Main chain ferrocenyl amides from 1-aminoferrocene-1′-carboxylic acid

Article abstract of DOI:10.1002/ejic.200300897

The non-natural amino acid 1-aminoferrocene-1′-carboxylic acid is synthesised from ferrocene in eight steps. The folding and association phenomena of amido-substituted ferrocenes in the crystal as well as in solution are studied by X-ray crystallography, IR and NMR spectroscopy and DFT calculations. The amino acid is selectively protected at the amino group with the use of the fluorenyl-9-methoxycarbonyl (Fmoc) group. An amide-linked ferrocene dimer is prepared using the HOBt/DCC protocol for amide formation. In the crystal the dimer forms a hydrogen-bonded sheet structure, while in solution dynamic intramolecular hydrogen bonds are observed by VT ¹H NMR and IR spectroscopy. The dynamic flipping process has been rationalised by DFT calculations. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.

Full text of DOI:10.1002/ejic.200300897

FULL PAPER
Main Chain Ferrocenyl Amides from 1-Aminoferrocene-1Ј-carboxylic Acid
Katja Heinze*[a] and Manuela Schlenker[a]
Keywords: Metallocenes / Hydrogen bonds / Peptides / Conformation analysis
The non-natural amino acid 1-aminoferrocene-1Ј-carboxylic
acid is synthesised from ferrocene in eight steps. The folding
and association phenomena of amido-substituted ferrocenes
in the crystal as well as in solution are studied by X-ray crys-
tallography, IR and NMR spectroscopy and DFT calculations.
The amino acid is selectively protected at the amino group
with the use of the fluorenyl-9-methoxycarbonyl (Fmoc)
group. An amide-linked ferrocene dimer is prepared using
the HOBt/DCC protocol for amide formation. In the crystal
the dimer forms a hydrogen-bonded sheet structure, while in
solution dynamic intramolecular hydrogen bonds are ob-
served by VT 1H NMR and IR spectroscopy. The dynamic
flipping process has been rationalised by DFT calculations.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
Introduction
giving a well-defined chain length and a primary structure
of the peptide which allows full structural characterisation
by NMR spectroscopic methods and X-ray crystallography,
as well as high-level calculations. The key ferrocene building
block is the non-natural amino acid 1-aminoferrocene-1Ј-
carboxylic acid. Its optimised synthesis and the full charac-
terisation of all intermediates using X-ray structural tech-
niques, VT NMR spectroscopy[18] and DFT calculations is
reported here, along with the application of fluorenyl-9-
methoxycarbonyl (Fmoc)[19] solution-phase chemistry for
N-protection and acid activation via benzotriazole ester.
Natural materials are often superior to their artificial
synthetic counterparts. The structural and functional vari-
ety of peptides is very impressive, especially when consider-
ing that only a few α-amino acids are incorporated. Intro-
duction of non-natural amino acids into peptides may lead
to novel biomaterials or hybrid materials with some proper-
ties that are similar to those of natural proteins such as
folding, or with additional properties such as conductive,
optical or magnetic properties.[1] The latter properties may
be obtained through incorporation of transition metals in
the main chain,[2] while folding and supramolecular organ-
isation into stable conformations may be achieved by for-
ming intra- and intermolecular hydrogen bonds to control
morphological aspects e.g. formation of nanotubes,[3]
fibres,[4] or hydrogels.[5]
Results and Discussion
Synthesis of 1-Aminoferrocene-1Ј-carboxylic Acid,
Ferrocene derivatives[6] have advantageous characteristics
such as excellent stability in water and air, and favourable
electrochemical properties which have led to applications
of ferrocene in molecular receptors, in sensor devices with
electrochemical detection,[7Ϫ10] and in labelling of biomole-
cules.[11,12] Furthermore, the inter-ring separation of ferro-
Hydrochloride
In 1998 the first synthesis of 1-aminoferrocene-1Ј-car-
boxylic acid 9 was reported by Butler and Quayle.[20] How-
ever, the method yielded a mixture of compounds which
could not be separated and purified. In the same year a
different synthetic approach was used by Ueyama et. al,
which gave pure 1-aminoferrocene-1Ј-carboxylic acid, hy-
drochloride 9 but in quite a low yield (28% from 6[21]). As
the yields of the reactions were unsatisfactory for a broader
investigation and only few spectroscopic data were
given,[20Ϫ22] we report on the optimised synthesis (51%
from 6) and detailed characterisation of 9 and all syn-
thetic intermediates.
