Aminomethyl-substituted ferrocenes and derivatives: Straightforward synthetic routes, structural characterization, and electrochemical analysis

Article abstract of DOI:10.1021/om400317s

A variety of aminomethyl-substituted ferrocenes and the parent compounds (iminomethyl)ferrocenes, azaferrocenophanes, and diferrocenylamines can be selectively synthesized from reductive amination of 1,1′-diformylferrocene or formylferrocene. The optimized one- or two-step reactions have delivered 13 new compounds, isolated in 65-97% yields, which include tertiary (ferrocenylmethyl)amines and azaferrocenophanes by using NaBH(OAc)₃ as a mild reducing agent and (iminomethyl)ferrocenes and secondary (ferrocenylmethyl)amines by using LiAlH₄. X-ray structures of representative members of these ferrocene derivative families have evidenced the preferred conformation adopted by ferrocene backbones, in which surprisingly the steric hindrance is apparently not systematically minimized. ¹⁵N NMR measurements on aminomethyl-substituted ferrocenes and derivatives are provided for the first time, establishing benchmark values ranging from -330 to -305 ppm (nitromethane δ 0 ppm). The cyclic voltammetry of these species evidences two clearly distinct oxidation potentials related to the iron(II) center and the amino function. These aminomethyl-substituted ferrocenes are potentially valuable for further ortho-directed functionalization of ferrocene.

Full text of DOI:10.1021/om400317s

Article
pubs.acs.org/Organometallics
Aminomethyl-Substituted Ferrocenes and Derivatives:
Straightforward Synthetic Routes, Structural Characterization, and
Electrochemical Analysis
Nejib Dwadnia,†,⊥ Fatima Allouch,†,⊥ Nadine Pirio,† Julien Roger,† Helene Cattey,† Sophie Fournier,†
́
̀
Marie-Josee Penouilh,† Charles H. Devillers,† Dominique Lucas,† Daoud Naoufal,‡ Ridha Ben Salem,§
́
and Jean-Cyrille Hierso*,†,∥
†Universite
21078 Dijon, France
‡Universite
Libanaise, Faculte
Beyrouth-Hadath, Lebanon
́
de Bourgogne, Institut de Chimie Molec
́
ulaire de l’Universite
des Sciences, Laboratoire de Chimie de Coordination Inorganique et Organomet
§Universite
́ ́
de Sfax, Faculte des Sciences, Laboratoire de Chimie Organique Physique, UR11ES74 3038 Sfax, Tunisia
́
de Bourgogne, UMR-CNRS 6302, 9 avenue Alain Savary,
́
́
́
allique,
∥Institut Universitaire de France (IUF), France
S
* Supporting Information
ABSTRACT: A variety of aminomethyl-substituted ferrocenes
and the parent compounds (iminomethyl)ferrocenes, azaferro-
cenophanes, and diferrocenylamines can be selectively synthe-
sized from reductive amination of 1,1′-diformylferrocene or
formylferrocene. The optimized one- or two-step reactions have
delivered 13 new compounds, isolated in 65−97% yields, which
include tertiary (ferrocenylmethyl)amines and azaferroceno-
phanes by using NaBH(OAc)3 as a mild reducing agent and
(iminomethyl)ferrocenes and secondary (ferrocenylmethyl)-
amines by using LiAlH4. X-ray structures of representative
members of these ferrocene derivative families have evidenced
the preferred conformation adopted by ferrocene backbones, in
which surprisingly the steric hindrance is apparently not
systematically minimized. 15N NMR measurements on aminomethyl-substituted ferrocenes and derivatives are provided for
the first time, establishing benchmark values ranging from 70 to 95 ppm (nitromethane δ 0 ppm). The cyclic voltammetry of
these species evidences two clearly distinct oxidation potentials related to the iron(II) center and the amino function. These
aminomethyl-substituted ferrocenes are potentially valuable for further ortho-directed functionalization of ferrocene.
complexes are accessible from B by deprotonation of the
secondary amine.
INTRODUCTION
■
Functionalized ferrocene derivatives are molecular edifices for
which a wide range of useful applications exist, particularly in
close relationship with homogeneous catalysis, electrochemis-
try, material and polymer sciences, and biomedical research.1
Driven by transition-metal-catalyzed applications, either
enantioselective1d,2 or achiral,3 the synthesis of ferrocene
derivatives incorporating atoms with donor bonding abilities
such as phosphorus atoms has attracted much attention.
Nitrogen-substituted ferrocenes have been comparatively much
less developed, even though a significant amount of works and
molecules have been reported since the 1950s.4 The synthesis
of 1,1′-diaminoferrocene5 (Scheme 1, A) has allowed the
development of 1,1′-ferrocene diamines (B)6 and iminoferro-
cenes (C),6c,7 successfully applied in catalytic olefin polymer-
ization and oligomerization reactions promoted by either early
(Ti, Zr) or late transition metals (Ni).7,8,4 Notably, amido
Before the work of McGowan and co-workers,9 only sporadic
examples of the related (aminoalkyl)ferrocene derivatives
(Scheme 1, E and D), which incorporate an alkyl spacer
between the ferrocene platform and a nitrogen-containing
moiety (mainly amines), had been reported. Concerning
aminomethyl-substituted ferrocenes (structures E and D in
which n = 1), which are invaluable building blocks,10 the need
for more efficiency and diversification in the synthetic modes is
clearly required: in particular with fewer synthetic steps, better
yields, and not being limited to the introduction of aliphatic
alkyl amines −NMe2 and −NEt2.11−13 McGowan and co-
workers reported the syntheses of 14 compounds of type E (n
Special Issue: Ferrocene - Beauty and Function
Received: April 13, 2013
© XXXX American Chemical Society
A
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Scheme 1. Nitrogen-Substituted Ferrocenes: (Aminoalkyl)ferrocene Derivatives D and E
Scheme 2. Targeted Aminomethyl-Substituted Ferrocenes and Parent Compounds
= 2−4) by addition of 2 equiv of adequately substituted
cyclopentadienyl salts to FeCl2, and a single example of an
aminomethyl-substituted ferrocene with a methylene spacer (n
= 1) bearing a 2-pyridinyl group has been described (yield
48%).9
Reductive amination of carbonyl compounds is a powerful
reaction in organic chemistry, able to deliver in high yield
primary, secondary, and tertiary amines with a great variety of
substituents.14 Mild and selective synthetic conditions can be
optimized if a convenient reducing agent is identified. We thus
explored in more detail the synthesis of easily available
ferrocene mono- and dicarbaldehydes for the production of
aminomethyl-substituted ferrocene derivatives, as depicted in
Scheme 2. We report herein the straightforward syntheses of a
variety of aminomethyl-substituted ferrocenes and parent
compounds ((iminomethyl)ferrocenes, azaferrocenophanes,
diferrocenylamines) in excellent yields. A cautious character-
ization by X-ray diffraction in the solid state of these species has
been performed, which highlights different preferred con-
formations for their ferrocene backbones. Multinuclear NMR in
solution includes rarely reported 15N NMR measurements. The
characterization of the (aminomethyl)ferrocenes and parent
compounds has been extended to electrochemical analysis, for
which voltammetric behavior is shown to be influenced by both
the iron center and the nitrogen-containing part of the
molecules.
RESULTS AND DISCUSSION
■
Reactivity of Secondary Amines. Reductive amination of
ferrocenecarbaldehyde has been previously reported as a few
single examples with various reductive agents. 1,6-Diferrocenyl-
2,5-diazahexane has been prepared from the monocarbaldehyde
B
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Scheme 3. (Aminomethyl)ferrocenes from Aliphatic and Cyclic Secondary Amines
formylferrocene reacted with 1,2-diaminoethane followed by
reduction with LiAlH4.15 Formylferrocene has been also
employed in reductive amination using the milder NaBH-
(OAc)3 to produce N,N-(dimethyl)aminomethylferrocene16 as
well as bis(ferrocenylmethyl)cyclen.17 NaBH4 has been
employed with the dicarbaldehyde ferrocene-1,1′-dicarboxalde-
hyde to form in moderate yield N,N′-(diisopropyl)-1,1′-
ferrocenylmethyldiamine.12e We identified NaBH(OAc)3 as
best suited to achieve the reduction of the ferrocene iminium
formed from reaction of 1,1′-diformylferrocene with the
secondary amine Et2NH in dichloroethane, which gives 1,1′-
bis((N,N-diethylamino)methyl)ferrocene 1 (Scheme 3).
Table 1
δ(1H)
δ(13C)
(aminomethyl) Cp−CH2 Cp−CH2
δ(15N)
δ(1H) Cp δ(13C) Cp
a
ferrocene
(ppm)
3.48
(ppm)
52.2
(ppm)
(ppm)
(ppm)
1
76.0
4.05, 4.08 68.7, 71.7,
83.4
2
3
4
3.43
3.33
3.47
55.1
58.8
52.2
86.0
79.0
74.8
4.05, 4.12 68.6, 70.4,
83.9
4.04, 4.08 68.5, 71.0,
82.7
3.96, 3.99 68.4, 70.6,
83.2
a
CH3NO2 at 0.0 ppm was used as reference.
