Structurally defined reactions of sodium TMP-zincate with nitrile compounds: Synthesis of a salt-like sodium sodiumdizincate and other unexpected ion-pair products

Article abstract of DOI:10.1002/anie.200704341

Zany zincation: Seemingly simple zincation reactions of aromatic or aliphatic nitriles are in reality highly complicated affairs involving separated ion pairs (see X-ray structure; yellow Na, blue N, green Zn; left cation, right anion) or joined ion pairs. The results also show that the free zincate anions can engage in complicated dismutation processes. (Chemical Equation Presented)

Full text of DOI:10.1002/anie.200704341

Angewandte
Chemie
DOI: 10.1002/anie.200704341
Zincation
Structurally Defined Reactions of Sodium TMP–Zincate with Nitrile
Compounds: Synthesis of a Salt-Like Sodium Sodiumdizincate and
Other Unexpected Ion-Pair Products**
William Clegg, Sophie H. Dale, Eva Hevia, Lorna M. Hogg, Gordon W. Honeyman,
Robert E. Mulvey,* Charles T. OꢀHara, and Luca Russo
The recent development of modern alkali-metal ate reagents
has provided a passport to previously unconquered areas of
metalation chemistry.[1] Thus the less-electropositive metal
(Mg, Al, Zn, or Mn[2]) anionically activated within the ate
reagent can be transformed into a super metalating agent,
making possible direct low-polarity metal–hydrogen exchange
reactions with aromatic compounds. As the alkali metal is
essential (on their own low-polarity organometallic com-
plexes are generally weak bases) but does not actually
perform the deprotonation, these reactions are best inter-
preted as alkali-metal-mediated metalations. TMP–zincates
(TMP is 2,2,6,6-tetramethylpiperidide) of lithium[3] and
sodium[4] have been demonstrated to be excellent reagents
for triggering direct zincation of a wide range of activated,[5]
and most spectacularly, non-activated aromatic com-
pounds.[4g,h] Herein we present the first systematic study and
structural definition of the reactivity of a TMP–zincate
towards nitrile compounds (Scheme 1). Each of the three
nitriles investigated reveals a new unexpected aspect of TMP–
zincate chemistry, collectively establishing for the first time
the existence and importance of Lewis base separated ion-
pair structures within this emerging topic.
(DFT) study[3f] theorized that ortho-zincation is favored
ꢀ
over the commonly observed 1,2-addition reaction to C N
owing to a lower energy transition state in which the Zn atom
is not involved in activation of the cyano function. For our
first study we chose the methyl-substituted benzonitrile, m-
tolunitrile, since it is an important molecular building block in
biomedicinal chemistry[6] and its potential metalation invokes
issues of regioselectivity. To our knowledge m-tolunitrile has
never been metalated, let alone zincated directly. We sought
to zincate it by subjecting it to sodium TMP–zincate
[(TMEDA)Na(tBu)(TMP)Zn(tBu)] in bulk hexane solution
containing excess TMEDA (N,N,N’,N’-tetramethylethylene-
diamine). Zincation was achieved (Scheme 1) but in an
unexpected way as the isolated product of the reaction, 1,
has the extraordinary ion-pair composition [(3-Me-
C6H4CN)2Na(TMEDA)2]+ [{6-Zn(tBu)2-3-Me-C6H3CN}2Na-
(TMEDA)2]À.[7] In explanation, two nitrile ligands regiose-
lectively zincated ortho to the cyano function (para to the
methyl group) are found in the anionic moiety, while two
neutral, nonmetalated nitrile ligands are found in the cationic
moiety. Ionic zincate 1 was obtained initially from a 1:1,
zincate base:m-tolunitrile stoichiometry, but commensurate
with the formula of 1 the yield was improved (from 29.3 to
48.9%) on changing to a 1:2 stoichiometry with an extra
equivalent of TMEDA. Retention of both tBu groups on the
newly developed arylzinc units suggested that the TMP–
zincate reagent functions as an amido (TMP) base with
elimination of TMPH and this was confirmed by detection of
TMPH in the filtrate of the reaction. Though such TMP
basicity has been postulated theoretically to be kinetically
preferable,[3e] this is the first structurally authenticated
experimental example found for a reaction performed in
hexane or indeed any other solution. It can be reasoned that
the released TMPH cannot reaminate the Zn center with
concomitant tBuH elimination owing to the absence of an
attached Na (Lewis acidic) site (i.e. consistent with a
separated ion-pair structure) to which it could “precoordi-
nate”, coupled with the fact that other stronger Lewis bases
(metalated and non-metalated nitriles; TMEDA) compete
with/win against sterically restricted TMPH for the coordi-
nation sites around Na. This finding is important as it shows
that the basicity of TMP–zincate reagents can be controlled
by modulation of ligand coordination. Crystallographic
characterization of 1[7] showed that the dominating feature
of the structure of this first ever “sodium sodiumdizincate”
complex (Figure 1) is a salt-like N6 octahedral coordination of
the central Na atom in both cationic and anionic moieties.