Scheme 1 summarises the reaction sequence starting from
ferrocene 1 to give 1-aminoferrocene-1Ј-carboxylic acid,
hydrochloride 9·HCl. The key synthon in this synthesis is
1-aminoferrocene (5). Although aminoferrocene is a known
compound, the main drawback for further preparative work
is the tedious multistage preparation starting from ferro-
˚
cene of about 3.3 A (close to the N···O distance in β-sheets
of peptides) and the rotational freedom of the cyclopen-
tadienyl rings has allowed to use ferrocene 1,1Ј-dicarboxylic
acid as an organometallic β-turn mimetic in ferrocene con-
jugates of amino acids and peptides,[13Ϫ16] and as a molecu-
lar pair of scissors.[17]
In our approach peptides with ferrocene moieties in the
backbone are sequentially built up by a stepwise synthesis
[a]
Anorganisch-Chemisches Institut der Universität Heidelberg,
Im Neuenheimer Feld 270, 69120 Heidelberg, Germany
Fax: (internat.) ϩ 49-6221-545707
E-mail: katja.heinze@urz.uni-heidelberg.de
Supporting information for this article is available on the
WWW under http://www.eurjic.org or from the author.
2974
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejic.200300897
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Main Chain Ferrocenyl Amides from 1-Aminoferrocene-1Ј-carboxylic Acid
FULL PAPER
cene, with ferrocenylazide[23,24], N-ferrocenylacetamide[25]
or N-ferrocenylphthalimide[26] as key intermediates. The
best method for a multigram synthesis of aminoferrocene
proves to be the Gabriel synthesis from N-ferrocenylphthal-
imide (4), although this route necessitates the synthesis of
1-haloferrocene or ferrocene boronic acid as precursors of
4. A high-yield synthesis of iodoferrocene 3 has been re-
ported by Bildstein et. al.[26] starting with the selective
mono-lithiation of ferrocene 1 with tBuLi, then isolating
the solid lithio-ferrocene 2 and quenching of 2 with iodine.
The reaction in pyridine of 3 with phthalimide and Cu2O
as catalyst has been reported to give the N-ferrocenylph-
thalimide 4.[26] However, the reaction is accompanied by the
formation of biferrocenes by copper-mediated CϪC coup-
ling even in the presence of excess phthalimide. The product
4 is thus contaminated with biferrocenes and phthalimide
which could not be removed. To circumvent these problems,
4 is prepared in the absence of solvent directly from 3 and
pre-formed CuϪphthalimide.[27,28] Hydrazinolysis of 4 in
ethanol gives pure 5, which is then N-acetylated with acetic
anhydride to form 1-(acetylamino)ferrocene 6. The N-ace-
tylamino group deactivates the substituted Cp ring, al-
lowing the selective FriedelϪCrafts acylation of 6 with 2,6-
dichlorobenzoyl chloride[21,24,29] at the unsubstituted Cp
ring giving 1-(acetylamino)-1Ј-(2,6-dichlorobenzoyl)ferro-
Scheme 1
cene (7). Basic hydrolysis of 7 introduces the desired COOH
group seen in 8. However, the yield of this reaction depends
highly on the exact stoichiometric amount of added water.