Under the optimized reaction conditions, 1 was formed in
high yield (97%)18 as a deep red oily product. It was
characterized in 1H NMR (solution in CDCl3) by the following
signals: for ethyl group protons signals at 1.02 (t) and 2.43 ppm
(q), for protons of the methylene spacer a signal at 3.48 ppm
(s), and for cyclopentadienyl ring (Cp) protons signals at 4.05
and 4.08 ppm. In 13C NMR, signals for Cp are found at 83.4,
71.7, and 68.7 ppm, methylene carbons at 52.2 and 46.5 ppm,
and the carbon methyl groups at 12.1 ppm. Due to the oily
nature of 1, no solid-state X-ray diffraction analysis could be
performed. We thus achieved further characterization of the
compound by examining its 15N NMR; these data are in general
fairly scarce in the literature. Due to the low natural abundance
of the heavier isotope 15N (0.36%), two-dimensional Fourier
transform NMR techniques are more appropriate to determine
the related chemical shift.19 Heteronuclear multiple bond
which is significantly deshielded in comparison to its congeners,
possibly due to steric reasons.22 In order to further explore the
structural features of these species, we conducted solid-state X-
ray diffraction studies. Figures 1−3 depict the molecular
structures obtained for (aminomethyl)ferrocenes 2−4, respec-
tively. Compound 2 crystallizes in the centrosymetric Pbcn
group. The iron atom is located on a C2 axis. The Cp rings are
in an almost eclipsed conformation, and the torsion angle C6−
Ct−Cti−C6i is equal to 64.27(7)°. The molecule belongs to the
C2 point group. Compound 3 crystallizes in the centrosymetric
P21/c group. The molecule is located on an inversion center
consistent with a staggered conformation of the Cp rings in
which the cyclic amine are in mutually trans positions (C6−
Ct−Cti−C6 = 180°). The molecule belongs to the Ci point
group.
2
correlation (HMBC) sequences allowed us to correlate JHN
Compound 4 crystallizes in the space group P1, and two
̅
3
and JHN (for N(CH2) and N(CH2CH3) groups, respectively)
rotamers A and B coexist in the unit cell in the ratio 2:1. The
rotamer A (Figure 3, top) belongs to the C2 point group
(noncrystallographic axis), and its amino groups have a cisoid
conformation with a torsion angle C11−Ct1−Ct2−C26 of
49.22(9)°, reminiscent of the conformation found for
compound 2. In relation to the existence of a crystallographic
inversion center, the rotamer B conversely exhibits a transoid
conformation, similar to what was observed for 3 (Figure 3,
bottom).
ranging between 5 and 8 Hz with the corresponding 15N
chemical shift found at 76.0 ppm in CDCl3.20 To the best of
our knowledge, such data have never been reported for
(aminoalkyl)ferrocenes, and thus, values provided here now
constitute a benchmark.21
The reductive amination conditions were applied without
notable changes to the more hindered cyclic secondary amines
pyrrolidine and piperidine, as well as dibenzylamine, to give in
satisfactory to good yields the (aminomethyl)ferrocenes 2
(65%), 3 (74%), and 4 (80%), respectively (Scheme 3). A
summary and comparison of their pertinent NMR data is
provided in Table 1.
Hydrogen, carbon, and nitrogen resonances for the aliphatic
alkyl amines 1 and 4 are very similar, while differences are
found with cyclic amines concerning the more sensitive carbon
and nitrogen nuclei. Concerning the latter, the five-membered
pyrrolidinyl cycle of 2 exhibits a 15N chemical shift at 86.0 ppm
The coexistence of rotamers in crystals has been also
reported for 1,1′-diformylferrocene,23 albeit with conformers
and mutual ratios different from those observed for 4. In the
case of 1,1′-diformylferrocene one eclipsed and one staggered
conformation of cyclopentadienyl rings is observed for the
rotamers (with dihedral angles for C−C bonds holding formyl
groups of about 137.8 and 42.9°, respectively). For 4,
cyclopentadienyl ring conformations are staggered in both
rotamers, leading to wider dihedral angles C11−Ct1−Ct2−C26
C
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Figure 1. Molecular structure of 2 (left) and view from above (right). Hydrogen atoms are omitted for clarity. Selected bond lengths (Å) and angles
(deg): Fe−Ct = 1.6498(18), N−C6 = 1.462(2), N−C7 1.465(2), N−C10 = 1.459(2); Ct−Fe−Cti = 179.65(8), C6−N−C7 = 114.61(13), C6−N−
C10 = 114.81(13), C7−N−C10 = 103.61(13); C6−Ct−Cti−C6i = 64.27(7). Symmetry transformation: (i) 2 − x, y, −z + 1.5.
Figure 2. Molecular structure of 3 (left) and view from above (right). Hydrogen atoms are omitted for clarity. Selected bond lengths (Å) and angles
(deg): Fe−Ct = 1.6549(19), N−C6 = 1.468(2), N−C7 = 1.459(3), N−C11 = 1.462(3); C6−N−C7 = 111.10(15), C6−N−C11 = 112.21(15), C7−
N−C11 = 110.28(15). Symmetry transformation: (i) −x, −y, −z.
and C46−Ct3−Ct3′−C46′ of about 49.2 and 180.0°,
respectively. Concerning 1,1′-diformylferrocene, the coexis-
tence of these rotamers has been attributed to the presence of
CO acceptor groups and of several C−H donors that may play
a role in controlling the crystal packing.23 This explanation is
probably not valid in the case of 4, for which N···H−C
interactions are absent in the rotamers. In any case, apparently
the steric hindrance in the ferrocenyl conformation is not
systematically minimized. We found some synthetic limitations
of the reductive amination method with diisopropylamine,
HN(i-Pr)2, and with the secondary diarylamine we tested,
HNPh2, despite the use of other stronger reductive agents such
as NaBH4.
Reactivity of Primary Amines. To further explore the
access to various (aminomethyl)ferrocene structures, we tested
the reactivity of primary amines to generate secondary amine
species susceptible to give amido coordination complexes upon
deprotonation in the presence of metals (similarly to the
evolution of B in Scheme 1). Various primary amines were
tested, and following the general conditions established for the
synthesis from secondary amines, we observed in each case
notable troubles of selectivity (Scheme 4). For instance, the
addition of 2 equiv of (4-phenylbutyl)amine to 1,1′-
formylferrocene followed by reduction with NaBH(OAc)3 led
to a mixture of the desired aminoferrocene 5 with a secondary
product identified as the 2-aza[3]ferrocenophane 6. Diluting
the solution by a factor of 10 did not improve this selectivity.
2-Aza[3]ferrocenophanes with structures similar to that of 6
have been previously formed by condensation of the diol 1,1′-
bis(hydroxymethyl)ferrocene with primary amines conducted
at high temperature (180 °C) with RuCl2(PPh3)3 as catalyst;24
By this method, yields ranging from 50% to 70% have been
reported. Synthetic methods of parent compounds based on
the amination of 1,1′-formylferrocene have been also reported
with lower yields,25 or very long reaction times.26 We were
dissatisfied with the chemoselectivity of the reductive amination
with primary amines; we thus looked for specific conditions
that might exclusively lead either to 2-aza[3]ferrocenophanes
(of type 6) or to the initially targeted [(monoalkyl)-
aminomethyl]ferrocenes (of type 5). Under the mild synthetic
conditions employed to produce 1 (room temperature, 18 h),
the 2-aza[3]ferrocenophanes 6−8 (Scheme 5) have been
synthesized in satisfactory 70−75% isolated yields by simply
adjusting the amount of primary amine to 1 equiv of
ferrocenedicarbaldehyde; this precludes the formation of the
(aminomethyl)ferrocenes. From a mechanistic view, a first
intermolecular condensation/reduction is followed by an
intramolecular condensation/reduction of the transitory imine
and/or iminium species formed. The formation of the bridge is
1
evidenced in H NMR with a shielding of the protons of the
methylene spacer (Cp−CH2−N), found around 2.80 ppm for
6−8 in comparison to values for 1−4 of around 3.40 ppm (see
Table 1). The bridge formation at the nitrogen atom is
associated with a 15N NMR signal found at 87.0 ppm for 6 and
89.2 ppm for 8.20 X-ray diffraction studies have been performed
on the 2-aza[3]ferrocenophanes formed (Figure 4).
Ferrocenophanes 6−8 present very similar crystallographic
structures, evidencing the three-membered CNC bridge linking
the two cyclopentadienyl rings of the ferrocene. Compound 6
crystallizes in the noncentrosymmetric Pna21 space group, and
7 and 8 crystallize in centrosymmetric P2 /n and P1 space
̅
1
groups. Due to the aza bridge, the cyclopentadienyl rings are
bent and exhibit dihedral angles (deviation from parallelism)
equal to 11.76(18)° for 6, 12.82(7)° for 7, and 11.99(8)° for 8.
