Condensation of nitriles with amides promoted by coordinatively unsaturated bis-nickel(ii)-hydroxy complex: A new route to alkyl- and aryl-imidoylamidines

Article abstract of DOI:10.1039/b919634j

A pentacoordinate bis(μ-hydroxy) nickel dimer promotes formation of alkyl- and aryl-imidoylamidines from nitriles and ureas or amides under mild conditions.

Full text of DOI:10.1039/b919634j

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Condensation of nitriles with amides promoted by coordinatively
unsaturated bis-nickel(II)-hydroxy complex: a new route to alkyl- and
aryl-imidoylamidinesw
Jeffrey P. Wikstrom,a Alexander S. Filatovb and Elena V. Rybak-Akimova*a
Received (in Berkeley, CA, USA) 21st September 2009, Accepted 16th November 2009
First published as an Advance Article on the web 3rd December 2009
DOI: 10.1039/b919634j
A
pentacoordinate bis(l-hydroxy) nickel dimer promotes
the preparation of moderately exotic precursors, such as
lithiobenzamidine,7 provide routes only to halogenated and
N-substituted 1,3,5-triazapentadienes,8 or suffer low yields.9 A
direct route to in situ formation of aromatic IDA metal
complexes from a variety of nitrile substrates is therefore
desirable.10
formation of alkyl- and aryl-imidoylamidines from nitriles and
ureas or amides under mild conditions.
Reactions of metal-coordinated nitriles with nucleophiles and
electrophiles,1 as well as radicals or their precursors,2 are
gaining popularity as mild methods of making C–N, C–O,
C–S, and C–C bonds. Incorporation of additional nitrogen
atoms into nitrile-derived molecules can be easily performed in
metal-assisted reactions with ammonia or amines, affording
amidines.1 Reactions of nitriles with significantly less nucleo-
philic amides appear to be unknown, though the synthetic
product is easily obtained by other means, i.e. the reaction
of amidines with imidoyl chlorides.3 On the other hand,
activation of amides and related molecules (especially urea)
with biomimetic metallocomplexes has attracted much attention;
the goal of understanding and mimicking catalytic hydrolysis
of amides and ureas in biology has driven this field. Metal-
bound hydroxide has proven efficient in many enzymes
particularly urease,4 which catalyzes the hydrolysis of urea
(closely related to amides) into ammonia and carbon dioxide.
Given that the partial hydrolysis product of nitriles are
amides, reactions of nitriles with amides or ureas are certainly
relevant to the study of self-condensation of nitriles. The
complete hydrolysis of nitriles or of amides would generate
ammonia, which can condense with two molecules of nitrile,
generating imidoylamidines (IDAs).
Nickel ions and compounds show promise in metal-
promoted IDA syntheses,11–13 but existing methods are limited.
In 2001, we described a novel direct route to methyl IDA:
the solvolysis of acetonitrile by a tris(2-picolyl)amine (TPA)
bis(m-hydroxo) nickel dimer.11 The resulting N-(1-iminoethyl)-
ethanimidamide nickel complex, formed in situ over a period
of months at room temperature or days at 75 1C, incorporated
three nitrogen atoms from CH3CN in each bidentate ligand.
Kukushin et al. reported a similar in situ formation of a series
of alkyl or p-anisolyl IDA ligands by solvolysis of the
corresponding nitriles, templated on nickel(II) perchlorate
and mediated by acetoxime.12 In 2006, McGaff et al. modified
this procedure to generate in situ a series of aromatic IDA
ligands, including derivatives of p-nitrobenzonitrile and
p-trifluorotoluonitrile,13 as well as derivatives of cyanopyridine
substrates (a similar complex was described by Chen et al.9),
formed not via solvolysis, but rather in methanol. Via this
method, IDA complexes were formed without the addition of
an oxime mediator or nickel-bound hydroxide, but attempts
to generate IDAs from unsubstituted benzonitrile were
unsuccessful.
We herein describe the results of applying our recently
characterized coordinatively unsaturated [(tBuDPA)2(m-OH)2-
Ni2](ClO4)2 (tBuDPA = bis(2-pyridylmethyl)tert-butylamine)
complex14 (1), a 2Ni–2OH dimer structurally similar to the
coordinatively saturated bis(m-hydroxo) dimer supported by
TPA.11 Over a period of hours, at room temperature, this
complex is converted to tBuDPA nickel(II) bis(imino(phenyl)-
methyl)amide perchlorate (3), by way of a tBuDPA nickel(II)
acetyl(imino(phenyl)methyl)amide perchlorate intermediate
(2) (see Fig. 1).