Removal of the acetyl protection group with hydrochloric
acid furnishes the ferrocene-containing amino acid 9 as
the hydrochloride.[21]
Crystal Structures of 4-8
2-Ferrocenyl-isoindole-1,3-dione (4) crystallises in the
monoclinic space group P21/n without inclusion of solvent
˚
Table 1. Selected bond lengths (A) and angles (°) of complexes 4, 5, 6, 7, 8, 10, 11, 12 and 13
4
5
6
7
8
10(A)
10(B)
11
12
13(Fe1) 13(Fe2)[d]
Fe1ϪC1
Fe1ϪC2
Fe1ϪC3
Fe1ϪC4
Fe1ϪC5
Fe1ϪC6
Fe1ϪC7
Fe1ϪC8
2.040(4) 2.097(3)
2.044(4) 2.061(4)
2.043(4) 2.033(4)
2.033(4) 2.028(4)
2.043(4) 2.056(4)
2.039(4) 2.048(4)
2.044(4) 2.051(4)
2.042(4) 2.043(4)
2.043(4) 2.042(4)
2.032(4) 2.042(4)
1.421(5) 1.405(5)
2.04(2)
2.05(2)
2.02(2)
2.02(2)
2.04(2)
2.07(2)
2.00(2)
2.03(2)
2.04(2)
2.04(2)
1.56(4)
1.25(4)
Ϫ
2.101(3) 2.073(3) 2.064(2) 2.060(2) 2.067(4) 2.078(2) 2.082 2.087
2.071(3) 2.056(4) 2.050(2) 2.061(2) 2.071(4) 2.069(3) 2.055 2.041
2.044(4) 2.033(4) 2.037(2) 2.038(2) 2.043(4) 2.036(3) 2.019 2.026
2.032(4) 2.041(4) 2.038(2) 2.036(2) 2.029(4) 2.033(2) 2.028 2.021
2.051(3) 2.064(4) 2.043(2) 2.032(2) 2.037(4) 2.052(2) 2.039 2.032
2.040(3) 2.043(4) 2.024(2) 2.023(2) 2.010(4) 2.047(2) 2.014 2.053
2.050(4) 2.040(4) 2.033(2) 2.035(2) 2.017(4) 2.035(2) 2.032 2.053
2.054(4) 2.047(4) 2.062(2) 2.063(2) 2.054(4) 2.045(3) 2.034 1.999
2.053(4) 2.052(4) 2.059(2) 2.055(2) 2.061(4) 2.059(2) 2.017 2.002
2.035(4) 2.035(4) 2.038(2) 2.041(2) 2.040(4) 2.058(2) 2.032 2.065
1.405(4) 1.413(5) 1.407(2) 1.409(2) 1.399(5) 1.405(3) 1.395 1.408
1.351(5) 1.350(5) 1.349(2) 1.348(2) 1.370(6) 1.347(4) 1.347 1.370
Fe1ϪC9
Fe1ϪC10
C1ϪN1
N1ϪC11
N1ϪC12
C11ϪO1
C12ϪO2
C13ϪO2
C13ϪO3
N1ϪC11ϪO1
N1ϪC12ϪO2
O2ϪC13ϪO3
1.416(5)
1.409(5)
1.196(5)
1.211(5)
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
1.26(4)
Ϫ
Ϫ
Ϫ
126(4)
Ϫ
Ϫ
161.2
Ϫ
Ϫ34.6
1.236(4) 1.228(5) 1.226(2) 1.225(2) 1.203(5) 1.233(3) 1.229
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
1.221(4) 1.217(4) 1.252(2) 1.248(2) 1.206(4) 1.238(3)
1.335(5) 1.301(2) 1.300(2) 1.424(5)
Ϫ
Ϫ
Ϫ
Ϫ
126.6(4)
125.6(4)
Ϫ
Ϫ
122.8(3) 122.5(4) 123.5(2) 123.3(2) 122.5(4) 123.0(2) 124.0 122.1
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
122.9(4) 123.3(2) 123.6(2) 120.3(4)
Ϫ
Ϫ
Ϫ
C1ϪC5/subst1[a] 18.1
Ϫ
162.3
13.4
Ϫ18.6
17.8
174.2
Ϫ4.8
173.7
172.5
16.3
11.8
7.0
11.2
16.8
171.6
21.0
177.3
36.3
8.2
5.9 168.6
C6ϪC10/subst2[b]
Ϫ
Ϫ
178.3
Ϫ4.2
Ϫ
28.6
δ[c]
Ϫ6.0
25.2
[a]
[b]
Subst1 is the plane defined by the first three atoms of the substituent at C1. Subst2 is the plane defined by the first three atoms of
[c]
[d]
the substituent at C6. δ is defined as the relative rotation of Cp rings (0° ϭ fully eclipsed; 36° ϭ fully staggered).
N1, O1 stand for the atoms C21ϪC30, C13, N2, O2, respectively.
C1ϪC10, C11,
Eur. J. Inorg. Chem. 2004, 2974Ϫ2988
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K. Heinze, M. Schlenker
FULL PAPER
molecules (Figure 1). Bond lengths and angles in this com- giving two different hydrogen bonds in the crystal:
pound compare well with similar systems (Table 1).[30] The N1H1···O1X (N1 to O1X distance: 2.87 A) and
˚
˚
plane of the phthalimido ring system is slightly rotated out N1XH1X···O1 (N1X···O1 2.73 A). A similar hydrogen-
of the adjacent Cp ring plane (angle between planes 18°). bonded chain has been observed in the related iodo-substi-
In a similar ferrocenyl-(2,3-naphthalimide) system with a tuted complex CpFeCpC(ϭO)NHCH2I with a repeating
[32]
˚
˚
CH2 link between ferrocene and the naphthalimide, the sub- distance of 9.55 A and a N to O distance of 2.96 A.