Similar geometrical features have been reported in the literature
for ferrocene derivatives incorporating such [−CH2−NR−
CH2−] bridging groups: for instance, in N-methyl-N-
(benzylpropyl)-2-aza[3]ferrocenophane hexafluorophosphate
and N-hexyl-N-methyl-2-azonia[3]ferrocenophane iodide.27
Compound 8 has been very recently described with identical
crystallographic characteristics.25
D
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Figure 3. Molecular structure of 4 (left) and view from above (right). Hydrogen atoms are omitted for clarity. The two rotamers A (top) and B
(bottom) are present in the unit cell. Selected bond lengths (Å) and angles (deg) for rotamer A: Fe1−Ct1 = 1.651(2), Fe1−Ct2 = 1.650(2), N1−
C11 = 1.474(3), N1−C12 = 1.463(3), N1−C19 = 1.466(3), N2−C26 = 1.473(3), N2−C27 = 1.469(3), N2−C34 = 1.463(3); Ct1−Fe1−Ct2 =
179.34(11), C11−N1−C12 = 112.11(16), C11−N1−C19 = 113.09(17), C12−N1−C19 = 111.35(16), C26−N2−C27 = 113.20(15), C27−N2−
C34 = 110.47(16), C26−N2−C34 = 112.90(16); C11−Ct1−Ct2−C26 = 49.22(9). Selected bond lengths (Å) and angles (deg) for rotamer B:
Fe2−Ct3 = 1.654(2), N3−C46 = 1.466(3), N3−C47 = 1.468(3), N3−C54 = 1.459(3); C46−N3−C47 = 110.24(17), C47−N3−C54 = 111.84(17),
C46−N3−C54 = 111.09(17). Symmetry transformation: (i) −x, −y, 1 − z.
Scheme 4. (Aminomethyl)ferrocene Derivatives from Primary Amines
Scheme 5. 2-Aza-[3]ferrocenophane from 1,1′-Formylferrocene Reacted with Primary Amines
In order to selectively form the targeted [(monoalkyl)-
aminomethyl]ferrocene derivatives the experimental conditions
have to be changed. First, we isolated the intermediary imine
formed (Scheme 6);28 then more drastic reduction conditions
E
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were applied by using LiAlH4 on imines in highly dilute THF
solution. Following this procedure ferrocenylimines 9 and 11
were isolated in excellent yield and their reduction led to
[(alkyl)aminomethyl]ferrocenes 10 and 12 in high yield. In this
way the concomitant formation of ansa-ferrocene was fully
circumvented. In our hands the ((N-alkylimino)methyl)-
ferrocenes 9 and 11 were obtained as oily brown products
respectively characterized in 1H NMR by their NCH protons
at 7.98 and 8.02 ppm and in 13C NMR by their corresponding
signals at 159.8 ppm. Despite repeated efforts, 15N NMR of
imino compounds was unsuccessful due to magnetization
transfer problems between protons and nitrogen.
The reduction of the imine function of 9 and 11 is
quantitative and provides compounds 10 and 12, respectively.
1
These secondary amines were characterized in H NMR by
their H−N protons at 1.09 and 1.15 ppm and in 15N NMR by
their corresponding signals at 71.5 and 95.7 ppm, respectively.
As for compound 2,22 it is also tempting here to associate the
low-field chemical shift of 95.7 ppm found for 12 with steric
reasons rather than electronic reasons. Indeed, as shown by X-
ray diffraction (Figure 5), the tetrahedral deformation at
Figure 5. Molecular structure of 1,1′-bis(N-(tert-butyl)amino)-
methyl)ferrocene (12). Selected bond lengths (Å) and angles (deg):
Fe1−Ct1 = 1.656 (2), Fe1−Ct2 = 1.655(2), N1−C11: = 1.460(3),
N1−C12 = 1.483(3), N2−C16 = 1.451(3), N2−C17 = 1.483(3);
C11−N1−C12 = 116.72(18), C16−N2−C17 = 117.77(17), Ct1−
Fe−Ct2 = 177.76(11); C11−Ct1−Ct2−C16 = −155.22(9).
Figure 4. Molecular structures of 2-aza[3]ferrocenophanes 6 (top), 7
(middle), and 8 (bottom). Hydrogen atoms are omitted for clarity.
Selected bond lengths (Å) and angles (deg) are as follows. For 6: Fe−
Ct1 = 1.635(3), Fe−Ct2 = 1.631(3), N−C11 = 1.471(4), N−C12 =
1.471(4), N−C13 = 1.476(5); Ct1−Fe−Ct2 = 171.57(19), C11−N−
C12 = 113.5(3), C11−N−C13 = 111.1(2), C12−N−C13 = 111.6(2);
C11−Ct1−Ct2−C12 = −0.70(12). For 7: Fe−Ct1 = 1.6368(17), Fe−
Ct2 = 1.6352(16), N−C11 = 1.479(2), N−C12 = 1.475(2), N−C13 =
1.478(2); Ct1−Fe−Ct2 = 170.82(9), C11−N−C12 = 111.04(14),
C11−N−C13 = 107.64(13), C12−N−C13 = 110.25(13); C11−Ct1−
Ct2−C12 = 1.89(7). For 8: Fe−Ct1 = 1.6350(13), Fe−Ct2 =
1.6355(13), N−C11 = 1.4757(16), N−C12 = 1.4769(16), N−C13 =
1.4679(16); Ct1−Fe−Ct2 = 171.25(6), C11−N−C12 = 111.78(10),
C11−N−C13 = 109.78(10), C12−N−C13 = 110.10(10); C12−Ct1−
Ct2−C11 = 1.22(5).
nitrogen is marked in comparison to other derivatives
presented herein with angles C11−N1−C12 = 116.72(18)°
and C16−N2−C17 = 117.77(17)°, while mostly values
between 109 and 114° have been found for 3, 4, 6−8, and
13 (see below). Compound 12 crystallizes in the non-
centrosymmetric P21 group with an almost eclipsed con-
formation for the cyclopentadienyl rings, in which the two (tert-
butylamino)methyl groups are in trans positions with the
Scheme 6. Two-Step Selective Synthesis of [(Alkyl)aminomethyl]ferrocenes 10 and 12 from 1,1′-Formylferrocene, via
Ferrocenylimines 9 and 11
F
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torsion angle C11−Ct1−Ct2−C16 = −155.22(9)°. The
molecule belongs to the C2 point group (noncrystallographic
axis).
The ferrocene compounds 1−12 all combine a single
ferrocene platform with either two or one nitrogen-containing
moiety (Scheme 2). We envisioned that a complementary
structure accessible from primary amines would combine two
ferrocene moieties on an amine platform (Scheme 7), possibly
leading to different properties, in particular regarding electro-
chemical behavior.
compound having a structural analogy with 13 has been
fortuitously formed from zinc-promoted rearrangement of an
(aminomethyl)ferrocene derivative.29 Our present method-
ology is thus a straightforward way to produce this kind of
unusual structure from RNH2 amine precursors.
Electroanalytical Studies. Substituted ferrocene molecules
are able to lose one electron (Fe(II) → Fe(III)) at potentials
that are a function of the electron-donating ability of the
substituents attached to the cyclopentadienyl rings, without
experiencing fragmentation of their metallocenic backbone.1
This property constitutes a useful characterization of the
influence of these pendant fragments. Additionally, in the case
of the novel (aminomethyl)ferrocene derivatives prepared
herein the electrochemical behavior of the nitrogen-containing
moiety is also of interest. Electrochemical studies reported with
ligand molecules parent to those synthesized herein have been
proved to be of fundamental interest to assess, from their
coordination chemistry, their potential as redox sensors toward
various transition-metal cations.30 We conducted comparative
electrochemical analyses on a selection of ferrocenes
representative of the different families developed herein (see
Scheme 2). Thus, the cyclovoltammetric behavior (CV) of 2−
4, 7, 8, 10, and 13 was investigated in dichloromethane with 0.2
mol/L NBu4PF6 as supporting electrolyte. These conditions are
well-suited for studies in anodic electrochemistry, as they
provide a large potential window in the positive range.
Additionally, this medium is poorly nucleophilic, thus
minimizing the possibility of interference in the electrode
process.
Among the series of (aminomethyl)ferrocenes 1−4,
compound 3 is a representative example: its CV recorded at
100 mV/s is displayed in Figure 7 (top left). Two well-
separated oxidations occur at, respectively, −0.01 and 0.73 V vs
Fc+/Fc0 (see Table 2). These potential values are indicative of
the electron transfer operating successively on the Fe(II)
center31 and on the amino function.32
Figure 7 (top right) also presents the CV of 3 obtained when
the potential scan is restricted to the ferrocenyl oxidation zone.