There is only one report[3a] of a reaction of this type,
namely between the simplest aromatic nitrile, benzonitrile,
and lithium TMP-zincate “Li[tBu2Zn(TMP)]”, in THF solu-
tion (that is, in a bulk Lewis basic solvent). Excellent yields of
ortho-metalation (up to 96%) were realized, though the
reaction remained structurally opaque as its outcome was
determined indirectly by electrophilic interception with
iodine and benzaldehyde.
A subsequent computational
[*] Dr. E. Hevia, L. M. Hogg, Dr. G. W. Honeyman, Prof. R. E. Mulvey,
Dr. C. T. O’Hara
WestCHEM
Department of Pure and Applied Chemistry
University of Strathclyde
Glasgow, G1 1XL (UK)
Fax: (+44)141-552-0876
E-mail: r.e.mulvey@strath.ac.uk
Prof. W. Clegg, Dr. S. H. Dale, Dr. L. Russo
School of Natural Sciences (Chemistry)
Newcastle University
Newcastle upon Tyne, NE1 7RU (UK)
[**] This research was supported by the UK Engineering and Physical
Science Research Council through grant award no. GR/T27228/01
and EP/D076889/1. TMP is 2,2,6,6-tetramethylpiperidide.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or fromthe author.
Angew. Chem. Int. Ed. 2008, 47, 731 –734
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
731

Communications
cyano function. The molecular structure of 2
(Figure 2) establishes its contacted ion-pair
nature, with the bis(TMEDA) chelated Na
datively bound to the cyano N atom, making
Na five coordinate overall.
Six-coordination of Na (as in 1), and there-
fore the opportunity for an ionic zincate struc-
ture may not necessarily be prohibited by the
large steric demands of the cyanonaphthyl
ligand as the reaction producing 2 is not totally
clean and other products are formed (see the
Supporting Information). Kinetic factors are
presumably responsible for this mixture as also
observed in reactions of sodium TMP–zincate
with anisole.[4f]
To attempt to gain more understanding of
the structural maneuvers taking place prior to
zincation of the nitrile, we studied the reaction
between sodium TMP–zincate and aliphatic
ꢀ
trimethylacetonitrile, tBuC N, the hydrogen
atoms of which are generally not accessible to
metalation.[8] Maintaining the trend of surprising
outcomes seen with 1 and 2, this reaction
(Scheme 1) also afforded an unexpected crystal-
line product in the sodium trialkylzincate
[{(tBuCN)2Na(TMEDA)2}+(tBu3Zn)À]
(3).[7]
This was produced initially from a 1:1:2 mixture
of the TMP–zincate, tBuCN, and TMEDA, but
repeating the preparation with a 1:2:2 stoichi-
ometry (matching that in the cationic moiety)
improved the yield. The Lewis base separated
ion-pair structure of 3 (Figure 3) was confirmed
by X-ray crystallography. Mimicking 1, the
cation of 3 exhibits N6 octahedral coordination
of Na with trans-disposed, neutral tBuCN
ligands and equatorially disposed TMEDA
ligands. In contrast to the dizincate of 1, the
anion of 3 is a simple monozincate, but its
Scheme 1. Reactions of sodiumTMP–zincate with aromatic and ali-
phatic nitriles in the presence of additional N,N,N’,N’-tetramethylethyl-
_
enediamine (TMEDA; NN) that give isolated crystalline products.
Except for substitution of one H by a tBu2Zn unit in each of
the two nitrile ligands of the anion, both ions exhibit near-
identical structures with the nitriles occupying trans (N-Na-N
angle, 1808) positions. Perfect octahedral symmetries are
prevented only by the restricted bite angle of the TMEDA
ligands (mean N-Na-N, 72.88) which occupy the four remain-
ing octahedral sites.