stituent ring plane is located almost perpendicular to the
Cp ring plane.[30]
Figure 1. Molecular structure of 4 in the crystal
Figure 3. Hydrogen bonding of 6 in the crystal
Aminoferrocene 5 crystallises in the tetragonal space
group I41/a (Figure 2). The bond lengths and angles are
comparable with those found for 1,1Ј-diaminoferrocene
(Table 1).[31] In the crystal the individual molecules of 5 are
connected through NϪH···N hydrogen bonds forming a
The disubstituted ferrocene 7 crystallises in the mono-
helical arrangement along the crystallographic 41 screw axis
clinic space group P21/c (Figure 4, Table 1). Due to steric
interactions the plane of the dichlorobenzene substituent is
located almost perpendicular to the plane of the C6ϪC10
cyclopentadienyl ring (angle between planes: 82.9°). The
molecules of 7 are connected through intermolecular
˚
(Figure 2) with a helical pitch of 5.93 A (corresponding to
˚
the crystallographic c-axis). The N to N distance is 3.26 A,
and are in agreement with the distances found in the struc-
ture of 1,1Ј-diaminoferrocene (3.26, 3.10, 3.39 A).
[31]
˚
NϪH···O hydrogen bonds between the NHamide group and
the COamide group of a neighbouring molecule, forming
chains along the 21 screw axis with a repeating distance of
˚
9.02 A; this is similar to that observed in structure 6 (Fig-
˚
ure 3). The O1 to N1 distance is 2.88 A and is similar to
those found in 6 and the related complexes H3CC(ϭ
[21]
˚
O)NHCpFeCpC(ϭO)NHCH3 (2.85 and 2.87 A)
and
H3CC(ϭO)NHCpFeCpC(ϭO)OCH3 (2.93 A[33]).
˚
Figure 2. Hydrogen bonding of 5 in the crystal; view approximately
along c
Compound 6 crystallises in the monoclinic space group
P21/n (Figure 3, Table 1). The molecules of 6 are connected
through intermolecular NϪH···O hydrogen bonds that con-
nect the NHamide group and the COamide group of a neigh-
bouring molecule, forming chains along the n glide plane
˚
with a repeating distance of 9.54 A (Figure 3). However,
the NHϪCOϪCH3 group is disordered over two positions, Figure 4. Hydrogen bonding of 7 in the crystal
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Main Chain Ferrocenyl Amides from 1-Aminoferrocene-1Ј-carboxylic Acid
FULL PAPER
The acid 8 crystallises in the orthorhombic space group O)OCH3 that forms a dimer with an N to O distance of
[33]
˚
Pbca with inclusion of one methanol molecule (Figure 5, 2.93 A.
Table 1). The ferrocene complexes are connected through
Properties of 4؊9
OϪH···O hydrogen bonds between the acid OH group
˚
(O3H6···O4; O3 to O4 distance: 2.56 A) over the methanol
NMR spectroscopic data of compounds 4Ϫ13 are col-
lected in Table 2 and Table 3, while UV/Vis spectroscopic
and cyclic voltammetric data of 4Ϫ13 are given in Table 4.