Despite the well-ploughed fields of organonitrile activation
chemistry,1 amidine coordination chemistry,5 and the acetyl-
acetone (acac) analog nacnac,6 the topic of metal complexation
by IDAs has lacked attention, particularly aromatic IDAs,
though they are attractive ligands for modification; the bridge-
head nitrogen atom provides an additional potential route for
tuning the electronic properties of the ligand relative to the
similar acac. More versatile aromatic substituents offer several
advantages for tuning the ligand environment, both sterically
and electronically. Synthetic routes to aromatic IDAs have
been known since 1952,7,8 but known methods tend to require
a Tufts University, 62 Talbot Ave, Medford, MA 02155, USA.
E-mail: Elena.rybak-akimova@tufts.edu; Fax: +1-617-627-3443;
Tel: 617-627-3413
b SUNY Albany, 1400 Washington Aves, Albany, NY 12222, USA.
E-mail: afilatov@albany.edu
w Electronic supplementary information (ESI) available: UV/Vis of 1
to 2 and 2 to 3; CIF of 3 and crystallographic tabular materials;
synthesis and characterization of 2 and 3; ESI-MS results of 15N
isotopic labeling. CCDC 748549. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/b919634j
Fig. 1 Formation of 3 from 1, nitriles, and amides. R = Me, Ph.
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The first step of condensation of nitriles with amides
promoted by 1 is a clean and facile process. When 1 is
dissolved in benzonitrile with one equivalent of acetamide
per nickel in an argon atmosphere, the green solution turns
purple within an hour at room temperature; the visible
absorption band of the starting material 1 at 628 nm
(e = 16 cmꢁ1 Mꢁ1 per nickel) disappears, and new absorption
bands at 558 and 773 nm grow in. Very tight isosbestic points
indicate the absence of other colored species in the course of
the transformation of 1 into 2 (see ESI).w
distorted axial position relative to the otherwise square-planar
IDA and pyridyl nitrogens, resulting in a square-pyramidal
geometry with an unusually long axial amine–Ni bond length
of 2.539 A. The equatorial Ni–N bond lengths are much
shorter (1.836 to 1.930 A), on par with the 1.900 A average
Ni–N bond length for square-planar nickel complexes with
four chelating nitrogen atoms,16 and which indicates a very
strong equatorial ligand field. Despite this long Ni–N distance,
the association between the nickel and the amine nitrogen
appears to persist in solution, as room-temperature magneto-
metry of solid 3 (m = 3.2 BM) and NMR studies of its solution
confirm it is paramagnetic. The carbon–nitrogen bond lengths
of the 1,3,5-triazapentadienate backbone are 1.316 and 1.347 A,
indicating significant delocalization of the negative charge.
Mass spectrometry studies with 15N-acetamide and unlabeled
benzonitrile indicated that one nitrogen in each of 2 and 3
derives from acetamide (see ESI).w This overall stoichiometry
corresponds to hydrolysis of the acetamide, generating a single
molecule of ammonia which condenses with two molecules of
nitrile. However, an assay using the indophenol method for
determination of ammonia,17 performed on a methanolic
solution of 1 with two molar equivalents of acetamide,
indicated no ammonia was formed. Therefore, coordinated
nitriles are intimately involved in the process of ammonia
abstraction from acetamide. Fig. 1 displays the starting
materials, intermediates, and products we observed.
ESI-MS of the purple intermediate 2 indicates that the
2Ni–2OH nickel dimer has been disrupted, leaving in its place
a 1 : 1 Ni:tBuDPA complex, the base peak m/z = 474 of
which suggests one acetamide molecule and one benzonitrile
molecule have been incorporated into the coordination sphere
of the nickel (the isotopic pattern supports this formulation).
This suggests condensation of the acetamide and benzonitrile,
with the resulting anion coordinated in bidentate fashion
to the nickel(II) center, as indicated in Fig. 1. 2 can be
precipitated out of solution by addition of diethyl ether,
resulting in a stable purple solid precipitate, which when
redissolved and examined by UV/Vis or ESI-MS corresponds
to the original solution, which decomposes over time, preventing
crystallization. IR of 2 is consistent with a bound amide
moiety showing the absence of the characteristic O–H stretch
of 1 at 3641 cmꢁ1 and the presence of the carbonyl CQO
stretch at 1668 cmꢁ1
.
The conversion of 1 to 2 requires at least two transforma-
tions: formation of the imidoylamide intermediate species
from its precursors, and breakup of the 2Ni–2OH dimer into
mononuclear nickel complexes. The imidoylamide likely forms
via nucleophilic attack on the cyano carbon of the (coordinated)
nitrile by the amide nitrogen, possibly activated through
partial deprotonation by bridging hydroxide in the dinickel
complex. The order of these two steps, and whether they are
sequential or simultaneous, is currently unknown. Aminolysis
by a nickel–hydroxy dimer, resulting in elimination of water
and formation of monomeric complex, has been described by
Overnight, 2 in benzonitrile solution gives way to an
orange-brown product (see Fig. S1, ESIw), tBuDPA nickel(II)
bis(imino(phenyl)methyl)amide perchlorate (3). The final
product 3, similarly observed by ESI-MS, is likewise a 1 : 1
Ni:tBuDPA complex, the base peak m/z = 535 of which
implies a second benzonitrile molecule has replaced the acetyl
group, creating a bidentate anionic IDA ligand. 3 remains
stable in solution at ambient conditions for weeks, and can be
isolated as analytically pure dark green solid.