Endeavoring to extend the concept of alkali-metal-
mediated zincation to polycyclic aromatic nitriles, we next
subjected 1-cyanonaphthalene to the same sodium TMP–
zincate reagent (Scheme 1). Synergic zincation was success-
fully accomplished but again it was manifested in a surprising
and different way. Thus the isolated product was not an ionic
zincate, but the discrete molecular species [(TMEDA)2Na{2-
Zn(tBu)2-1-N C-C10H6}] (2).[7] Similar to that in 1, zincation is
delivered through amido (TMP) activity of the base which
ꢀ
Figure 1. Ion-pair structure of 1 showing cation (left) and anion (right).
Hydrogen atoms and minor disorder components are omitted for
clarity.
leaves a Zn(tBu)2 unit at the deprotonated site ortho to the
732
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Angewandte
Chemie
evidence of chemistsꢀ continued fascination for zinc chemistry
as recently highlighted in a review.[10]
Experimental Section
1: BuNa (2 mmol, 0.16 g) was suspended in hexane (10 mL) and
sonicated for 10 min to form a fine dispersion. TMPH (2 mmol,
0.34 mL) was added and the creamy, white suspension formed was
stirred for 1h. tBu2Zn (2 mmol, 0.36 g) in hexane was then added
followed by TMEDA (2 mmol, 0.3 mL) to give a yellow solution
which was stirred for around 45 min before meta-tolunitrile (2 mmol,
0.24 mL) was introduced. The solution became red and slightly
cloudy. Approximately 5 mL toluene was added to give a red/orange
homogeneous solution. Crystallization occurred at À248C (orange
crystals, yield 0.39 g, 29.3%).
2: BuNa (2 mmol, 0.16 g) was suspended in hexane (10 mL) and
sonicated for 10 min to form a fine dispersion. TMPH (2 mmol,
0.34 mL) was added and the creamy, white suspension formed was
stirred for 1 h. tBu2Zn (2 mmol, 0.36 g) in hexane was then added
followed by TMEDA (4 mmol, 0.6 mL) to give a yellow solution
which was stirred for around 45 min before 1-cyanonaphthalene
(2 mmol, 0.3 g) was introduced. The solution became red and a dark
precipitate formed almost immediately. Hexane was removed from
the mixture in vacuo and 7 mL of toluene was added to give a dark
red solution which was stirred for around 45 min. A dark red
crystalline solid formed (0.45 g) at À248C which was used for the
NMR spectroscopic analysis and the X-ray crystallographic study. No
absolute yield can be given as this solid contained more than one
metallo product (see NMR analysis in the Supporting Information).
3: BuNa (2 mmol, 0.16 g) was suspended in hexane (10 mL) and
sonicated for 10 min to form a fine dispersion. TMPH (2 mmol,
0.34 mL) was added and the creamy, white suspension formed was
stirred for 1 h. tBu2Zn (2 mmol, 0.36 g) in hexane was then introduced
followed by two molar equivalents of TMEDA (4 mmol, 0.6 mL) to
give a yellow solution which was stirred for around 45 min before
cooling to À208C. tert-Butylcyanide (2 mmol, 0.18 mL) was then
added to the solution. The solution became orange/red and a dark
precipitate formed immediately. The solution was allowed to come to
room temperature slowly (over 2 h). 10 mL of toluene were added to
give a dark red solution with some fine precipitate. On removing
some solvent in vacuo to make the solution more polar, the
precipitate dissolved, leaving a dark red/orange solution. A large
crop (0.45 g, 35%) of small, red, needle-like crystals formed overnight
(at room temperature) which were employed for the X-ray crystallo-
graphic study and characterized by NMR spectroscopy.
Figure 2. Molecular structure of 2. Hydrogen atoms and minor disor-
der components are omitted for clarity.
Figure 3. Ion-pair structure of 3 showing cation (left) and anion (right).
Hydrogen atoms and second disorder components are omitted for
clarity.
composition is not heteroleptic [tBu2(TMP)Zn]À, which
would signify a straightforward scission of sodium TMP–
zincate, but the homoleptic trialkylzincate [tBu3Zn]À, indicat-
ing that dismutation has occurred.
Taken together, the three new crystal structures are highly
illuminating. They establish that 1) nitrile molecules coordi-
nate preferentially to the Na centers of these bimetallic Na/
Zn reagents, and can do so even in the company of TMEDA;
2) Lewis base separated ion pairs play a prominent part in
TMP–zincate chemistry; and most significantly, 3) the free
zincate anions can engage in complicated dismutation pro-
cesses.