In solution, the phthalimide substituent of 4 undergoes
an easy torsional vibration around the C1ϪN1 bond lead-
ing to a time-averaged Cs symmetry of the molecule. Thus,
and the amide CO group (O4H23···O1; O4 to O1 distance:
2.69 A) to form a helical chain along a twofold axis (paral-
˚
lel to the b axis). These chains are further connected
through NH···O hydrogen bonds between the amide NH
group and the acid CO group (N1H1···O2; N1 to O2 dis-
˚
1
in the H and 13C NMR spectra signal sets for a Cs-sym-
tance: 2.91 A). The same NH···O hydrogen-bonding motif
metric molecule are observed, e.g. only one 13C resonance
for the carbonyl carbon nuclei at δ ϭ 167.0 is seen (Table 3;
in contrast to the two erroneous reported values of δ ϭ
165.1 and 167.0[26]). The IR absorption spectrum shows the
signals assigned to the symmetric and asymmetric CO vi-
brations at 1778 cmϪ1 and 1717 cmϪ1, respectively. In the
UV/Vis spectrum of 4 bands corresponding to the ferrocene
unit and to the phthalimide substituent are observed, and
are in agreement with those reported for a similar ferro-
cenyl-1,8-naphthalimide (Table 4).[30] Further, the cyclic
voltammogram of 4 displays waves corresponding to the
oxidation of the ferrocene moiety at E1/2 ϭ 450 mV and
the reduction of the phthalimide group at E1/2 ϭ Ϫ1470
mV (Table 4).[30]
has also been observed in the crystal structure of the corre-
sponding methyl ester H3CC(ϭO)NHCpFeCpϪC(ϭ
The hydrogen bonding observed in the crystal of amino-
ferrocene 5 is also seen in the solid-state IR absorption
spectrum: the signals for the NH stretching vibrations ap-
pear at 3400 cmϪ1 and 3336 cmϪ1. The signal for the NH2
deformation vibration is observed at 1621 cmϪ1. In concen-
Figure 5. Hydrogen bonding of 8 in the crystal
1
Table 2. H NMR spectroscopic data of complexes 4Ϫ13, atom numbering according to the numbering in the crystal structures
[b]
∆δNH-1
H-1
Ϫ
H-2/5
5.01
H-3/4
H-7/10
4.21 (br. s, 7 H)
4.09
H-8/9
H-12
Ϫ
Substituent(s)
4[b]
5[b]
6[b]
7[b]
8[b]
9[c]
Ϫ
7.74 (m, 2 H, H-15), 7.86
(m, 2 H, H-14)
Ϫ
Ϫ
2.63
3.98
3.83
Ϫ
(br. s, 2 H) (pt, 2 H)[a] (pt, 2 H)[a]
(br. s, 5 H)
4.15
(br. s, 5 H)
4.60
(br. s, 4 H)
4.46/4.79
(br. s, 2 ϫ 2 H)
Ϫ2.9
Ϫ3.4
Ϫ12
Ϫ
6.59
(br. s, 1 H) (br. s, 2 H) (br. s, 2 H)
6.73 4.69 4.15
(br. s,1 H) br. s, 2 H) (br. s, 2 H)
7.15 4.65 4.07
(br. s, 1 H) (br. s, 2 H) (br. s, 2 H)
4.53
3.97
2.00
(s, 3 H)
2.02
(s, 3 H)
2.11
(s, 3 H)
Ϫ
Ϫ
7.33Ϫ7.42 (m, 3 H, H-16/17/18)
Ϫ
Ϫ
8.13
4.30/4.51/4.63/4.89 (pt, 4 ϫ 2 H)[a]
Ϫ
10[d] Ϫ7.0
4.55
3.91
4.25/4.66
(br. s, 2 ϫ 2 H)
Ϫ
4.30 (br. s, 1 H, H-14), 4.47(d[e],
2 H, H-13), 7.32 (m, 4 H, H-17/18),
7.68 (d[f], 2 H, H-16), 7.78(d[f],
2 H, H-19)
(br. s, 1 H) (br. s, 2 H) (br. s, 2 H)
11[b] Ϫ3.9
12[b] Ϫ5.7
7.42
(br. s, 1 H) (br. s, 2 H) (br. s, 2 H)
7.78 4.44 4.03
(br. s, 1 H) (br. s, 2 H) (br. s, 2 H)
4.91
4.15
4.72/5.08
(br. s, 2 ϫ 2 H)
4.34/4.66
1.90
7.44Ϫ7.64 (m, 3 H, H-16/17/18),
(s, 3 H) 8.08 (d[g], 1 H, H-15)
2.02
1.05Ϫ1.80 (m, 20 H, CyϪCH2),
(br. s, 2 ϫ 2 H)
(s, 3 H) 3.48Ϫ3.59 (m, 1 H, H-15),
4.26 (m, 1 H, H-21), 5.88 (d[h], 1 H, NH)
Ϫ
13[b] Ϫ6.6
Ϫ11
7.13
(br. s, 1 H) (br. s, 2 H) (br. s, 2 H)
8.33 4.89 4.12
(br. s, 1 H) (br. s, 2 H) (br. s, 2 H)
4.49
4.17
4.44/4.68
(br. s, 2 ϫ 2 H)
4.26
2.10
(s, 3 H)
Ϫ
Ϫ
(br. s, 5 H)
[a] A non-resolved duplet of duplets is denoted pseudo-triplet ‘‘pt’’. [b] In CD2Cl2. [c] In D2O. [d] In [D]8THF. [e] 3JH,H ϭ 6.2 Hz. [f] 3JH,H ϭ
[g] 3
[h] 3
6.8 Hz.
J
H,H
ϭ 8.4 Hz.