The response fulfills the characteristics of a one-electron fast
electron transfer:34 i.e., a separation between the forward
anodic and backward cathodic peak (ΔEp = Epa − Epc)
approaching 58 mV (found experimentally at 74 mV) and a
difference between the half-peak and peak potentials Epa − Epa/2
near 55 mV (found experimentally at 57 mV). Additionally, the
current peak ipa grows proportionally to v1/2 in accordance with
a diffusion-controlled process, and a ratio of peak currents close
to unity is observed (experimental: ipc/ipa = 0.84).35
Scheme 7. N,N-Bis((ferrocenyl)methyl)-N-butylamine (13)
The reaction of 2 equiv of formylferrocene with n-butylamine
followed by reductive amination with NaBH(OAc)3 led to the
formation of N,N-bis((ferrocenyl)methyl)-N-butylamine (13),
which was isolated in a satisfactory 68% yield. The compound
1
was characterized in H and 13C NMR by the intense signals
found respectively at 4.01 and 68.5 ppm due to the
unsubstituted H−C of cyclopentadienyl rings. The chemical
shift for 13 in 15N NMR found at 76.8 ppm is very similar to
that of 1, probably due to their analogous connection
framework around nitrogen. The X-ray structure of 13 was
resolved (Figure 6), which confirmed that the amine group
connects two ferrocene moieties. This compound crystallizes in
the centrosymmetric P21/c group with ferrocenyl moieties
positioned exo to each other and the nitrogen atom placed in a
fairly regular environment with C21−N−C22 = 111.2(3)°,
C21−N−C23 = 110.4(3)°, C22−N−C23 = 112.9(3)°, and N−
C distances around 1.47−1.48 Å. An interesting, but intractable,
As shown in Figure 7 (top left), when the potential scan is
extended to +1.32 V, an oxidation peak related to the amine
moiety appears (O2 peak). This corresponds to an electro-
chemically irreversible phenomenon with no associated
cathodic peak at the same potential on the reverse scan. On
the other hand, the reverse scan displays a fairly intense peak
arising at +0.39 V (R2*). This evolution evidences a chemical
reaction occurring on the (aminomethyl)ferrocene after the
oxidation electron transfer; the product of this reaction is then
reduced, and this corresponds to peak R2*. Such a cascade
process may be related to anodic reactions of aliphatic tertiary
amines containing acidic hydrogen atoms in the α position
(Scheme 8). The reaction pathway proceeds through the
intermediacy of a nitrogen-centered radical cation which is
deprotonated and further oxidized to an iminium ion.32
Eventually, the iminium can be hydrolyzed by traces of water
Figure 6. Molecular structure of N,N-bis((ferrocenyl)methyl)-N-
butylamine (13). Hydrogen atoms are omitted for clarity. Selected
bond lengths (Å) and angles (deg): Fe1−Ct1 = 1.647(4), Fe1−Ct2 =
1.648(5), Fe2−Ct3 = 1.649(4), Fe2−Ct4 = 1.651(5), N−C21 =
1.473(6), N−C22 = 1.485(5), N−C23 = 1.477(6); C21−N−C22 =
111.2(3), C21−N−C23 = 110.4(3), C22−N−C23 = 112.9(3), Ct1−
Fe1−Ct2 = 178.9(2), Ct3−Fe2−Ct4 = 178.3(3).
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Figure 7. Cyclic voltammograms of complexes 3 (top), 7 (middle), and 13 (bottom) in CH2Cl2/0.2 mol L−1 NBu4PF6. Working electrode: platinum
disk (Φ = 1 mm). Potential scan rate: 100 mV/s. Inversion potential: 1.32 V (left) and 0.32 V (right).
Scheme 8. Electroinduced Cascade Reaction from Oxidation of a Tertiary Aliphatic Amine
to yield the corresponding aldehyde and secondary amine
(Scheme 8).
the formation of ferrocenium derivatives 3a−c (Scheme 10).
The formation of 3a would then results from the deprotonation
of the methylene group in the lateral chain of 3; the proton
acidity at this position is indeed expected to increase due to the
proximity of the positively charged ferrocenium. Protonation
and/or hydrolysis reactions of the formed ferroceniums (as
In addition, the H+ liberated in the reaction sequence is able
to protonate the starting amine to form an electroinactive
ammonium species (Scheme 9).
The reactivity depicted in Schemes 8 and 9 may be
transposed in the anodic reaction of 3, potentially leading to
H
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oxidation (peak O1) is also reversible in the case of 4, 7, and 8
(see the characteristic parameters in Table 2) but chemically
irreversible in the case of 2 and 10. Only minor variations are
noted in the half-wave potentials, which are fixed at either
−0.01 or −0.03 V. Bridged 2-azaferrocenophanes have the most
negative E1/2 values (7 and 8, Table 2). This shift is limited in
magnitude to −30 mV in comparison to the mean value of the
nonbridged compounds (E1/2 = 0.00 V from 2, 3, 4, and 10).
This differs from previous comparisons between ferrocene
derivatives having three bridging atoms and their nonbridged
analogues,31 comparisons for which the bridged compound was
Table 2. Cyclic Voltammetry of Ferrocene Derivatives 2−4,
a
7, 8, 10, and 13
second
oxidation
first oxidation step
Ep −
step
ΔE
Ep/2
b
p c
d
compd
E1/2 (V)
(mV)
(mV)
|ipa/ipc|
σp
Ep (V)
e
2
3
4
7
0.02
69
57
56
56
50
75
92
0.73
0.79
1.07
1.14
1.24
g
−0.01
74
65
73
76
0.84
0.92
0.92
0.93
−0.11
−0.11
−0.13
−0.13
−0.01
−0.03
−0.03
0.00
generally stabilized with accordingly a more positive E1/2
.
f
8
The Hammet parameter, σp, for the substituent on
cyclopentadienyl rings can be extracted from the relationships
(1) and (2):31
e
10
13
h
−0.04, 0.03
129
1.08
a
Experimental conditions: working electrode material, platinum;
EL(vs NHE) = 1/2[E1/2(vs Fc+/Fc0) + 0.63]
sweep rate, 100 mV/s; all potentials referenced to the Fc+/Fc0 couple,
(1)
0.2 mol/L NBu4PF6 in CH2Cl2; uncompensated resistance Ru not
b
taken into account.33 Calculated as the half-sum of Epa and Epc at the
c
EL = 0.45σp + 0.36
(2)
first oxidation step. Calculated as the difference between Epa and Epc.
d
e
σp is the Hammett parameter for the substituent on Cp. Peak O1 is
f
The σP values obtained range between −0.13 and −0.11,
which confirms a weak electrodonating effect from amino-
methyl to Cp. In comparison, the σP value estimated for the
ferrocene bearing an electron-rich 2,5-dimethylpyrrolidin-1-yl
group directly attached to the cyclopentadienyl ring was found
to be −1.03.36
While all the compounds reported herein combine ferrocenyl
and nitrogen-containing groups, the ratio of the two entities
changes in the series. Hence, compounds 2−4 and 10
incorporate a single ferrocene and two amine moieties (tertiary,
or secondary for 10); conversely 7 and 8 combine a ferrocene
with a single bridging tertiary amine, and finally compound 13
connects two ferrocenyl moieties via one tertiary amine. The
influence of these structural differences is easily evidenced by
comparison of the cyclic voltammograms of, for instance, 3, 7
and 13 (Figure 7), for which the relative intensity of O2 vs O1
is found to be as follows: 3 > 7 > 13.
A careful examination of the short potential scan CV of 13
(Figure 7, bottom right) reveals that the observed trace results
from the sum of two closely spaced one-electron systems.
Digital simulation of the CV response has allowed extraction of
the respective formal potentials of the two ferrocene derivative
systems (Table 2).37 A molecule bearing two independent and
chemically equivalent redox centers should theoretically exhibit
a ΔE° value equal to 35.6 mV.38 The separation of 72.0 mV
observed in the case of 13 is clearly indicative of a certain extent
of electronic “communication” between the two electroactive
iron centers. This communication might occur through space as
a result of the electrostatic repulsion between electrogenerated
charges or internally through the 2-azopropylene bridge.
Analogous electrochemical signatures have been described for
molecules accommodating two ferrocenyl groups connected via
a conjugated π system.39
chemically irreversible: Epa is given as a substitute for E1/2. The
electrochemistry of this compound was previously described:24,27 our
data are included for appropriate comparison within the whole series.
g
h
Not observed clearly. E1/2 identified to the formal potential, E°,
obtained by numeric simulation (see the Supporting Information).
Scheme 9
described above for amines and iminiums, respectively) may
also occur.
Accordingly, the peak R2* in the CV of 3 (Figure 7, top) is
associated with the FeIII → FeII reduction of one or several of
these compounds. The more positive potential of R2* in
comparison to R1 in the compounds is attributable to the
substituents on the Cp rings. They are expected to exert an
electroattractive effect on ferrocenium. To definitively attribute
peak R2*, the ammonium form of 3 (3·2H+) as well as the 1,1′-
diformylferrocene have been analyzed in cyclic voltammetry.
Both display a unique electrochemically reversible one-electron
oxidation in the accessible potential range, thus generating 3b,c
(Scheme 10) at the electrode, respectively. The corresponding
reduction peak is different from R2* (potential at 0.39 V) with
values found at 0.30 and 0.58 V, respectively. Therefore, R2*
could be the trace associated with 3a (Scheme 10) with
consistently a potential fairly close to 3b.
The other ferrocene derivatives 2−4, 7, 8, 10, and 13 were
analyzed under the same conditions (see Table 2). These
species have an electroanalytical behavior roughly similar to
that of 3 with two net oxidation peaks present at potentials in
accordance with anodic reactions respectively occurring at the
iron center and methylamine moieties. At 100 mV/s, the first
Scheme 10
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parameters. Hydrogen atoms attached to carbon atoms were included
in calculated positions and refined as riding atoms. Crystallographic
data are reported in the Supporting Information.