To conclude, by structurally defining the metal containing
products of these reactions with nitriles, a new category of
zincate, a sodium sodiumdizincate, has been uncovered,
which would have been otherwise missed if the reaction had
been investigated indirectly through electrophilic trapping
methods. This salt-like organic compound establishes a link
between air-sensitive heterometallic organozinc chemistry
and air-stable (aqueous-based) heterometallic inorganic zinc
chemistry, which is currently attracting attention in areas such
as hydrogen adsorption.[9] These findings provide yet more
Received: September 20, 2007
Published online: December 7, 2007
Keywords: ion pairs · metalation · nitriles · sodium · zinc
.
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Angew. Chem. Int. Ed. 2008, 47, 731 –734
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www.angewandte.org
733

Communications
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C28H46N6Na+C44H80N6NaZn2
,
Mr = 1336.6, triclinic, space
À
¯
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group P1, a = 10.187(3), b = 12.209(4), c = 17.637(5) Š, a =
73.426(5), b = 87.412(5), g = 76.154(5)8, V= 2041.0(11) Š3, Z =
1 (both ions on inversion centers), 1calcd = 1.087 gcmÀ3, T=
150 K, m(Mo Ka) = 0.64 mmÀ1 (l = 0.71073 Š); 14870 reflec-
tions measured, 6448 unique, Rint = 0.015; R (F, F2 > 2s) = 0.045,
wR (F2, all data) = 0.128, S (F2) = 1.026, 493 refined parameters
and 433 restraints, constrained
H
atoms, difference map
À3
extremes + 1.12 and À0.62 eŠ
.
Crystal data for 2:
C31H56N5NaZn, Mr = 587.2, monoclinic, space group P21/c, a =
12.1597(14), b = 13.6753(17), c = 21.433(4) Š, V= 3550.7(9) Š3,
[4] a) P. C. Andrikopoulos, D. R. Armstrong, H. R. L. Barley, W.
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C. T. OꢀHara, Angew. Chem. 2006, 118, 6698; Angew. Chem. Int.
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Kennedy, R. E. Mulvey, Chem. Commun. 2007, 598; i) B.
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Z = 4, 1calcd = 1.098 gcmÀ3 T= 150 K, m(MoKa) = 0.73 mmÀ1
, ;
37071 reflections measured, 6851 unique, Rint = 0.054; R (F,
F2 > 2s) = 0.046, wR (F2, all data) = 0.111, S (F2) = 1.031, 459
refined parameters and 626 restraints, constrained H atoms,
difference map extremes + 0.69 and À0.53 eŠÀ3. Crystal data for
3: C22H50N6Na+C12H27ZnÀ, Mr = 658.4, monoclinic, space group
C2/c, a = 19.018(4), b = 11.656(2), c = 20.795(4) Š, b = 94.58(3)8,
V= 4595.0(15) Š3, Z = 4 (cation on an inversion center, anion
disordered on a twofold rotation axis), 1calcd = 0.952 gcmÀ3, T=
150 K, m(MoKa) = 0.57 mmÀ1; 26012 reflections measured, 4018
unique, Rint = 0.049; R (F, F2 > 2s) = 0.056, wR (F2, all data) =
0.134, S (F2) = 1.050, 250 refined parameters and 132 restraints,
constrained H atoms, difference map extremes + 0.34 and
À0.18 eŠÀ3. CCDC 661569 (1), 661570 (2) and 661571 (3)
contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
[8] The same cyanide has been used to form the complex
(tBuCN·LiHMDS)2, which led the authors to conclude that
complexes of the type RCN·MR’ are probably of general
importance in reactions of cyanides with organometallic com-
pounds R’M, see: G. Boche, I. Langlotz, M. Marsch, K. Harms,
G. Frenking, Angew. Chem. 1993, 105, 1207; Angew. Chem. Int.
Ed. Engl. 1993, 32, 1171.
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Angew. Chem. Int. Ed. 2007, 46, 7685.
[6] E. Elzein, R. Kalla, X. Li, T. Perry, E. Parkhill, V. Palle, V.
Varkhedkar, A. Gimbel, D. Zeng, D. Lustig, K. Leung, J.
Zablocki, Bioorg. Med. Chem. Lett. 2006, 16, 302.
[9] S. S. Kaye, J. R. Long, Chem. Commun. 2007, 4486.
[10] H. Vahrenkamp, Dalton Trans. 2007, 4751.
[7] For synthetic details and NMR spectroscopic characterization
see the Supporting Information. Crystal data for 1:
734
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ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2008, 47, 731 –734