J
H,H
ϭ 7.4 Hz.
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K. Heinze, M. Schlenker
Table 3. 13C NMR spectroscopic data of complexes 4Ϫ13; atom numbering according to the numbering in the crystal structures
FULL PAPER
C-1
C-2/5 C-3/4 C-6 C-7/10 C-8/9 C-11 C-12 C-13
Substituent(s)
4[a]
5[a]
6[b]
7[a]
8[c]
9[d]
10[e]
89.3 63.4
65.9
63.6
65.0
67.5
66.3
69.9
69.2
69.6
71.8/74.6
71.5/72.9
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
123.5 (C-14), 132.5 (C-13), 134.6 (C-15), 167.0 (C-11)
Ϫ
Ϫ
106.5 58.7
95.0 62.1
96.3 64.1
98.1 62.3
168.9 24.5
80.6
74.0
168.9 24.1 197.3 129.0 (C-16), 131.1 (C-17), 132.3 (C-15), 138.9 (C-14)
168.9 24.3 172.5
Ϫ
Ϫ
Ϫ
Ϫ
63.7, 68.2, 70.5, 72.7, 81.3, 86.4
Ϫ
Ϫ
175.0
99.1 61.2
98.6 63.4
94.1 66.0
65.9
67.2
66.9
73.2
65.6
79.4
80.8
71.3/72.3
72.4/74.9
71.3/71.7
70.1/71.0
171.6 47.9 (C-14), 120.1 (C-19), 125.4 (C-16), 127.3 and 127.8
(C-17/18), 141.8 (C-20), 144.8 (C-15), 154.0 (C-12)[f]
11[a]
12[a]
13[e]
169.4 24.0 167.3 109.2, 120.8, 125.5, 129.5 (C-15/16/17/18), 129.6, 144.1
(C-14/19)
169.3 23.8 169.8 25.1, 25.9, 26.6, 31.4, 32.8 (CyϪCH2), 50.7 (C-15),
55.7 (C-21)
Ϫ
Ϫ
97.8 63.2
98.3 61.5
65.9
64.4
169.4 23.6 174.9
Ϫ
69.6
Ϫ
Ϫ
[a]
[b]
[c]
[d]
[e]
[f]
In CD2Cl2. In CDCl3. In [D]8DMSO. In D2O. In [D]8THF. C13 under THF signal.
Table 4. UV/Vis and cyclic voltammetric data of complexes 4Ϫ13
Table 5. Characteristic IR spectroscopic data of the amide groups
of complexes 6, 7, 8, 11, 12 and 13
λmax (ε)[a]
λmax (ε)[b]
E1/2
E1/2
[c]
[d]
6
7
8
11
12
13
4
443 (370)
443 (195)
441 (215)
480 (755)
441 (350)
431 (160)[e]
441 (230)
457 (430)
441 (450)[f]
451 (650)[f]
325 (1670)
Ϫ
Ϫ
358 (1400)
Ϫ
Ϫ
347 (590)
370 (555)
Ϫ
Ϫ
450
130
325
585
525
Ϫ1470
Ϫ
Ϫ
Ϫ1480
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
5
amide A (solid)[a]
amide A (CH2Cl2)[a] 3435 3431 3303 3428/3363 3291 3430/3292
3262 3275 3322 3359
3319 3327/3316
6
7
amide I (solid)[b]
amide I (CH2Cl2)[b] 1685 1687 1691 1689
amide II (solid)[c]
1580 1574 1569 1548
amide II (CH2Cl2)[c] 1532 1531 1557 1536
1655 1659 1666 1682
1672 1660/1646
1677 1679/1660
1569 1560
8
9
2205)
525
10
11
12
13
1526 1559/1529
670
465
285/590
[a] Amide A ϭ ν˜NH,stretching [b] Amide I ϭ ν˜CO,stretching ϩ ν˜NH,bending
.
[c]
ϩ ν˜CN,stretching
.
Amide II ϭ ν˜NH,bending ϩ ν˜CN,stretching.
[a]
λmax(ferrocene) in nm, ε in Ϫ1cmϪ1 in CH2Cl2; extinction con-
sence of hydrogen bonding (Table 2); thus, 6 is not associ-
ated in solution. The cyclic voltammogram of 6 shows that
it is oxidised at ϩ325 mV (vs. SCE), a much more positive
forms to Lambert-Beer’s law in the concentration range 2Ϫ10 m.