CONCLUSION
■
Aminomethyl-substituted ferrocenes are key building blocks
applied, for instance, in the synthesis of efficient bioactive
compounds and as platforms for further synthesizing ortho-
substituted ferrocenes. However, for these compounds more
efficient synthetic modes and structural diversification are
needed. This has been achieved herein especially by reducing
the number of synthetic steps, by getting better yields and
selectivity, and also by the introduction of amino groups other
than the classical aliphatic alkyl amines −NMe2 and −NEt2. We
optimized the straightforward syntheses of a variety of 13
aminomethyl-substituted ferrocenes (giving either tertiary
amines 1−4 or secondary amines 5, 10, and 12) and the
parent compounds (iminomethyl)ferrocenes (9, 11), azaferro-
cenophanes (6−8), and a diferrocenylamine (13). Compounds
1−13 are obtained in two or three synthetic steps (in 65−97%
yield) from ferrocene via the reductive amination of 1,1′-
diformylferrocene or formylferrocene. Depending on the
targeted ferrocene derivatives, the choice of NaBH(OAc)3 or
LiAlH4 as reducing agent was determining for the selectivity of
the reaction. 15N NMR measurements of aminomethyl-
substituted ferrocenes and derivatives are provided for the
first time, establishing benchmark values ranging from 71.5 to
95.7 ppm. For representative compounds the characterization
has been extended to X-ray diffraction structures, evidencing
the preferential conformation of ferrocene backbones, and also
to electrochemical analysis, in which two very distinct
oxidations occur, indicative of the electron transfer operating
successively on the Fe(II) center and on the amino function.
The synthesis of (aminomethyl)ferrocene derivatives is part of
a research program for the synthesis and study of new (N,X)-
substituted ferrocenes, and further works will aim at their ortho-
directed functionalization.
Electrochemical Analysis. All electrochemical measurements
were carried out in a standard three-electrode glass cell under an
inert atmosphere of dry oxygen-free argon. A double-junction
saturated calomel electrodewith background electrolyte between
two fritswas used as the reference electrode. The formal potential of
the [Fc+/Fc] couple was found to be 0.38 V in 0.2 M [NBu4][PF6]/
CH2Cl2 media vs SCE. Cyclic voltammograms were registered with
the use of a PGSTAT302N potentiostat (Autolab-Ecochemie). A well-
polished platinum disk (1 mm diameter) served as working electrode.
Platinum wire was used as the counter electrode. Digital simulation of
the cyclic voltammogram for 13 was achieved with the commercial
software DIGISIM 3.05 (Bioanalytical Systems). For the synthesis of
[NBu4][PF6], tetra-n-butylammonium hydroxide (Alfa-Aesar, 40% w/
w aqueous solution) was mixed with a stoichiometric amount of HPF6
(Sigma Aldrich, 65% w/w aqueous solution). The obtained salt was
crystallized three times from ethanol and kept in an oven at 80 °C for
several days. Copies of cyclic voltammograms are available upon
request to the authors.
Synthesis of 1,1′-Diformylferrocene and Formylferrocene.
To a vigorously stirred mixture of degassed ferrocene (2.0 g, 10.75
mmol) with 3.54 mL of tetramethylethylenediamine (TMEDA)
cooled to 0 °C (2.2 equiv, 23.65 mmol) was added dropwise 14.8
mL of a 1.6 M solution of n-butyllithium in hexane cooled to −80 °C,
over 15 min (2.2 equiv, 23.65 mmol). The mixture was then stirred at
room temperature overnight. The mixture was filtered, and the solid
was rinsed with heptane. The resulting solid in 20 mL of heptane was
cooled to −80 °C, and the dropwise addition of 1.8 mL of DMF was
conducted (2.2 equiv, 23.65 mmol). The mixture was stirred at −80
°C for 2 h, hydrolyzed with 10 mL of H2O, then extracted with
CH2Cl2. The combined organic phases were dried on MgSO4, and the
solvent was removed in vacuo. From SiO2 column chromatography a
first fraction of unreacted ferrocene (<10%) is eluted with pure
heptane, then with a 1/1 EtOAc/heptane mixture, formylferrocene is
obtained (0.34 g, 2.1 mmol, 20% yield), and finally elution with pure
EtOAc gives 1,1′-diformylferrocene as a bright red crystalline solid
after evaporation of this third fraction (yield 71%, 3.7 g, 15.28 mmol).
Due to our interest in formylferrocene as a reagent for our
investigation, we did not conduct optimization of the yield of 1,1′-
EXPERIMENTAL SECTION
■
General Procedures. The reactions were carried out in oven-dried
glassware (115 °C) under an argon atmosphere using Schlenk and
vacuum-line techniques. Solvents were dried and freshly distilled prior
to use by standard methods. All the chemicals were used as supplied,
without further purification. 1,1′-Diformylferrocene was prepared from
ferrocene according a slightly modified reported procedure.40 Amines
from commercial sources were used. Sodium triacetoxyborohydride
reducing agent was stored under argon. Flash chromatography was
performed on silica gel (220−440 mesh). The identity and purity of
the products were established at the “Chemical Analysis platform and
Molecular Synthesis University of Burgundy” using high-resolution mass
spectrometry, multinuclear NMR, and elemental analysis. The exact
masses were obtained from a LTQ-Orbitrap XL (THERMO). 1H
(300.13, 500.13, or 600.13 MHz) and 13C NMR spectra (75.5, 125.8,
or 150.9 MHz) (δ in ppm) were recorded in CDCl3 at 298 K (unless
otherwise stated) on a Bruker 300 Avance, Bruker 500 Avance DRX,
or Bruker 600 Avance II spectrometer. Elemental analysis was
performed on an Analyzer CHNS/O Thermo Electron Flash EA
1112 Series. The 15N NMR chemical shifts measured by 1H−15N
heteronuclear multiple-bond correlation spectroscopy (HMBC) were
recorded in CDCl3 at 300 K on a Bruker Avance II 600 MHz
spectrometer with a BBI 5 mm probe. Neat nitromethane has been
used as an external standard reference, for which the 15N chemical shift
is taken to be 0 ppm.
diformylferrocene.44 1,1′-Diformylferrocene: H NMR δ 9.94 (s, 2H,
1
CHO), 4.88 (pt, 4H, α-Cp-CH), 4.66 (pt, 4H, β-Cp-CH); 13C{1H}
NMR δ 192.9 (s, 2C, CHO), 80.7 (s, 2C, ipso-Cp), 74.3 (s, 4C, α-Cp-
CH), 70.87 (s, 4C, β-Cp-CH); HR-MS (C12H10O2Fe) ESI [M + Na+]
m/z calcd 264.9916, found 264.9922, [err] 2.426 ppm. Anal. Calcd for
C12H10O2Fe (242.05): C, 59.54; H, 4.16. Found: C, 59.48; H, 4.38.
1
Formylferrocene: H NMR δ 9.95 (s, H, CHO), 4.79 (s, 2H, α-Cp-
CH), 4.60 (s, 2H, β-Cp-CH), 4.27 (s, 5H, Cp); 13C{1H} NMR δ 193.4
(s, 1C, CHO), 79.4 (s, 1C, 1-Cp), 73.1 (s, 2C, α-Cp-CH), 69.6 (s, 7C,
2β-Cp-CH + 5C-Cp′-CH). Anal. Calcd for C11H10FeO (214.04): C,
61.73; H, 4.71; Found: C, 61.41; H, 4.38.
1,1′-Bis((N,N-diethylamino)methyl)ferrocene (1). To a solu-
tion of 1,1′-diformylferrocene (0.53 g, 2.18 mmol) in dichloroethane
(30 mL) was added diethylamine (2.0 equiv, 0.45 mL, 4.36 mmol),
and the mixture was stirred for 1 h at room temperature. To this
suspension was added 1.38 g of sodium triacetoxyborohydride (3
equiv, 6.54 mmol). The mixture was stirred at room temperature
overnight. The reaction mixture was hydrolyzed by addition of 1 M
NaOH (20 mL), the phases were separated, and the aqueous phase
was extracted with CH2Cl2 (3 × 30 mL). The combined organic
phases were dried on MgSO4, and the solvents were removed in vacuo.