The X-ray structure of 3, shown in Fig. 2,15 confirms
this proposed formulation. In agreement with literature
precedence12,13 and ESI-MS, the cationic fragment shows a
1 : 1 Ni:tBuDPA complex with a N0-benzimidoyl-benzamidine
ligand occupying the remainder of the nickel’s coordination
sphere. The nickel cation is located in a pentacoordinate
environment; the central amine of the tBuDPA ligand is in a
Lo
´
pez et al.,18 and may play a role in the conversion of 1 to 2.
One possible pathway of formation of 3 from 2 includes
hydrolysis of the imidoylamide species at the carbonyl carbon,
generating acetate and a reactive amidine species which
attacks a second nitrile molecule, resulting in the IDA species
3 (Fig. S5, ESIw). The mechanism of these reactions, which
may include monomer–dimer equilibria, will be studied in due
course.
This imidoylamidine formation reaction may be general;
preliminary experiments confirm that both the nitrile and
the amide reagents can be varied without loss of reactivity
(Table S5, ESIw). The reaction scope in the nitrile component
was tested by replacing benzonitrile (an aromatic nitrile) with
the most common aliphatic nitrile, acetonitrile. An analogous
reaction occurs, resulting ultimately in the formation of the
same bis(acetimidoylacetamidine) nickel monomeric complex
described by Kryatov11 and others;12,19 this has been confirmed
by ESI-MS (m/z = 353) and single-crystal X-ray diffraction.
Methyl analogs of 2 and 3 were observed by ESI-MS
(m/z = 511 and 510, respectively), indicating the reaction
proceeds through the same intermediates in both benzonitrile
and acetonitrile. Mass spectrometry studies with d3-acetonitrile
Fig. 2 The cationic fragment of 3, with ellipsoids drawn at the 50%
probability level. Hydrogens are omitted for clarity.
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led to the analogs of 2 and 3 with molecular ion masses
supporting incorporation of one and two deuterated acetonitrile
molecules, respectively (m/z = 514 and 516).
3 S. O. Chua, M. J. Cook and A. R. Katritzky, J. Chem. Soc. Perk.
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Substitution of 1,1-dimethylurea for acetamide, under the
same conditions, resulted in the formation of the appropriate
dimethylamino derivative of 2, and ultimately the same
material 3, observed by ESI-MS. This unusual result indicates
that a combination of dinickel complex 1 and nitrile abstracts
ammonia from dimethylurea and inserts a nitrogen atom in
the IDA product. This is a remarkable transformation, given
the high resonance stabilization of urea and substituted ureas.
Although the enzyme urease readily catalyzes the hydrolysis of
urea and substituted ureas, synthetic model complexes of
urease rarely split urea,20 and extant models show reactivity
only at elevated temperature,17,21 while we observe facile
room-temperature transformation.
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In conclusion, we have demonstrated a novel methodology
for the generation of iminoamide and IDA nickel complexes
from solvent acetonitrile or benzonitrile at room temperature
and over a short period of time. This new reaction is promoted
by a coordinatively unsaturated dinickel(II) bis-hydroxy-
bridged complex tBuDPA2(m-OH)2Ni2(ClO4)2, a structural
model of the active site of urease enzyme, and appears general-
izable to a variety of nitriles, including aliphatic nitriles and
aromatic nitriles lacking an electron-withdrawing group in the
para position to the cyano group. Use of 1,1-dimethylurea as
an alternative to acetamide indicates the reaction may be
further generalizable with other amides, and even resonance-
stabilized, resistant to hydrolysis ureas are activated by
bis-hydroxo-bridged dinickel complex 1. Further research on
identifying the potential parameters of this chemistry, and
clarifying the reaction mechanism, is underway.
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15 Crystal structure data for 3 [C30H33N6NiClO4]: M = 635.78,
monoclinic, P21/n,
a
=
12.3250(9),
b
=
17.1390(12),
c = 14.1153(10) A, b = 104.325(1)1, Z = 4, V = 2889.0(4) A3,
Dc = 1.462 g cmꢁ3, T = 173(2) K, 24 185 reflections measured,
6292 unique reflections, Rint = 0.041, 388 parameters refined, R1,
wR2 [I 4 2s(I)] = 0.0443, 0.1020; R1, wR2 (all data) = 0.0619,
0.1128; S = 1.02.
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´ ´
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Financial support by the NSF (CHE 0750140, CHE-MRI
0821508, CHE-MRI 0320783) is appreciated. AF is very
grateful to the University at Albany for supporting the
X-ray center at the Department of Chemistry.
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This journal is The Royal Society of Chemistry 2010
426 | Chem. Commun., 2010, 46, 424–426