[b]
[c]
λmax(substituent) in nm, ε in Ϫ1cmϪ1 in CH2Cl2. Oxidation
E1/2(ferrocene) in mV vs. SCE 10Ϫ3 in CH3CN/nBu4NPF6. [d] Re-
duction E1/[2e(]substituent) in mV vs. SCE 10Ϫ3 in CH3CN/ potential than the amino compound 5 (Table 4).
[f]
nBu4NPF6. In H2O. In THF.
An IR spectroscopic investigation of 7 shows the pres-
ence of hydrogen bonds in the solid state, while in solution
trated solutions the bands of the NH stretching vibrations no hydrogen bonding is detected (Table 5). This is also veri-
are slightly shifted to 3425 and 3354 cmϪ1 showing the fied by the 1H chemical shift of the amide proton resonating
presence of hydrogen bonding (in dilute solutions these at δ ϭ 6.73 with ∆δNH ϭ Ϫ3.4 ppb KϪ1 in CD2Cl2
bands are observed at 3757 and 3692 cm )
Ϫ1 [24]. Compound (Table 2). Thus, 7 like 6 does not associate in solution. The
5 is oxidised at ϩ130 mV (vs. SCE), a much more positive UV/Vis absorption band for the ferrocene unit of 7 at
potential than 1,1Ј-diaminoferrocene (approximately Ϫ200 480 nm is probably admixed with a charge transfer compo-
mV vs. SCE[31]). Obviously, the electron-donating effect of nent (from the electron-rich ferrocene to the electron-de-
the amino groups to the metal centre is additive.[34]
ficient aromatic system), and thus appears at a relatively
In the solid-state IR absorption spectrum of 6 the charac- low energy and with a high intensity (Table 4).[35] The ab-
teristic amide vibrations confirm the presence of hydrogen sorption band for the aromatic substituent appears at
bonds (Table 5). In dilute solutions, however, the bands as- 358 nm. The ferrocene moiety is oxidised at 585 mV and
signed to amide A and amide I are shifted to higher ener- the aromatic substituent is reduced at Ϫ1480 mV (Table 4).
gies, while that of amide II is shifted to a lower energy,
The hydrogen bonding observed in the crystal of 8 is also
suggesting that hydrogen bonding is absent (Table 5). This apparent in the solid-state IR absorption spectrum
1
finding is also corroborated by the H NMR spectrum of 6 (Table 5). In solution the IR absorption data suggest a hy-
as the signal for the amide proton appears at δ ϭ 6.59 in drogen bond involving the amide hydrogen atom (Table 5).
CD2Cl2 at 293 K (Table 2). A weak temperature depen- In the proton NMR spectrum a signal at δ ϭ 7.15 in
dence is indicative of either a non-bonded hydrogen atom CD2Cl2 (δ ϭ 8.40 in THF, Table 2) is observed which is
or a hydrogen atom involved in a locked hydrogen assigned to the amide proton on the basis of the NOESY
bond.[13,18] For 6, the weak temperature dependence of spectrum (correlation between NH and CH3). This low-
∆δNH ϭ Ϫ2.9 ppb KϪ1 is interpreted in terms of the ab- field chemical shift as well as the large temperature depen-
2978
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Main Chain Ferrocenyl Amides from 1-Aminoferrocene-1Ј-carboxylic Acid
FULL PAPER
dence ∆δNH ϭ Ϫ12 ppb KϪ1 confirm that the NH proton phate buffer, pH 7) to give the N-protected amino acid
is involved in a dynamic hydrogen bond in solution, which 1-[(fluoren-9-yl)methyloxycarbonylamino]ferrocene-1Ј-
can arise from either intermolecular association or intra- carboxylic acid (10) (Scheme 3).
molecular folding processes.[13,18] The characteristic signal
for the vibration of the acid carbonyl group appears at 1715
cmϪ1 in CH2Cl2 and in THF, and is similar to that found
for ferrocenedicarboxylic acid (1720 cmϪ1 in THF), and
suggests the formation of carboxylic acid dimers. As both
functional groups are involved in hydrogen bonding, a dy-
namic intermolecular aggregation in solution is proposed
(Scheme 2). The cis orientation of the amide groups neces-
sary for intermolecular dimerisation (Scheme 2) is con-
firmed by NOESY spectroscopy (correlation peak between
the CH3 group and Cp protons H-2/5).