Column chromatography on SiO2 using CH2Cl2/MeOH/triethyl-
amine (90:9:1) gave 1,1′-bis((N,N-diethylamino)methyl)ferrocene as
a red oily product in 97% yield after solvent evaporation (0.75 g, 2.10
mmol). 1H NMR: δ 1.02 (t, 12H, JHH = 7 Hz, CH2CH3), 2.43 (q, 8H,
JHH = 7 Hz, CH2CH3), 3.48 (s, 4H, Cp-CH2-N), 4.05, 4.08 (m
(AA′BB′), 4H each, Cp-CH). 13C{1H} NMR: δ 12.1 (s, 4C,
CH2CH3), 46.5 (s, 4C, CH2CH3), 52.2 (s, 2C, Cp-CH2−N), 68.7
(s, 4C, 3,4-Cp), 71.7 (s, 4C, 2,5-Cp), 83.4 (s, 2C, 1-Cp). 15N NMR: δ
X-ray Structure Analysis. X-ray analyses of compounds 2−4, 6−
8, 12, and 13 were achieved from intensity data collected on a Nonius
Kappa CCD instrument at 115 K. The structures were solved by direct
methods (SIR92)41 and refined with full-matrix least-squares methods
based on F2 (SHELXL-97)42 with the aid of the WINGX program.43
All non-hydrogen atoms were refined with anisotropic thermal
J
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76.0. HR-MS (C20H33N2Fe) ESI: [M + H+] m/z calcd 357.1987,
found 357.1997, [err] 2.722 ppm. Elemental analyses were
unsatisfactory (oily product).
bis((N,N-dibenzylamino)methyl)ferrocene as a brown crystalline solid
in the second fraction in 80% yield after solvent evaporation (2.0 g,
3.30 mmol). Orange-yellow single crystals suitable for X-ray diffraction
studies were obtained from a concentrated solution in heptane kept at
1,1′-Bis((pyrrolidin-1-yl)methyl)ferrocene (2). To a solution of
1,1′-diformylferrocene (1.00 g, 4.13 mmol) in dichloroethane (30 mL)
was added pyrrolidine (2.3 equiv, 0.89 mL, 9.5 mmol), and the mixture
was stirred for 1 h. To this suspension was added 2.01 g of sodium
triacetoxyborohydride (2.3 equiv, 9.5 mmol). The mixture was stirred
at room temperature overnight. The reaction mixture was hydrolyzed
by addition of 1 M NaOH (20 mL), the phases were separated, and
the aqueous phase was extracted with CH2Cl2 (3 × 30 mL). The
combined organic phases were dried on MgSO4 and the solvents
removed in vacuo. Silica gel was deactivated by pouring it into 60 mL
of heptane in the presence of 10% NEt3, followed by drying in vacuo.
Column chromatography on deactivated SiO2 using heptane/ethyl
acetate (4/1) followed by heptane/ethyl acetate (3/2) gave as a
second fraction 1,1′-bis((pyrrolidin-1-yl)methyl)ferrocene as a reddish
crystalline solid in 65% yield after solvent evaporation (0.94 g, 2.66
mmol). Orange-yellow single crystals suitable for X-ray diffraction
studies were obtained from a concentrated solution in heptane kept at
1
−30 °C. H NMR: δ 3.38 (s, 4H, Cp-CH2-N), 3.47 (s, 8H, N-CH2-
Ph), 3.96, 3.99 (m (AA′BB′), 4H each, Cp-CH), 7.26−7.36 (m, 20H,
Ph-CH). 13C{1H} NMR: δ 52.1 (s, 2C, Cp-CH2-N), 57.1 (s, 4C, N-
CH2-Ph), 68.4 (s, 4C, 3,4-Cp),70.6 (s, 4C, 2,5-Cp), 83.1 (s, 2C, 1-Cp),
126.7 (s, 4C, p-Ph-CH), 128.2 (s, 8C, m-Ph-CH) 128.7 (s, 8C, o-Ph-
CH), 139.9 (s, 4C, ipso-Ph-C). 15N NMR: δ 74.8. HR-MS
(C40H40FeN2) ESI: [M + Na+] m/z calcd 627.24338, found
627.24152, [err] 2.858 ppm. Anal. Calcd for C40H40FeN2 (604.60):
C, 79.46; H, 6.67; N, 4.63. Found: C, 79.12; H, 6.68; N, 4.69.
1,1′-Bis(N-(4-phenylbutyl)amino)methyl)ferrocene (5). A
procedure similar to that which was used for synthesizing 1 was
employed. By reacting 0.50 g of 1,1′-diformylferrocene (2.06 mmol)
and 4-phenylbutylamine (2 equiv, 0.65 mL, 4.11 mmol) in
dichloroethane (30 mL), followed by treatment with sodium
triacetoxyborohydride (3 equiv, 1.27 g, 6.18 mmol), 5 was obtained
in 60% yield (0.60 g, 1.18 mmol) as a brown powder after column
chromatographic purification to remove the ansa byproduct (SiO2,
CH2Cl2/MeOH 19/1). Alternatively, following the two-step proce-
dure which was employed to form 10, the (aminomethyl)ferrocene 5
was obtained in 80% overall yield. 1H NMR: δ 1.58 (m, 8H,
CH2CH2CH2CH2), 1.94 (s, broad, 2H, NH), 2.61 (q, 8H, JHH = 7 Hz,
NCH2 + CH2Ph), 3.52 (s, 4H, Cp-CH2-N), 4.07, 4.13 (m (AA′BB′),
4H each, Cp-CH), 7.15−7.30 (m, 10H, Ph). 13C{1H} NMR: δ 29.1 (s,
2C, CH2CH2CH2Ph), 35.80 (s, 2C each, CH2Ph), 48.4 (s, 2C,
NCH2), 58.8 (s, 2C, Cp-CH2-N), 68.7 (s, 4C, 3,4-Cp), 69.3 (s, 4C,
2,5-Cp), 85.7 (s, 2C, 1-Cp), 126.4 (s, 1C, p-Ph-CH), 129.1 (s, 2C, m-
Ph-CH), 129.2 (s, 2C, o-Ph-CH), 142.7 (s, 1C, ipso-Ph-C). HR-MS
(C32H40N2Fe) (ESI): [M + H]+ m/z calcd 509.26141, found
509.25906; [err] 4.532 ppm. Anal. Calcd for C32H40N2Fe: C, 75.58;
H, 7.93; N, 5.51. Found: C, 75.92; H, 7.32; N, 5.39.
1
3
−30 °C. H NMR: δ 1.72 (quintet, 8H, JHH = 4 Hz, py-β-N-CH2),
3
2.47 (quintet, 8H, JHH = 4 Hz, py-α-N-CH2), 3.43 (s, 4H, Cp-CH2-
N), 4.05, 4.12 (m (AA′BB′), 4H each, Cp-CH). 13C{1H} NMR: δ 23.3
(s, 4C, py-β-N-CH2), 53.5 (s, 4C, py-α-N-CH2), 55.1 (s, 2C, Cp-CH2-
N), 68.6 (s, 4C, 3,4-Cp), 70.4 (s, 4C, 2,5-Cp), 83.9 (s, 2C, 1-Cp). 15N
NMR: δ 86.0. HR-MS (C20H28FeN2) ESI: [M + H+] m/z calcd
353.16748, found 353.16763, [err] 0.460 ppm. Anal. Calcd for
C20H28FeN2 (352.29): C, 68.19; H, 8.01; N, 7.95. Found: C, 68.58; H,
7.95; N, 7.91.
1,1′-Bis((piperidin-1-yl)methyl)ferrocene (3). To a solution of
1,1′-diformylferrocene (1.00 g, 4.13 mmol) in dichloroethane (30 mL)
was added piperidine (2.3 equiv, 0.94 mL, 9.5 mmol), and the mixture
was stirred for 1 h. To this suspension was added 2.01 g of sodium
triacetoxyborohydride (2.3 equiv, 9.5 mmol). The mixture was stirred
at room temperature overnight. The reaction mixture was hydrolyzed
by addition of 1 M NaOH (20 mL), the phases were separated, and
the aqueous phase was extracted with CH2Cl2 (3 × 30 mL). The
combined organic phases were dried on MgSO4, and the solvents were
removed in vacuo. Silica gel was deactivated by pouring it into 80 mL
of heptane in the presence of 10% NEt3, followed by drying in vacuo.
Column chromatography on deactivated SiO2 using heptane/ethyl
acetate (7/3) followed by heptane/ethyl acetate/methanol (15/10/1,
with a gradual increase of ethyl acetate/methanol), gave in the second
fraction 1,1′-bis((pyrrolidin-1-yl)methyl)ferrocene as a brown solid in
74% yield after solvent evaporation (1.17 g, 3.07 mmol). Brown single
crystals suitable for X-ray diffraction studies were obtained from a
concentrated solution in pentane kept at −30 °C. 1H NMR: δ 1.35 (m,
4H, pip-γ-N-CH2), 1.52 (m, 8H, pip-β-N-CH2), 2.31 (m, 8H, pip-α-N-
CH2), 3.33 (s, 4H, Cp-CH2-N), 4.04, 4.08 (m (AA′BB′), 4H each, Cp-
CH). 13C{1H} NMR: δ 24.2 (s, 2C, pip-γ-N-CH2), 25.8 (s, 4C, pip-β-
N-CH2), 53.7 (s, 4C, pip-α-N-CH2), 58.8 (s, 2C, Cp-CH2-N), 68.5 (s,
4C, 3,4-Cp), 70.9 (s, 4C, 2,5-Cp), 82.7 (s, 2C, 1-Cp). 15N NMR: δ
79.0. HR-MS (C22H32FeN2) ESI: [M + H+] m/z calcd 381.19879,
found 381.19898, [err] 0.557 ppm. Anal. Calcd for C22H32FeN2
(380.35): C, 69.47; H, 8.48; N, 7.37. Found C, 69.25; H, 8.57; N, 7.08.
1,1′-Bis((N,N-dibenzylamino)methyl)ferrocene (4). To a solu-
tion of 1,1′-diformylferrocene (1.0 g, 4.13 mmol) in dichloroethane
(30 mL) was added dropwise dibenzylamine (2.3 equiv, 1.82 mL, 9.5
mmol), and the mixture was stirred for 1 h at room temperature. To
this suspension was added 2.01 g of sodium triacetoxyborohydride (2.3
equiv, 9.5 mmol). The mixture was stirred at room temperature
overnight under argon. Then, the reaction mixture was hydrolyzed by
addition of 1 M NaOH (20 mL). The phases were separated, and the
aqueous phase was further extracted with CH2Cl2 (3 × 30 mL). The
combined organic phases were dried with MgSO4, and the solvents
were removed in vacuo. Silica gel was deactivated by pouring it into 60
mL of heptane in the presence of 10% NEt3, followed by drying in
vacuo. Column chromatography on deactivated SiO2 using heptane/
ethyl acetate (4/1) followed by heptane/ethyl acetate/methanol (15/
10/1, with a gradual increase of ethyl acetate/methanol), gave 1,1′-
N-(4-Phenylbutyl)-2-aza[3]ferrocenophane (6). A procedure
similar to that which was used for synthesizing 1 was employed. By
reacting 0.50 g of 1,1′-diformylferrocene (2.06 mmol) and 4-
phenylbutylamine (1 equiv, 0.30 mL, 2.06 mmol) in dichloroethane
(30 mL), followed by treatment with sodium triacetoxyborohydride (3
equiv, 1.27 g, 6.18 mmol), 6 was obtained in 70% yield as a yellow
powder (0.50 g, 1.39 mmol) after column chromatographic
purification (SiO2, CH2Cl2/MeOH 19/1). Single crystals suitable for
X-ray diffraction were obtained from slow evaporation of a
1
concentrated solution of 6 in CH2Cl2. H NMR: δ 1.64, 1.74 (m, 2
H each, CH2), 2.68 (m, 4 H, CH2), 2.86 (s, 4H, Cp-CH2-N), 4.04,
4.07 (m, 4 H each, Cp-CH), 7.16−7.30 (m, 5H, Ph-CH). 13C{1H}
NMR: δ 30.2 (s, 2C, NCH2CH2CH2), 36.6 (s, 1C, CH2Ph), 53.0 (s,
2C, Cp-CH2−N), 58.1 (s, 1C, NCH2CH2), 69.8 (s, 4C, 3,4-Cp), 70.6
(s, 4C, 2,5-Cp), 83.8 (s, 2C, 1-Cp), 126.4 (s, 1C, p-Ph-CH), 129.1 (s,
2C, m-Ph-CH), 129.2 (s, 2C, o-Ph-CH), 142.7 (s, 1C, ipso-Ph-C). 15N
NMR: δ 87.0. HR-MS (C22H25FeN) ESI: [M + H+] m/z calcd
360.14094, found 360.13964, [err] 3.550 ppm. Anal. Calcd for
C22H25FeN (359.29): C, 73.54; H, 7.01; N, 3.90. Found: C, 73.37; H,
7.00; N, 3.90.
N-(n-Butyl)-2-aza[3]ferrocenophane (7). A procedure similar to
that used for synthesizing 1 was employed by reacting 0.50 g of 1,1′-
diformylferrocene (2.06 mmol) and n-butylamine (1 equiv, 0.21 mL,
2.06 mmol) in 20 mL of dichloroethane, followed by treatment with
sodium triacetoxyborohydride (3 equiv, 1.27 g, 6.18 mmol). The
reaction was monitored by thin-layer chromatography and pursued
until 1,1′-diformylferrocene disappeared. Then the mixture was
quenched by a saturated NaHCO3 solution in water and was extracted
with CH2Cl2 (60 mL). The organic phases were dried over MgSO4
and evaporated to dryness. The oily residue was purified by column
chromatography on deactivated SiO2 (by using first 4/1 and then 3/2
heptane/ethyl acetate, and at the end of the chromatography a few
milliliters of methanol). This gave pure N-(n-butyl)-2-aza[3]-
ferrocenophane (7) as a yellow solid in the second fraction in 75%
1
yield after solvent evaporation (0.43 g, 1.52 mmol). H NMR: δ 0.97
(t, 3H, JHH = 7 Hz, CH3), 1.42, 1.59, 2.69 (m, 2H each, CH2), 2.89 (s,
K
dx.doi.org/10.1021/om400317s | Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
4H, Cp-CH2-N), 4.08 (m (AA′BB′), 8 H, Cp-CH). 13C{1H} NMR: δ
14.0 (s, 1C CH3), 20.7, 29.9, 57.5 (s, 1C each, CH2), 52.2 (s, 2C, Cp-
CH2-N), 69.0 (s, 4C, 3,4-Cp), 69.8 (s, 4C, 2,5-Cp), 83.9 (s, 2C, 1-Cp).
HR-MS (C16H21FeN2) ESI: [M + H+] m/z calcd 284.10945, found
284.10963, [err] 0.593 ppm. Anal. Calcd for C16H21FeN2 (283.10): C,
67.86; H, 7.47; N, 4.95. Found: C, 67.21; H, 7.89; N, 4.66.
calcd 353.16748, found 353.16708, [err] 1.097 ppm. Anal. Calcd for
C20H28FeN2 (352.29): C, 68.19; H, 8.01; N, 7.95. Found: C, 64.99; H,
7.88; N, 6.78 (best values obtained to date, oily product).
Following the procedure used to form compound 10, the
(iminomethyl)ferrocene 11 (1.13 g, 3.2 mmol) in dilute solution
(25 mL of THF) was reacted with LiAlH4 to quantitatively give 12 as a
1
reddish solid (1.08 g, 3.04 mmol, 95% yield). H NMR: δ 1.15 (s,
N-(Benzyl)-2-aza[3]ferrocenophane (8). The procedure used
for synthesizing 7 was employed by reacting 0.33 mL of benzylamine
(3.02 mmol) and 0.87 g of 1,1′-diformylferrocene (1.2 equiv, 3.60
mmol) in 20 mL of dichloroethane, followed by treatment with
sodium triacetoxyborohydride (2 equiv, 1.27 g, 6.18 mmol), to give
after column chromatographic purification on deactivated silica gel
(heptane/ethyl acetate 4/1) the 2-aza[3]ferrocenophane 8 as a yellow
solid. The solid was recrystallized from a concentrated solution in
pentane kept at −30 °C. The pure product 8 was obtained in 70%
yield (0.67 g, 2.11 mmol) and was suitable for X-ray diffraction
18H, CH3-t-Bu), 3.44 (s, 4H, Cp-CH2-N), 4.05, 4.14 (m (AA′BB′),
4H each, Cp-CH), 8.02 (s, 2H, NCH). 13C{1H} NMR: δ 29.1 (s,
6C, CH3-t-Bu), 41.8 (s, 2C, Cp-CH2-N), 50.5 (s, 2C, CCH3-t-Bu),
68.1 (s, 4C, 3,4-Cp), 68.6 (s, 4C, 2,5-Cp), 88.4 (s, 2C, 1-Cp). 15N
NMR: δ 95.7. HR-MS (C20H32FeN2) ESI: [M + H]+ m/z calcd
357.19879, found 357.19798, [err] 2.205 ppm. Anal. Calcd for
C20H32FeN2 (356.33): C, 67.41; H, 9.05; N, 7.86. Found: C, 67.53; H,
8.79; N, 7.33.
N,N-Bis[(ferrocenyl)methyl]-N-butylamine (13). A procedure
similar to that which was used for synthesizing 1 was employed. By
reacting 1,1′-diformylferrocene (1.00 g, 4.67 mmol) dissolved in 25
mL of dichloroethane with n-butylamine (0.5 equiv, 0.23 mL, 2.33
mmol) followed by treatment with sodium triacetoxyborohydride (2.3
equiv, 2.01 g, 9.50 mmol) and quenching by a saturated NaHCO3
solution in water, bis(ferrocenyl)methylbutylamine 13 was obtained in
68% yield as an orange solid (0.74 g, 1.58 mmol) after purification by
column chromatography on deactivated silica gel (eluent CH2Cl2/
MeOH 4:/1). Orange single crystals suitable for X-ray diffraction
studies were obtained from a concentrated solution in heptane kept at
1
analysis. H NMR: δ 2.82 (s, 4H, Cp-CH2-N), 3.77 (s, 2 H, N-CH2-
Ph), 3.99, 4.04 (m (AA′BB′), 4 H each, Cp-CH), 7.15−7.40 (m, 5H,
Ph−CH). 13C{1H} NMR: δ 51.1 (s, 2C, Cp-CH2-N), 60.9 (s, 1C, N-
CH2-Ph), 68.1 (s, 4C, 3,4-Cp), 68.8 (s, 4C, 2,5-Cp), 82.6 (s, 2C, 1-
Cp), 125.9 (s, 1C, p-Ph-CH), 127.3 (s, 2C, m-Ph-CH), 127.6 (s, 2C, o-
Ph-CH), 138.7 (s, 1C, ipso-Ph-C). 15N NMR: δ 89.2. HR-MS
(C19H19FeN) ESI: [M + H+] m/z calcd 318.09287, found 318.09398,
[err] 3.453 ppm. Anal. Calcd for C19H19FeN (317.21): C, 71.94; H,
6.04; N, 4.42. Found: C, 71.64; H, 5.91; N, 4.30.
1,1′-Bis((N-(n-butyl)amino)methyl)ferrocene (10) via 1,1′-
Bis((N-(n-butyl)imino)methyl)ferrocene (9). n-Butylamine (2.45
mL, 24.79 mmol) was dissolved in 10 mL of dry THF (solution 2.48
M), and a solution of 2.00 g of 1,1′-diformylferrocene (0.33 equiv, 8.26
mmol) in 5 mL of dry CH3CN (solution 1.65 M) was added dropwise
with vigorous stirring over 15 min. The mixture was evaporated to
dryness after 2 h of stirring at room temperature, and a brown oil was
collected, washed with pentane, and dried in vacuo for 2 h to give 2.62
g of imine 9 (90% yield). 1H NMR: δ 0.90 (t, 6H, JHH = 7.0 Hz, CH3),
1.32, 1.58, 3.39 (m, 4H each, CH2), 4.28, 4.56 (s, 4 H each, Cp-CH),
7.98 (s, 2H, NCH). 13C{1H} NMR: δ 13.9 (s, 2C, CH3), 20.4, 33.0,
61.71 (s, 2C each, CH2), 69.2 (s, 4C, 3,4-Cp), 71.2 (s, 4C, 2,5-Cp),
81.8 (s, 2C, 1-Cp), 159.8 (s, 2C, NCH). 15N NMR could not be
obtained. HR-MS (C20H28N2Fe) ESI: [M + H]+ m/z calcd 353.16748,
found 353.16656, [err] 2.570 ppm. Anal. Calcd for C20H28N2Fe
(352.29): C, 68.19; H, 8.01; N, 7.95. Found: C, 68.39; H, 8.10; N,
7.91.
1
−30 °C. H NMR: δ 0.80 (t, 3H, JHH = 7 Hz, CH3), 1.19 (m, 2H,
CH2CH3), 1.35 (m, 2H, CH2CH2CH3), 2.21 (t, 2H, JHH = 7.5 Hz,
NCH2), 3.34 (s, 4H, Cp-CH2-N), 4.01 (s, 10H, 1′-5′-Cp-CH), 4.04,
4.10 (m (AA′BB′), 4H each, 2−4-Cp-CH). 13C{1H} NMR: δ 14.1 (s,
1C, CH3), 20.6 (s, 1C, CH2CH3), 29.3 (s, 1C, CH2CH2CH3), 51.9 (s,
1C, NCH2CH2), 52.5 (s, 2C, Cp-CH2−N), 67.7 (s, 4C, 3,4-Cp), 68.5
(s, 10C, 1′-5′-Cp), 70.2 (s, 4C, 2,5-Cp), 83.7 (s, 2C, 1-Cp). 15N NMR:
δ 76.8. HR-MS (C26H31FeN2) ESI: [M]+ m/z calcd 469.11505, found
469.11470, [err] 0.609 ppm. Anal. Calcd for C26H31FeN2 (469.22): C,
66.55; H, 6.66; N, 2.29. Found: C, 66.79; H, 6.63; N, 2.44.
ASSOCIATED CONTENT
■
S
* Supporting Information
Tables, figures, and CIF files giving H, 13C, and 15N NMR
1
spectra and HR-MS analysis for 1−13, crystal data and
structure refinement details for 2−4, 6−8, 12, and 13, and
simulation of the cyclic voltammetry response for 13. This
material is available free of charge via the Internet at http://
pubs.acs.org.
The (iminomethyl)ferrocene 9 (2.62 g, 7.44 mmol) was dissolved
in 25 mL of dry THF (solution 0.22 M), and 0.95 g of finely divided
LiAlH4 was poured into the solution under argon (3.5 equiv, 0.025
mol). After 1 h of stirring at room temperature, a portion of pentane
(20 mL) was added followed by several drops of an aqueous solution
of 1 M NaOH. The suspension was filtered, and the filtrate was
evaporated to give 2.51 g of (((n-butyl)amino)methyl)ferrocene 10 as
AUTHOR INFORMATION
Corresponding Author
*J.-C.H.: e-mail, jean-cyrille.hierso@u-bourgogne.fr; fax, +33-
380393682.
■
1
an orange oil (95% yield). H NMR: δ 0.88 (t, 6H, JHH = 7.2 Hz,
CH3), 1.09 (s, broad, 2H, NH), 1.32, 1.44 (m, 4H each, CH2), 2.58 (t,
4H, JHH = 7.2 Hz, CH2), 3.46 (s, 4H, Cp-CH2-N), 4.02, 4.09 (m
(AA′BB′), 4H each, Cp-CH). 13C{1H} NMR: δ 14.0 (s, 2C, CH3),
20.5, 32.2, 49.0 (s, 2C each, CH2), 49.4 (s, 2C, Cp-CH2-N), 68.2 (s,
4C, 3,4-Cp), 68.8 (s, 4C, 2,5-Cp), 87.3 (s, 2C, 1-Cp). 15N NMR: δ
71.5. HR-MS (C20H28FeN2) ESI: [M + H]+ m/z calcd 357.19720,
found 357.19879, [err] 4.389 ppm. Anal. Calcd for C20H28FeN2
(356.33): C, 67.41; H, 9.05; N, 7.86. Found: C, 67.65; H, 8.82; N,
8.16.
1,1′-Bis(N-(tert-butyl)amino)methyl)ferrocene (12) via 1,1′-
Bis((N-(tert-butyl)imino)methyl)ferrocene (11). The procedure
used for synthesizing 9 was employed by reacting tert-butylamine (1.05
mL, 10.00 mmol) dissolved in dry THF (8 mL) and a solution of 1,1′-
diformylferrocene (0.80 g, 3.30 mmol) in dry CH3CN (5 mL), to give
1.13 g of the (iminomethyl)ferrocene 11 as a light brown oil (3.20
mmol, 97% yield). 1H NMR: δ 1.19 (s, 18H, CH3-t-Bu), 4.24, 4.50 (s,
4 H each, Cp-CH), 8.02 (s, 2H, NCH). 13C{1H} NMR: δ 29.9 (s,
6C, CH3-t-Bu), 57.0 (s, 2C, CCH3-t-Bu), 69.3 (s, 4C, 3,4-Cp), 71.1 (s,
4C, 2,5-Cp), 82.7 (s, 2C, 1-Cp), 154.5 (s, 2C, NCH). 15N NMR
could not be obtained. HR-MS (C20H28FeN2) ESI: [M + H]+ m/z
Author Contributions
⊥These authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This paper is dedicated to Prof. Irina P. Beletskaya for her
outstanding contributions to transition-metal chemistry. This
■
work was supported by the CMCU (Comite
Cooperation Universitaire Franco-Tunisien) through the PHC
Utique program 13G1209 (Ministeres des Affaires Etrangeres de
la Republique Francaise et Ministere de l’Enseignement Superieur et
de la Recherche Scientifique de la Republique Tunisienne) with
financial support for the Ph.D. grant of D.N.; these
organizations are sincerely thanked. The “Conseil Regional de
́
Mixte pour la
́
̀
̀
́
̧
̀
́
́
́
Bourgogne” also supported this work through the program
L
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Organometallics
Article
Cawthray, J. F.; de kock, C.; Patrick, B. O.; Smith, P. J.; Adam, M. J.;
Orvig, C. Organometallics 2012, 31, 5736.
PARI IME-SMT08 with a Ph.D. grant for F.A. shared with the
Lebanese Foundation “Azm et Saada”. The cooperation
(11) Methods for preparing ((N,N-dimethylamino)methyl)ferrocene
include: (a) Hauser, C. R.; Lindsay, J. K. J. Org. Chem. 1956, 21, 382.
(b) Pauson, P. L.; Sandhu, M. A.; Watts, W. E. J. Chem. Soc. C 1966,
251. (c) Routaboul, L.; Chiffre, J.; Balavoine, G. G. A.; Daran, J.-C.;
Manoury, E. J. Organomet. Chem. 2001, 637−639, 364.
(12) Methods for preparing 1,1′-bis((N,N-dialkylamino)methyl)
ferrocene include: (a) Osgerby, J. M.; Pauson, P. L. J. Chem. Soc.
1961, 4604. (b) Knox, G. R.; Munro, J. D.; Pauson, P. L.; Smith, G.
H.; Watts, W. E. J. Chem. Soc. 1961, 4619. (c) Holwerda, R. A.;
Robinson, T. W.; Bartsch, R. A. Organometallics 1991, 10, 2652.
(d) Glidewell, C.; Royles, B. J. L.; Smith, D. M. J. Organomet. Chem.
1997, 527, 259. (e) Herberich, G. E.; Gaffke, A.; Eckenrath, H. J.
Organometallics 1998, 17, 5931. (f) Ralambomanana, D. A.;
Razafimahefa-Ramilison, D.; Rakotohova, A. C.; Maugein, J.;
́ ́
between the “Universite de Bourgogne” and the “Universite
Libanaise” benefited a CEDRE program 2010−2012 (project
09 SCI F 33/L 50).
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between 110 and 113° (see data accompanying ORTEP drawings in
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40% yield; in the absence of further comments by the authors, this low
yield might be related to the selectivity issues we observed . See details
in ref 30a.
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