl halides by multiplying
the krel values (krel = 1.0 for bromobenzene) with 6.0 ꢁ 10ꢀ6
Figure 2. Time-dependent concentrations of 4-methoxyphenyl-
magnesium chloride (O) and 2-tolylmagnesium chloride (Δ)
obtained by treatment of 2-tolylmagnesium chloride (starting
concentration = 0.286 M) with 1-iodo-4-methoxybenzene
(starting concentration = 0.262 M) in THF at 0 °C.
Mꢀ1 ꢀ1. In this way, we have calculated the half-reaction
s
times12 listed in Figure 3 for the halogenꢀmagnesium ex-
change in THF solutions which are 1 M in aryl halide and 1
M in i-PrMgCl LiCl, to give chemists an idea of the time
3
yields eq 2, which calculates the competition constant κ
from the ratios [P1]t/[R1]t and [P2]t/[R2]t, which were
determined by gas chromatography.
needed for a specific halogenꢀmagnesium exchange.
Though the environment of the halogens in the three an-
alogously substituted bromo- and iodobenzenes (Scheme 3,
top) differs significantly, iodine is always exchanged
log(1 þ [P1]t=[R1]t)
K ¼
ð2Þ
(11) Herein, κcalcd have been calculated by minimizing ΣΔ2, where
log(1 þ [P2]t=[R2]t)
2
Δ2 = (κ ꢀ κcalcd
)
by Lindo Systems Inc.
using the program “What’s Best! 4.0 Commercial”
Each of the six bold-printed aryl halides shown in Figure 3
was subjected to competition experiments with several
(12) τ1/2 = 1/kc0 (k = second-order rate constant, c0 = initial
concentration).
Org. Lett., Vol. XX, No. XX, XXXX
C

6 ꢁ 104 times faster than bromine, which is, therefore,
considered to be a typical I/Br ratio. The lower two entries
of Scheme 3 show that in, 2-halobenzotrifluoride and
2-halothiophenes, the Br/Cl ratio is in the same order of
magnitude (kBr/kCl ≈ 106) which we consider an approx-
imate value for this pair of halogens.
comparison with τ1/2 in Figure 3, one can, therefore,
conclude that krel of p-cyanophenyl tosylate in the listing
of Figure 3 must be smaller than 10ꢀ1; i.e., tosylate is
exchanged at least 104 times more slowly than a bromide.
This result is consistent with previously reported selective
exchanges of bromide in the presence of tosyloxy groups
(Scheme 5).15
Scheme 3. Effect of Different Halogens on the Relative Rates of
Halogen/Mg Exchange: Data from Figure 3 and Refs 9b and 9c
Scheme 5. No Exchange Reactions between ArOTs and
i-PrMgCl LiCl
3
Attempts to determine the arylsulfinylꢀmagnesium
exchange rates of bis(p-chlorophenyl)sulfoxide and bis-
(p-tolyl)sulfoxide by competition experiments, as de-
scribed in Scheme 4, did not yield reproducible results.
Probably the aryl sulfoxides are so reactive, i.e., the
arylsufinyl group is exchanged so fast, that the corre-
sponding competition constants κ depended on the rate
of mixing (macroscopic diffusion control13). Though it
is not possible to determine precise exchange rates, the
approximately 3-times higher reactivity of bis(p-tolyl)-
sulfoxide compared with p-iodoanisole indicates that
the exchange rate of the p-tolylsulfinyl group is of
similar magnitude as that of iodine.14
In summary, the qualitatively known increase of
halogenꢀmagnesium exchange rates in the order ArCl <
ArBr < ArI has been quantified as 1:106:1011 for the reac-
tions of haloarenes with i-PrMgCl LiCl in THF at 0 °C. If
3
one assumes that further substituents have similar effects on
iodideꢀmagnesium and chlorideꢀmagnesium exchange
reactions as previously reported for bromideꢀmagnesium
exchange reactions9 (the data in Scheme 3 support this view),
one can combine the data in this work with the previously
reported substituent effects to predict the most likely site of
exchange in functionalized polyhalogenated arenes.
Acknowledgment. We thank the Alexander von Hum-
boldt Foundation (research fellowship to L.S.), the
Deutsche Forschungsgemeinschaft (SFB 749), and the
Fonds der Chemischen Industrie for support of this work.
Scheme 4. Determination of Relative ArylsulfinylꢀMagnesium
Exchange Rates
Supporting Information Available. Experimental proce-
dure and data for the determination of the relative exchange
rates κ and determination of exchange reactions between
Grignard reagent and aryl halide. This material is available
free of charge via the Internet at http://pubs.acs.org.
No exchange reaction between p-cyanophenyl tosylate
and i-PrMgCl LiCl was observed within one day. By
3
(13) Holm, T. J. Org. Chem. 2000, 65, 1188.
(14) As p-bromoanisole and p-bromotoluene have been found
to be equally reactive, the same is assumed for p-iodoanisole and
p-iodotoluene.
(15) Ren, H.; Knochel, P. Chem. Commun. 2006, 726.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX