Pyridine N-alkylatfon by lithium, magnesium, and zinc alkyl reagents: Synthetic, structural, and mechanistic studies on the bis(imino)pyridine system

Article abstract of DOI:10.1021/ja042657g

The 2,6-bis(α-iminoalkyl)pyridines 2,6-[ArNC(CR₃)] ₂C₅H₃N [R = H, D; Ar = 2,6-i-Pr ₂C₆H₃ (DIPP), 2,6-Me₂C ₆H₃ (DMP)] react with MeLi in Et₂O to give a binary mixture of products: the pyridine N-methylated species 2,6-[ArNC(CR ₃)]₂C₅H₃N(Me)Li(OEt₂) and the deprotonated/dedeuterated species 2-[ArNC(CR₃)],6-[ArNC(=CR ₂)]C₅H₃NLi(OEt₂). For R = D, the product ratio is 2:1 in favor of the N-methylated product, while, for R = H, the deprotonated product is favored by 5:1, increasing to 8:1 in toluene solvent. Warming solutions of the N-methylated species leads to clean conversion to the thermodynamically preferred deprotonated species. Crossover experiments show that MeLi is re-formed and dissociates from the terdentate ligand before deprotonating the ketimine methyl unit. For MgR₂ (R = Et, i-Pr) and ZnR₂ (R = Et) reagents, N-alkylation products are formed exclusively, but derivatives containing bulky aryl substituents are found to undergo further rearrangement to 2-alkylated species, arising by migration of the alkyl group of the N-alkyl moiety to the adjacent ring carbon atom. The reversibility of the N-alkylation process has been probed using deuterio-labeled Mg alkyl reagents and mixed alkyl zinc species. A cationic zinc derivative is shown to undergo "reverse" alkyl migration, from the heterocycle nitrogen atom to the zinc center. EPR spectroscopy reveals a paramagnetic intermediate in which the unpaired electron is delocalized over the heterocycle and di-imine moieties of the ligand, indicating that the N-alkylation reactions proceed via single electron-transfer processes.

Full text of DOI:10.1021/ja042657g

Published on Web 03/29/2005
Pyridine N-Alkylation by Lithium, Magnesium, and Zinc Alkyl
Reagents: Synthetic, Structural, and Mechanistic Studies on
the Bis(imino)pyridine System
Ian J. Blackmore,† Vernon C. Gibson,*,† Peter B. Hitchcock,‡ Charles W. Rees,†
David J. Williams,† and Andrew J. P. White†
Contribution from the Department of Chemistry, Imperial College London, Exhibition Road,
London SW7 2AY, UK, and Department of Chemistry, UniVersity of Sussex, Falmer,
Brighton BN1 9QJ, UK
Received December 7, 2004; E-mail: v.gibson@imperial.ac.uk
Abstract: The 2,6-bis(R-iminoalkyl)pyridines 2,6-[ArNC(CR3)]2C5H3N [R ) H, D; Ar ) 2,6-i-Pr2C6H3 (DIPP),
2,6-Me2C6H3 (DMP)] react with MeLi in Et2O to give a binary mixture of products: the pyridine N-methylated
species 2,6-[ArNC(CR3)]2C5H3N(Me)Li(OEt2) and the deprotonated/dedeuterated species 2-[ArNC(CR3)],6-
[ArNC(dCR2)]C5H3NLi(OEt2). For R ) D, the product ratio is 2:1 in favor of the N-methylated product,
while, for R ) H, the deprotonated product is favored by 5:1, increasing to 8:1 in toluene solvent. Warming
solutions of the N-methylated species leads to clean conversion to the thermodynamically preferred
deprotonated species. Crossover experiments show that MeLi is re-formed and dissociates from the
terdentate ligand before deprotonating the ketimine methyl unit. For MgR2 (R ) Et, i-Pr) and ZnR2 (R ) Et)
reagents, N-alkylation products are formed exclusively, but derivatives containing bulky aryl substituents
are found to undergo further rearrangement to 2-alkylated species, arising by migration of the alkyl group
of the N-alkyl moiety to the adjacent ring carbon atom. The reversibility of the N-alkylation process has
been probed using deuterio-labeled Mg alkyl reagents and mixed alkyl zinc species. A cationic zinc derivative
is shown to undergo “reverse” alkyl migration, from the heterocycle nitrogen atom to the zinc center. EPR
spectroscopy reveals a paramagnetic intermediate in which the unpaired electron is delocalized over the
heterocycle and di-imine moieties of the ligand, indicating that the N-alkylation reactions proceed via single
electron-transfer processes.
1. Introduction
It has long been recognized that conjugated nitrogen ligands,
especially imines, can be non-innocent in their coordination
chemistry, readily engaging in metal-to-ligand charge transfer
and sometimes undergoing alkyl migration reactions. The latter
were first extensively documented for R-diimine complexes of
magnesium and zinc, where alkylations were observed at the
imine carbon and nitrogen moieties, respectively, and shown
to proceed via single electron transfer (SET) processes.5 While
the available evidence has suggested that bis(imino)pyridine
ligands remain intact during polymerization reactions on iron
and cobalt,1c it has been found that when attached to vanadium,
Bis(imino)pyridines have attracted considerable interest in
recent years due to their capacity to stabilize highly active
ethylene polymerization catalysts based on the late transition
metals iron and cobalt1 and the earlier transition metals
vanadium2 and chromium.3 Despite many investigations directed
toward broadening the family of terdentate ligands suited to
the stabilization of iron-based catalysts,4 the productivities have
been found to fall off dramatically upon the introduction of
significant changes to the bis(imino)pyridine core. There is thus
a need to understand why bis(imino)pyridines should be so
specially suited to the stabilization of polymerization-active
metal centers.
(4) (a) Britovsek, G. J. P.; Mastoianni, S.; Solan, G. A.; Baugh, S. P. D.;
Redshaw, C.; Gibson, V. C.; White, A. J. P.; Williams, D. J.; Elsegood,
M. R. J. Chem.sEur. J. 2000, 6, 2221. (b) Ma, Z.; Wang, H.; Qiu, J.; Xu,
D.; Hu, Y. Macromol. Rapid Commun. 2001, 22, 1280. (c) Ma, Z.; Sun,
W.-H.; Li, Z.-L.; Shao, C.-X.; Hu, Y.-L.; Li, X.-H. Polym. Int. 2002, 51,
994. (d) Britovsek, G. J. P.; Gibson, V. C.; Hoarau, O. D.; Spitzmesser, S.
K.; White, A. J. P.; Williams, D. J. Inorg. Chem. 2003, 42, 3454. (e) Chen,
Y.; Qian, C.; Sun, J. Organometallics 2003, 22, 1231. (f) Schmidt, R.;
Hammon, U.; Gottfried, S.; Welch, M. B.; Alt, H. G. J. Appl. Polym. Sci.
2003, 88, 476. (g) Abu-Surrah, A. S.; Lappalainen, K.; Piironen, U.;
Lehmus, P.; Repo, T.; Leskela¨, M. J. Organomet. Chem. 2002, 55. (h)
Chen, Y.; Chen, R.; Qian, C.; Dong, X.; Sun, J. Organometallics 2003,
22, 4312. (i) Ivanchev, S. S.; Tolstikov, G. A.; Badaev, V. K.; Oleinik, I.
I.; Ivancheva, N. I.; Rogozin, D. G.; Oleinki, I. V.; Myakin, S. V. Kinet.
Catal. 2004, 45, 176. (j) Paulino, I. S.; Schuchardt, I. J. Mol. Catal. A:
Chem. 2004, 211, 55. (k) Bluhm, M. E.; Folli, C.; Do¨ring, M. J. Mol. Catal.
A: Chem. 2004, 212, 13. (l) Smit, T. M.; Tomov, A. K.; Gibson, V. C.;
White, A. J. P.; Williams, D. J. Inorg. Chem. 2004, 43, 6511.
† Imperial College London.
‡ University of Sussex.
(1) (a) Small, B. L.; Brookhart, M.; Bennett, A. M. A. J. Am. Chem. Soc.
1998, 120, 4049. (b) Britovsek, G. J. P.; Gibson, V. C.; Kimberley, B. S.;
Maddox, P. J.; McTavish, S. J.; Solan, G. A.; White, A. J. P.; Williams,
D. J. Chem. Commun. 1998, 849. (c) Britovsek, G. J. P.; Bruce, M.; Gibson,
V. C.; Kimberley, B. S.; Maddox, P. J.; Mastroianni, S.; McTavish, S. J.
P.; Redshaw, C.; Solan, G. A.; Stro¨mberg, S.; White, A. J. P.; Williams,
D. J. J. Am. Chem. Soc. 1999, 121, 8728.
(2) Reardon, D.; Conan, F.; Gambarotta, S.; Yap, G.; Wang, Q. J. Am. Chem.
Soc. 1999, 121, 9318.
(3) Estruelas, M. A.; Lo´pez, A. M.; Me´ndez, L.; Oliva´n, M.; On˜ate, E.
Organometallics 2003, 22, 395.
9
6012
J. AM. CHEM. SOC. 2005, 127, 6012-6020
10.1021/ja042657g CCC: $30.25 © 2005 American Chemical Society

Pyridine N-Alkylation by Li/Mg/Zn Alkyl Reagents
A R T I C L E S
Scheme 1
the alkylaluminum cocatalyst can give rise to alkylation at the
pyridine carbons of the ligand backbone,2 presumably via
external attack of the cocatalyst on the transition metal bonded
bis(imino)pyridine ligand. For chromium6 and manganese,7
products arising from ligand coupling reactions are found.
In parallel studies, we8 and Gambarotta and co-workers9
found that treatment of bis(imino)pyridines with MeLi unex-
pectedly afforded a product in which the methyl group had
attacked the pyridine nitrogen atom. To our knowledge, this
was the first time that nonelectrophilic alkylation at pyridine
nitrogen had been documented. In order to understand more
about this remarkable reaction and its possible relevance to
highly active transition metal polymerization systems, we
embarked on a more detailed investigation of the MeLi reaction
along with related reactions of bis(imino)pyridines with mag-
nesium dialkyl and zinc dialkyl reagents. Here, we describe
synthetic, structural, and mechanistic investigations that examine
the site selectivity of the alkylation, the reversibility of the
process, the structures of key alkylation products, and the
mechanism by which the alkylation process occurs.
Scheme 2
gave a mixture of the N-alkylated product 2 and the deproto-
nated product 3, but now in a ratio of 1:5. The greater amount
of the deprotonated product compared to the dedeuterated
product is consistent with the greater C-D bond strengths
associated with the deuterio-methyl derivative. When the
reaction was carried out in toluene, different ratios were
2. Results
2
2
2
obtained. For example, H6-1 gave H6-2 and H5-3 in a 1:1
ratio, while ligand 1 gave 2 and 3 in a ratio of 1:8.
2.1. Reactivity of Bis(imino)pyridines toward Methyl-
lithium. In a preliminary communication we described the
reaction of the partially deuterated 2,6-bis(R-iminoalkyl)-
pyridine, 2,6-[(DIPP)NC(CD3)]2C5H3N (2H6-1, DIPP ) 2,6-
Pri2C6H3), with MeLi to give a deep blue solution from which
the N-methylated product 2H6-2 was isolated in reasonable
(60%) yield.8 Gambarotta and co-workers found that a closely
related, though binuclear, analogue could be isolated using per-
protio 1, and that this compound undergoes a thermal conversion
to the de-protonated product 3.9 In our hands we had found
that the reaction of the per-protio ligand did not afford
substantial yields of the N-methylated product but rather more
of the deprotonated species. The reason for the selective
crystallization of the minor product, arising from N-methylation,
is most probably related to the lower solubility of the dimeric
species. We have, therefore, reinvestigated reactions of per-
protio and deuterated 1 with MeLi with a view to understanding
more about the site selectivity in the protio and deuterio systems.
Treatment of an Et2O suspension of 2,6-[(DIPP)NC(CD3)]2-
C5H3N (2H6-1, DIPP ) 2,6-Pri2C6H3) with 1 equiv of MeLi at
-78 °C or at room temperature gave a blue-red dichroic
solution. After removal of the volatile components, the 1H NMR
spectrum of the crude product revealed a 2:1 mixture of the
N-methylated product 2H6-2 and the dedeuterated product 2H5-3
(Scheme 1). Selective recrystallization of this mixture from Et2O
gave 2H6-2 in 50% isolated yield (75% based on 2H6-2).
Treatment of per-protio bis(imino)pyridine 2,6-[(DIPP)NC-
(CH3)]2C5H3N (1) with MeLi under identical conditions also
Changing the aryl substituents had little effect on the ratio
of products. For example, treatment of the 2,6-dimethylphenyl
analogue 2,6-[(DMP)NC(CD3)]2C5H3N (2H6-4, DMP ) 2,6-
Me2C6H3) with 1 equiv of MeLi gave a similar 2:1 mixture of
the N-methylated product, 2H6-5, and the dedeuterated product,
2H5-6.
From the earlier reports, there was an indication that the
alkylation reaction is reversible. Gambarotta and co-workers had
found that treatment of their binuclear N-methylated complex
with iPrBr led to the re-formation of 1,9 while our studies on
reactions of N-methylated 2H6-2 with FeCl3 had shown that the
deuterated bis(imino)pyridine, 2H6-1, is regenerated along with
a polymerization system (in the presence of added methylalu-
minoxane, MAO) of comparable activity to (1)FeCl2/MAO.8
In further investigations of the stability of the N-methylated
2
products, complex H6-2 was found to be stable for extended
periods at room temperature. However, gentle warming of a
C6D6 solution to 35 °C or above led to its clean conversion to
2H5-3 with loss of methane (Scheme 2), a reaction similar to
that observed for the per-protio system.
With a view to establishing whether this transformation
occurred via an intramolecular pathway, in which the methyl
group migrates to the imine carbon with subsequent loss of
methane, or via the re-formation of MeLi which dissociates from
the ligand and is then available to dedeuterate the ligand
backbone, a crossover experiment was performed. A sample of
2H6-2 was heated in C6D6 to 35 °C in the presence of 1 equiv
of the per-protio ligand 1 (Scheme 3). The reaction proceeded
smoothly and cleanly over 48 h to afford a mixture of 2H5-3, 1,
(5) (a) van Koten, G.; Jastrzebski, J. T. B. H.; Vrieze, K. J. Organomet. Chem.
1983, 250, 49. (b) Kaupp, M.; Stoll, H.; Preuss, H.; Kaim, W.; Stahl, T.;
van Koten, G.; Wissing, E.; Smeets, W. J. J.; Spek, A. L. J. Am. Chem.
Soc. 1991, 113, 5606. (c) Kaim, W. Acc. Chem. Res. 1985, 18, 160. (d)
Ashby, E. C. Acc. Chem. Res. 1988, 21, 414. (e) Wissing, E.; Kaupp, M.;
Boersma, J.; Spek, A. L.; van Koten, G. Organometallics 1994, 13, 2349.
(6) Sugiyama, H.; Aharonian, G.; Gambarotta, S.; Yap, G. P. A.; Budzelaar,
P. H. M. J. Am. Chem. Soc. 2002, 124, 12268.
2
and the crossover products 3 and H6-1. This provides strong
evidence that MeLi is reformed and dissociates from the
deuterated ligand prior to deprotonation of 1.
(7) Reardon, D.; Aharonian, G.; Gambarotta, S.; Yap, G. P. A. Organometallics
2002, 21, 786.
2.2. Reactivity of Bis(imino)pyridines toward Dialkylmag-
nesium Reagents. In the case of magnesium alkyls, deproto-
nation of the ketimine methyl groups does not occur, presumably
due to the lower basicity of the magnesium-alkyl moiety
(8) Clentsmith, G. K. B.; Gibson, V. C.; Hitchcock, P. B.; Kimberley, B. S.;
Rees, C. W. Chem. Commun. 2002, 1498.
(9) Khorobkov, I.; Gambarotta, S.; Yap, G. P. A.; Budzelaar, P. H. M.
Organometallics 2002, 21, 3088.
9
J. AM. CHEM. SOC. VOL. 127, NO. 16, 2005 6013

A R T I C L E S
Scheme 3
Blackmore et al.
compared to its lithium relative. Therefore, for the study of the
magnesium system, per-protio bis(imino)pyridines were em-
ployed throughout. Several bis(imino)pyridines reacted cleanly
with MgR2 reagents to give N-alkylated products according to
Scheme 4. The relatively unhindered DMP-substituted ligand,
4, was found to react with MgMe2 to give a deep purple solution
indicative of N-methylation. However, workup yielded only an
intractable mixture of products. When reacted with MgEt2, 4
gave a similar deep purple solution, but in this case, a clean
product, 7, was isolated. Its 1H NMR spectrum revealed an AX2
pattern of resonances centered at 5.55 and 6.73 ppm assignable
to the protons at the 4- and 3-positions of the former pyridine
ring, respectively, consistent with a mirror plane of symmetry
bisecting the central heterocycle. Singlets at 1.82 and 2.21 ppm
are attributable to inequivalent methyl substituents of the aryl
groups, while a quartet resonance centered at -0.21 ppm is
assigned to the methylene unit of the magnesium-bonded ethyl
group. A low field quartet resonance at 2.71 ppm is attributable
to the methylene protons of the N-ethyl moiety. These data are
consistent with the N-ethylated product 7 (Scheme 4). Analo-
gous spectral features were found for the deep red product, 8,
arising from the reaction of 4 with the MgPri2 again indicating
that alkylation at pyridine nitrogen had occurred.
red needles. Over a period of several weeks at room temperature,
the latter species slowly underwent a further transformation.
We shall return to this shortly (section 2.5).
In a further attempt to isolate an N-methylated species,
MgMe2 was reacted with the most sterically hindered bis(imino)-
pyridine, 1. When the reaction was carried out in toluene, a
deep blue-purple solid was isolated and found to be the
N-methylated species 12. In diethyl ether, 12 is isolated as a
highly crystalline, dioxane-bridged dimer 12a. The dioxane is
carried over from the in-situ-generated MgMe2 and can be
removed to afford 12 upon trituration with toluene followed by
recrystallization from pentane solution. Upon changing MgMe2
to MgEt2, the N-ethylated product 13 is observed to form by
NMR spectroscopy, but it undergoes a rearrangement at a rate
comparable with its formation to give a species analogous to
that observed upon rearrangement of 11 (see section 2.5).
Treatment of the aldimine ligands 14 and 15 with both
MgMe2 and MgEt2 led to intractable mixtures, whereas their
reaction with MgPri2 led to the isolation of 16 as a bright purple,
microcrystalline solid and 17 as a deep red, waxy solid. The
isolated yields were relatively low as a result of the high
solubility of both products. The absence of backbone methyl
groups manifests itself by allowing rapid rotation of the phenyl
substituents of 16 on the NMR time scale, a broad singlet
resonance now being observed for the ortho-methyl substituents.
Scheme 4
2.3. Molecular Structures of N-Alkylated Bis(imino)-
pyridine Magnesium Complexes. Crystals of 7 and 8 suitable
for X-ray structure determinations were grown from saturated
pentane solutions at room temperature, and crystals of 11 and
12a were grown from Et2O solutions at room temperature
(Figures 1, 2, 3, and 4, respectively, showing atoms as 50%
ellipsoids). Bond parameters for 7, 8, 11, and 12a are collected
in Table 1.
The N-alkylated ligand is very similar in all four structures.
When comparing them with complexes of bis(imino)pyridines1
the most striking feature is the tetrahedral nature of the former
pyridine nitrogen where bond angles lie within the range 106°-
112° and the bond lengths around this nitrogen are all indicative
of single bonds. The bonds through the backbone of the ligand
between the imine nitrogens are indicative of delocalization,
although the carbon-carbon bonds between the imine func-
tionality and the heterocycle are generally slightly longer.
Interestingly, the structures of 7, 8, and 11 all show that the
N-alkyl group is orientated with the bulky methyl substituents
of the ethyl or isopropyl groups directed away from the
heterocycle toward the magnesium alkyl fragment. This orienta-
tion is favored as it allows the methine or a methylene hydrogen
to be directed toward the 4-position of the heterocycle thus
In the event that greater steric protection might be required
to isolate an N-methylated species, the reaction of the 2,6-
diethylphenyl (DEP)-substituted ligand 9 with MgMe2 was
investigated. A similar color change to dark purple was
observed, but again it did not prove possible to isolate a clean
product. However, 9 reacted smoothly with MgEt2 to give the
N-alkylated complex 10 and with MgPri2 to afford 11 as dark
9
6014 J. AM. CHEM. SOC. VOL. 127, NO. 16, 2005

Pyridine N-Alkylation by Li/Mg/Zn Alkyl Reagents
A R T I C L E S
Figure 4. Thermal ellipsoid plot for 12a (at 50% probability level).
Figure 1. Thermal ellipsoid plot for 7 (at 50% probability level).
are the bond lengths associated with the magnesium centers,
since these become longer as the steric conflict around the
magnesium center is increased. The bond lengths in 7 are of
less accuracy but are comparable with those in 8. In the case of
8 the bonds to the imine nitrogens, Mg-N(1) and Mg-N(3),
are 2.112(2) and 2.131(2) Å, respectively, and the bond to the
heterocycle nitrogen, Mg-N(2), is slightly longer at 2.146(2)
Å, while the bond to the isopropyl carbon, Mg-C(29), is 2.122-
(2) Å. The magnesium-imine nitrogen bonds in 11 are, on
average, slightly longer at 2.147(1) and 2.139(1) Å for Mg-
N(1) and Mg-N(3), respectively. The bond to the heterocycle
nitrogen, Mg-N(2), is again longer than its counterpart in 8 at
2.180(1) Å as is the magnesium-carbon bond, Mg-C(33), at
2.157(2) Å. The bond lengths associated with the magnesium
center in 12a are again longer, although this may be partially
due to the presence of a fifth donor atom, in this case the oxygen
of dioxane. The magnesium-imine nitrogen bond, Mg-N(1)
and Mg-N(3), are now 2.179(2) and 2.245(2) Å, respectively.
The bond to the heterocycle nitrogen, Mg-N(2), is now 2.226-
(2) Å, and the bond to the methyl carbon, Mg-C(35), is 2.157-
(2) Å. The bond between the magnesium center and the oxygen
of the coordinating dioxane is rather long at 2.305(1) Å
suggesting a weak interaction.
Figure 2. Thermal ellipsoid plot for 8 (at 50% probability level).
2.4. Reactivity of Bis(imino)pyridines toward Dialkyl Zinc
Reagents. By contrast to MgMe2, treatment of bis(imino)-
pyridine ligands with ZnMe2 did not lead to any reaction even
after extended periods of time. This is likely to be a consequence
of the stronger Zn-C bond strength for Zn-Me relative to its
longer chain homologs.10 Consistently, the reaction between 4
and ZnEt2 proceeded smoothly and cleanly (by NMR) to afford
the purple N-ethylated complex 18 (Scheme 5) as the sole
product after approximately 24 h. Its 1H NMR spectrum revealed
a similar series of resonances to those observed for its
magnesium analog.
Figure 3. Thermal ellipsoid plot for 11 (at 50% probability level); side
view.
The molecular structure of 18 is shown in Figure 5. It
crystallizes with two independent molecules (A and B, shown
in Figure 5a and b, respectively) which have approximately the
same conformation. The biggest differences between the two
molecules lie in the torsion angles about the N1-Ar bond (ca.
88° and 78° in molecules A and B, respectively) and in the
orientation of the Zn-Et ethyl moiety, the N2-Zn-C28-C29
minimizing the interaction between the N-alkyl group and the
carbons in the 3-, 4-, and 5-positions of the ring which has taken
on a “boatlike” conformation. This orientation also has the effect
of directing the bulk of the N-alkyl group toward the ortho-
aryl substituents.
The geometry around the magnesium center in 7, 8, and 11
is best described as severely distorted tetrahedral and, in the
case of 12a, as distorted trigonal-bipyramidal with N2-Mg-O
as the axial direction. Of perhaps more significance, however,
(10) (a) Bryndza, H. E.; Fong, L. K.; Paciello, R. A.; Tam, W.; Bercaw, J. E.
J. Am. Chem. Soc. 1987, 109, 1444. (b) Britovsek, J. G. P.; Cohen, S. A.;
Gibson, V. C.; van Meurs, M. J. Am. Chem. Soc. 2004, 126, 10701.
9
J. AM. CHEM. SOC. VOL. 127, NO. 16, 2005 6015

A R T I C L E S
Blackmore et al.
Table 1. Selected Bond Lengths (Å) and Angles (deg) for 7, 8, 11, 12a, and 18 (for 7, Dimensions Are Given for the Ordered Molecule)
18
18
7
8
11
Mg]
12a
Mg]
(mol A)
(mol B)
[M
)
Mg]
[M
)
Mg]
[M
)
[M
)
[M
)
Zn]
[M
)
Zn]
M-N1
2.128(4)
2.165(4)
2.131(4)
2.134(6)
2.112(2)
2.146(2)
2.131(2)
2.122(2)
2.147(1)
2.180(1)
2.139(1)
2.157(2)
2.179(2)
2.226(2)
2.245(2)
2.157(2)
2.305(1)
1.455(2)
1.458(2)
1.495(2)
1.326(2)
1.324(2)
1.412(2)
1.392(2)
1.388(3)
1.396(3)
2.115(3)
2.127(3)
2.112(3)
1.988(4)
2.107(3)
2.133(2)
2.099(2)
1.981(3)
M-N2
M-N3
M-C(alkyl)
M-O
N2-C2
N2-C6
1.468(6)
1.462(6)
1.506(7)
1.317(5)
1.320(6)
1.409(6)
1.389(7)
1.392(7)
1.383(7)
1.466(2)
1.466(2)
1.520(2)
1.318(2)
1.317(2)
1.422(2)
1.388(2)
1.392(3)
1.390(3)
1.470(2)
1.468(2)
1.520(2)
1.323(2)
1.323(2)
1.420(2)
1.386(2)
1.395(2)
1.393(2)
1.457(4)
1.454(4)
1.509(4)
1.318(4)
1.314(4)
1.407(5)
1.391(5)
1.383(6)
1.392(5)
1.458(4)
1.453(4)
1.512(4)
1.308(4)
1.323(4)
1.420(4)
1.388(4)
1.388(5)
1.401(5)
109.72(18)
109.66(17)
108.12(18)
107.7(2)
109.7(2)
112.0(2)
N2-C(alkyl)
N1-C1
N3-C7
C1-C2
C2-C3
C3-C4
C4-C5
M-N2-C2
M-N2-C6
M-N2-C(alkyl)
C2-N2-C6
C2-N2-C(alkyl)
C6-N2-C(alkyl)
N2-M-O
N1-M-O
N3-M-O
C(alkyl)-M-O
110.2(3)
109.1(1)
109.1(1)
111.1(1)
109.8(2)
109.8(3)
107.3(3)
107.7(3)
109.7(4)
112.2(4)
109.5(1)
109.4(1)
107.1(1)
112.0(1)
109.9(1)
109.0(1)
111.2(1)
106.0(1)
110.0(1)
111.3(1)
111.7(1)
106.0(1)
109.7(1)
109.3(1)
108.9(1)
161.63(5)
97.20(5)
96.15(5)
92.85(6)
110.54(18)
108.55(18)
106.8(2)
109.7(2)
111.5(3)
Scheme 5
field quartet at 0.30 ppm attributable to the Zn-ethyl group, a
singlet at 1.69 ppm attributable to two equivalent ketimine
methyl groups, and a septet at 3.20 ppm attributable to one of
the two inequivalent aryl-isopropyl groups are observed. Further
characterization of this intermediate was not possible, since it
only ever constituted <10% of the reaction mixture and over a
period of 10 days it was observed to rearrange to a complex in
torsion angles being ca. 143° and 160°, respectively. The
remaining non-hydrogen atoms for the two independent mol-
ecules have an rms deviation for their best fit of ca. 0.07 Å.
Interestingly, whereas in the magnesium analogue 7 the N2 and
Mg ethyl substituents point to the same side of the molecule
(see Figure 1), in both independent molecules of the zinc species
18 the N- and Zn-bound ethyl groups point to opposite sides.
The geometry at the metal center in each independent molecule
in 18 is distorted tetrahedral with angles in the ranges 79.43-
(9)°-134.20(15)° in molecule A and 79.18(10)°-137.70(12)°
in molecule B. In each molecule the two most acute angles are
associated with the two five-membered N,N′ chelate rings, and
the most obtuse angle is for the N2-Zn-C28 unit. The Zn-R
bonds are consistently shorter than their Mg-R counterparts
in 7, and this is most noticeable for the ethyl substituent where
the Zn-C bonds [1.988(4) and 1.981(3) Å in molecules A and
B, respectively] are ca. 0.15 Å shorter than the corresponding
Mg-C bond in 7 [2.134(6) Å].
2.5. Tautomerization of N-Alkylated Products to C-
Alkylated Species. It was found that certain N-alkylated
derivatives of zinc and magnesium, especially those bearing
more sterically demanding substituents, undergo transformations
to give closely analogous products upon standing in solution at
room temperature. For example, treatment of a solution of the
most sterically hindered bis(imino)pyridine, 1, with 1 equiv of
ZnEt2 initially afforded a dark purple solution indicative of
N-alkylation. Monitoring the reaction by 1H NMR spectroscopy
(d2-DCM) revealed the growth of the distinctive AX2 pattern
attributable to the heterocycle protons and a quartet at 2.85 ppm
attributable to the N-ethyl group. Also, the growth of a high
1
which the mirror plane of symmetry had been lost. In the H
NMR spectrum of this second species, resonances were present
due to two distinct ketimine methyl groups, along with four
septets and eight doublets assignable to four inequivalent
isopropyl units. The protons in the 3-, 4-, and 5-positions of
the heterocycle are no longer split into an AX2 pattern but
instead give an AMX pattern. Complex multiplets, at 1.74 and
0.48 ppm, are attributable to the methylene protons for two
distinct ethyl environments. Significantly, it is the resonance
associated with the N-ethyl moiety that has undergone the most
significant change in chemical shift. An HMBC NMR experi-
ment revealed coupling between the methylene carbon of the
ligand ethyl group and the protons in the 4-position and one of
the protons in the 3-position of the heterocycle. The carbon in
the 2-position of the heterocyclic ring was confirmed as a
quaternary carbon by a DEPT-135 experiment and was observed
to couple with the methylene and methyl protons of the ligand
ethyl group and the protons in the 3- and 4-positions of the
heterocycle. These observations are consistent with the ethyl
group being attached to the 2-position of the heterocyclic ring
and indicates that migration of the ethyl unit from nitrogen to
carbon had occurred (Scheme 6). Attempts to grow crystals of
this product suitable for a single-crystal X-ray diffraction study
were unsuccessful. For the analogous reaction of 1 with MgEt2,
the N-ethylated species 13 is formed initially, but it cannot be
isolated, since it rearranges to a product with similar spectral
features to its zinc relative and consistent with the 2-alkylated
tautomer. When the size of the aryl group is reduced to DEP,
the rearrangement is no longer observed unless the size of the
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Pyridine N-Alkylation by Li/Mg/Zn Alkyl Reagents
A R T I C L E S
Figure 5. Structure of the two independent molecules present (A in part a, B in part b) in the crystals of 18 (50% thermal ellipsoids, chemical numbering
scheme).
magnesium alkyl is increased to isopropyl, suggesting that the
alkyl migration is largely driven by steric factors.
evolution of 4 or uptake of 2H6-4 even after 6 weeks, indicating
that MgEt2 does not dissociate from the ligand, at least on the
time scale of this experiment.
Scheme 6
Scheme 7
2.6. Reversibility of the N-Alkylation Reactions. The
reversibility of the N-alkylation reactions has been probed by
deuterium labeling studies. Addition of 1 equiv of Mg(CD3)2
to a sample of 12 in C6D6 led to a decrease in the intensity of
the magnesium methyl resonance as it rapidly exchanged with
the deutero-methyl groups of Mg(CD3)2 (Scheme 7). Over a
period of approximately 48 h the signal assigned to the N-methyl
group also decreased in intensity as it too was replaced by
deutero-methyl groups. Although this suggests that the N-
alkylation is indeed reversible (a direct exchange between the
N-methyl group and Mg(CH3)2 seems unlikely), it does not
inform as to whether in this case the Mg(CH3)2 first dissociates
from the ligand as opposed to the N-methyl group simply
migrating back and forth between the magnesium and the
pyridine nitrogen until the two sites are equilibrated. The
reaction between Mg(C2D5)2 and 7 led to similar observations,
but in this case, the incorporation of deutero-ethyl groups at
the pyridine nitrogen took 6 weeks to reach equilibrium.
To determine whether MgMe2 or MgEt2 first dissociate from
the ligand, 12 was monitored in the presence of 1 equiv of 2H6-
1. This led to the slow evolution of 1 with concomitant
Due to the less ready availability of deutero-alkyl zinc
reagents, a modified approach was adopted for the zinc system.
In this case, the mixed Et/OPri complex 19 was first synthesized
by alcoholyis of 18 using PriOH in the presence of a catalytic
amount of [H(Et2O)2][BArf4]. 19 was then treated with 1 equiv
of Mg(C2D5)2 to give the mixed [ZnEt(C2D5)] complex, 20
(Scheme 9). If N-ethylation is reversible, then “scrambling” of
the deutero- and protio-ethyl groups in 20 would occur. Since
this was not observed after a period of approximately 6 weeks,
it can be concluded that the N-ethylation in this complex is not
reversible. Consistently, addition of the deuterated ligand 2H6-4
to complex 18 afforded no exchange after approximately 6
weeks. Similarly, no scrambling of the ethyl and methyl groups
in 21 was observed, though this may be due, in part, to the
stronger ZnMe bond.
2
formation of H6-12, the reaction reaching equilibrium after
2.7. Cationic Derivatives. Complex 18 was treated with 1
equiv of the strong Lewis acid B(C6F5)3 in order to abstract the
zinc ethyl group and to form a cationic complex. Over the course
approximately 6 weeks at room temperature (Scheme 8). By
2
contrast, addition of 1 equiv of H6-4 to 7 did not lead to any
9
J. AM. CHEM. SOC. VOL. 127, NO. 16, 2005 6017

A R T I C L E S
Scheme 8
Blackmore et al.
Scheme 10
of approximately 24 h 18 was completely consumed and the
1H NMR spectrum revealed a shift of the AX2 pattern from its
position at 5.54 and 6.94 ppm to 8.59 and 8.38 ppm, indicative
of aromatization of the pyridine heterocycle. The presence of a
EtB(C6F5)3- counterion is shown in the 1H NMR spectrum by
Scheme 9
group does not migrate to the zinc center due to strong binding
of THF (Scheme 11), indicating that coordinative unsaturation
is a prerequisite for migration of the alkyl group back to the
metal center.
Scheme 11
the presence of broad quartet and triplet resonances centered at
1.10 and 0.52 ppm, respectively, whereas a zinc-ethyl group
is revealed by the presence of quartet and triplet signals at 0.20
and 0.46 ppm, respectively. The 19F NMR spectrum gave
resonances at -134.9 ppm, -167.5 ppm, and -170.1 ppm,
-
consistent with a noncoordinated EtB(C6F5)4 counterion.11
These observations indicate that an ethyl group is abstracted to
give the cationic ethyl complex 22 presumably via a short-lived
cationic N-alkyl intermediate (Scheme 10).
2.8. Mechanism of Alkylation. The mechanism of alkylation
processes at imino carbon and nitrogen centers of R-diimine
ligands have been shown to involve single electron-transfer
processes, and in many cases, the products of alkyl radical
coupling reactions are observed as byproducts.5 For the reactions
described here no products arising from coupling of alkyl
To determine whether it is the N-ethyl that is abstracted, or
rather the zinc ethyl followed by migration of the N-ethyl group
to the zinc center, the mixed alkyl complex 21 was treated with
B(C6F5)3 in d8-THF; THF is used as the NMR solvent here
because 21 is generated in situ by using MgMe2 which is
incompatible with d2-DCM. In this case, the zinc methyl
resonance underwent a significant downfield shift from -1.15
ppm to 0.5 ppm indicative of formation of the [MeB(C6F5)3]
anion.10 The resonances associated with the N-ethyl group and
the AX2 pattern assigned to the heterocycle protons showed only
small shifts. Analogous results were obtained upon treatment
of 18 with B(C6F5)3 in d8-THF. These observations allow us to
conclude that B(C6F5)3 reacts preferentially with the zinc-bonded
alkyl group rather than the N-alkyl moiety, but here the N-ethyl
1
radicals are observed by H NMR spectroscopy, and despite
the diamagnetic nature of all of the complexes, we decided to
examine them by EPR spectroscopy in an attempt to identify
2
potential radical intermediates. Complexes H6-2 and 18, for
which the N-alkylation had been shown to be irreversible at
room temperature, gave no discernible signal. Complex 7 gave
a very weak EPR signal, while for complex 12, where
N-alkylation has been found to be readily reversible, a strong,
though rather complex, EPR signal was observed. The spectrum
obtained at 175 K is shown in Figure 6 along with a simulated
spectrum for a radical delocalized over both the imine and
pyridyl moieties. Since the N-alkylated product and the proposed
ligand-MgMe2 adduct present in the equilibrium are diamag-
(11) (a) Coles, M. P.; Jordan, R. F. J. Am. Chem. Soc. 1997, 119, 8125. (b)
Yang, X.; Stern, C. L.; Marks, T. J. J. Am. Chem. Soc. 1994, 116, 10015.
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6018 J. AM. CHEM. SOC. VOL. 127, NO. 16, 2005

Pyridine N-Alkylation by Li/Mg/Zn Alkyl Reagents
A R T I C L E S
Table 2. Summary of Reaction Products Arising from Treatment
of MgR2 Reagents with Bis(aldimino)pyridines and
Bis(ketimino)pyridines Bearing Differing Aryl Substituents
Figure 6. Experimental (black) and simulated (blue) EPR spectra of 12 at
175 K.
netic, the signal is likely to arise from a radical intermediate
such as that shown in Scheme 12.
For bis(imino)pyridines containing small aryl substituents,
intractable mixtures of products are produced unless bulky MgR2
reagents are employed, while, for the least hindered metal alkyl,
MgMe2, an N-alkylated product is isolable only for the most
hindered bis(imino)pyridine. For the combination of bulky MgR2
with bulky bis(imino)pyridine, the N-alkylated products are
destabilized in favor of products in which the alkyl group has
migrated to the adjacent carbon atom within the heterocyclic
ring. It is thus clear that the stability of the N-alkylated products
is dependent upon a steric balance between the alkyl group and
the imino aryl substituents. This delicate energetic balance is
also seen to be influenced by the substituent at the imino carbon
atom, since the aldimine derivative 17, the product of the
reaction between MgPri2 and the 2,6-diisopropylphenyl aldimine
ligand, is stable as the N-alkylated species. The zinc system
displays closely related effects with the exception of ZnMe2
which is unreactive toward bis(imino)pyridines, most probably
due to the stronger Zn-C bond of ZnMe2 versus ZnR2 (R )
Et, Pr, Bu, etc.) species.10 Labeling studies on the magnesium
system show that the metal-to-nitrogen migration is reversible,
but only for the most hindered bis(imino)pyridine does dis-
sociation of MgR2 occur. The alkylation reaction is irreversible
(or at least exceedingly slow) in the case of alkylzinc reagents.
However, if the zinc alkyl group of an N-alkylated species is
first abstracted by a strong Lewis acid, the N-attached alkyl
group does then migrate to the zinc center.
Scheme 12
3. Discussion
The differing ratios of N-methylated to deprotonated (and
dedeuterated) species in the per-protio and deuterio systems are
readily explained by a kinetic isotope effect. The observation
that the N-methylated species is converted, on warming, to the
thermodynamically preferred deprotonated product suggests that
the unconventional N-alkylating capacity of MeLi arises from
initial complexation of MeLi by the tridentate ligand, followed
by migration of the methyl group to the adjacent N-atom. The
loss of aromaticity of the pyridine ring is evidently compensated
by the extensive delocalization of the negative charge over the
heterocyclic ring and the imino groups of the ligand backbone.
The crossover experiments confirm that this process is finely
balanced energetically, the reverse process readily occurring to
liberate MeLi which is then available to deprotonate the ketimine
methyl moiety. The observation of both the N-methylated and
the dedeuterated products in the low-temperature reaction of
MeLi with deuterio-bis(imino)pyridines is reflective of a kinetic
product distribution arising from initial attack by MeLi on the
ligand backbone (dedeuteration) versus MeLi complexation by
the terdentate bis(imino)pyridine prior to alkyl migration.
By contrast to lithium alkyls, magnesium and zinc dialkyl
reagents are insufficiently basic to deprotonate/dedeuterate the
ketimine units, thus allowing a more detailed study of the factors
directly affecting the N-alkylation process, as well as the stability
of the N-alkylated products. Table 2 gives a summary of the
products arising from treatment of bis(imino)pyridines with a
range of magnesium alkyl reagents, revealing a relatively narrow
window in which the N-alkylated products are stable.
Mechanism. The experimental observations indicate that the
first step of the reaction involves coordination of the metal alkyl
by the ligand to give a simple adduct (Scheme 13). Crossover
Scheme 13
experiments have shown that complexation is reversible for
DIPP derivatives but irreversible for the sterically less hindered
DMP systems. Terdentate complexation of the bis(imino)-
9
J. AM. CHEM. SOC. VOL. 127, NO. 16, 2005 6019

A R T I C L E S
Blackmore et al.
pyridine directs the alkylation away from the imino functionality,
which would at first appear to be the most likely site of
alkylation. Furthermore, attack at the imino carbon or nitrogen
atoms is disfavored by the presence of the ortho substituents
attached to the aryl groups. Once coordinated by the ligand, it
seems that the only site that can be alkylated directly is the
pyridine nitrogen which leads to a reduction in the steric
crowding around the metal center in the pentacoordinated
precursor. The EPR experiments on the magnesium system
strongly implicate single electron transfer (SET) processes, the
first step involving one-electron reduction of the bis(imino)-
pyridine to give a radical anion. Migration of one of the
magnesium alkyl groups then affords the diamagnetic N-
alkylated species. Although the loss of aromaticity of the
pyridine ring is unfavorable, this is partially compensated by
the extensive delocalization of the negative charge between the
imine nitrogens through the backbone of the ligand.
“noninnocent” behavior of the bis(imino)pyridine ligand system
and may illuminate why the combination of pyridine and imino
donors is so special in the metal-based chemistry and catalysis
they support.
5. Experimental Details
Details for the synthesis of compounds, their characterizing data,
and their reactions are collected in the Supporting Information.
X-ray Structure Determinations. Data for 7, 8, 11, and 12a were
collected on a Nonius KappaCCD diffractometer with graphite mono-
chromated Mo KR radiation (λ ) 0.710 73 Å). In each case a single
crystal coated in oil was mounted on a glass fiber in a stream of cold
nitrogen gas. Unit cell parameters were refined using the whole data
set. All frames of data were processed using the DENZO-SCALEPACK
programs.13 Empirical absorption corrections were applied.14 Structure
solution and refinement were carried out using SHELXL-9715 as
included in the WinGX package.16 For 7 the diffraction was weak and
limited in extent. Structure solution was by direct methods, and least
squares refinement was on all F2. Hydrogen atoms were included in
riding mode. For 7 there were two independent molecules, in one of
which there is disorder of the ethyl groups. For 8 there is disorder of
the C(30) and C(31) methyl groups, and the lower occupancy sites
were left isotropic and C-C(methyl) bond lengths in this group were
restrained. Data for 18 were collected on a Bruker P4/RA diffractometer
with graphite monochromated Cu KR radiation (λ ) 1.54 178 Å) using
the low-temperature oil drop technique. Structure solution and refine-
ment were carried out using the SHELXTL program system.17 Hydrogen
atoms were included in riding mode.
For the most sterically crowded N-alkylated complexes (such
as 11), the N-alkyl group migrates to the 2-position in what is
thought to be an irreversible rearrangement to relieve the steric
congestion. Although the 2-alkylated products are sterically
favored, they are probably disfavored in terms of π-bonding,
since they have lost both the aromaticity of the pyridine ring
and the compensatory delocalization of the formal negative
charge over the backbone of the ligand.
4. Conclusions
Acknowledgment. The Engineering and Physical Sciences
Research Council, UK, is thanked for a studentship to I.J.B.
Dr. D. Oduwole (Queen Mary and Westfield College, London,
UK) and Drs. E. McInnes and J. Wolowska (University of
Manchester, UK) are thanked for assistance with EPR measure-
ments and simulations.
The nonelectrophilic pyridine N-alkylation reactions docu-
mented in this study are, to our knowledge, unprecedented in
the long history of pyridine reaction chemistry.12 That such
transformations are seen in this system is undoubtedly attribut-
able to the special electronic and steric characteristics of 2,6-
bis(imino)pyridines. These facilitate strong binding of the
bis(imino)pyridine to the main group metal centers while
disfavoring attack at the imino nitrogen or carbon centers due
to the presence of bulky imino aryl substituents. A further
important factor is the capacity of pyridine and imino func-
tionalities to engage in metal-to-ligand charge transfer and, under
certain circumstances, even to formally accept one or more
electrons. When combined with the extensive charge delocal-
ization made possible through the two adjoining imino groups,
the aromatic stabilization of the pyridine moiety is overcome.
These results serve to highlight in a unique fashion the
Supporting Information Available: Experimental procedures
and characterization data, crystallographic data for structures
7, 8, 11, 12a, and 18. This material is available free of charge
via the Internet at http://pubs.acs.org.
JA042657G
(13) Otwinowski, Z.; Minor, W. In Processing of X-ray Diffraction Data
Collected in Oscillation Mode; Carter C. W., Jr., Sweet, R. M., Eds.;
Methods in Enzymology, Vol. 276: Macromolecular Crystallography, Part
A; Academic Press, 1997; pp 307-326.
(14) Blessing, R. H. Acta Crystallogr., Sect. A 1995, 51, 33.
(15) Sheldrick, G. M. SHELX97: Programs for Crystal Structure Analysis,
release 97-2; Institu¨t fu¨r Anorganische Chemie der Universita¨t: Tamman-
strasse 4, D-3400 Go¨ttingen, Germany, 1998.
(16) Farrugia, L. J. L. Appl. Crystallogr. 1999, 32, 837.
(17) SHELXTL PC, version 5.03; Siemens Analytical X-ray Instruments, Inc.:
Madison, WI, 1994. SHELXTL PC, version 5.1; Bruker AXS: Madison,
WI, 1997.
(12) For a detailed review, see: Scriven, E. F. V. In ComprehensiVe Heterocyclic
Chemistry; Katritzky, A. R., Rees, C. W., Boulton, A. J., McKillop, A.,
Eds.; Pergamon Press: Oxford, 1984; Vol. 2, p 165.
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6020 J. AM. CHEM. SOC. VOL. 127, NO. 16, 2005