Scheme 3
Compound 10 crystallises in the monoclinic space group
P21/c with the inclusion of half a molecule dichloromethane
per molecule (Figure 6, Table 1). The asymmetric unit con-
tains two independent molecules 10(A) and 10(B) which are
connected through double OϪH···O hydrogen bonds in-
volving the carboxylic acid functions (O3H6···O102,
˚
O3···O102 distance: 2.63 A; O103H106···O2, O103···O2 dis-
Scheme 2
˚
tance: 2.59 A) and double NϪH···O hydrogen bonds involv-
ing the cis-orientated urethane HNCO groups
˚
(N1H1···O101;
N1···O101
distance:
2.83
A;
DFT calculations (see Supporting Information) on
monomeric 8 show that the non-hydrogen-bonded structure
is the global minimum and the OacidϪH···Oamide hydrogen-
bonded structure is a local minimum 13 kJ molϪ1 higher in
energy, while no minimum is found for the
˚
N101H101···O1; N101-to-O1 distance: 2.86 A) to form a
dimer of approximate C2 symmetry (Figure 6). The same
two eight-membered rings have been detected in the crystal
structure of the related Boc-protected complex
HOOCϪCpFeCpNH(CϭO)OtBu (Boc ϭ tert-butoxycar-
N
amideϪH···Oacid hydrogen-bonded structure. However, the
˚
bonyl) with O···O distances of 2.66 and 2.66 A and N···O
dimeric fourfold hydrogen-bonded structure is calculated to
be a minimum 73 kJ molϪ1 more stable than two isolated
molecules of 8 (although this might be an overestimated
stabilisation energy due to the basis set superposition error
BSSE[36]), confirming the presence of intermolecular hydro-
gen bonds.
distances of 2.83 and 2.85 A.[37] The planes of the fluorenyl
˚
substituents are located almost perpendicular to the planes
of the cyclopentadienyl rings to which they are attached
[10(A): 91.2°, 10(B): 83.4°].
The amino acid 9 can be isolated as the hydrochloride
salt 9·HCl which is soluble and stable in water and dimethyl
sulfoxide. Neutralisation of an aqueous solution of 9·HCl
with sodium hydroxide immediately leads to the precipi-
tation of the zwitterionic compound, which rapidly decom-
poses to a black material at pH Ͼ 7. The solid-state IR
absorption spectrum of 9·HCl shows absorption bands that
are assigned to the NH and OH groups at 3366, 3177 and
3135 cmϪ1, indicating extensive hydrogen bonding which is
probably intermolecular in nature. The UV/Vis absorption
band for the ferrocene moiety of 9·HCl appears at 431 nm,
and is blue-shifted by more than 500 cmϪ1 relative to the
bands of e.g. 4Ϫ6 (441Ϫ443 nm) probably due to the cat-
ionic nature of the complex.
Figure 6. Hydrogen bonding of 10 in the crystal
The hydrogen bonding observed in the crystal of 10 is
also confirmed by the IR absorption spectrum which shows
the absorption bands assigned to the NH and OH groups
between 3500Ϫ2800 cmϪ1, signals for the carbonyl groups
at 1707 (vs) and 1664 (s) cmϪ1, and signals at 1560 (w) and
Peptide Chemistry
A) N-Protection, Crystal and Solution Structure of 10
Since the stability of 9 in alkaline solution is rather poor, 1544 (w) cmϪ1. This pattern in the spectral region
N-protection of 9 with fluorenyl-9-methyl chloroformate 1800Ϫ1500 cmϪ1 is in accordance with the pattern for a
(Fmoc-Cl) has been carried out in buffered solution (phos- cis-orientation of the urethane moiety of 10 calculated by
Eur. J. Inorg. Chem. 2004, 2974Ϫ2988
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K. Heinze, M. Schlenker
FULL PAPER
DFT [1682 (1.00), 1668 (0.46), 1548 (0.11), 1510 (0.09) lar type of aggregation Ϫ albeit more stable Ϫ has been
cmϪ1; see Supporting Information].
proposed for the similar complex 8 (Scheme 2).
In CH2Cl2 solution two dominant bands are observed at
1707 (vs) and 1673 (s) cmϪ1 and two weak bands at 1570 B) COOH Activation, Crystal and Solution Structures of
and 1542 cmϪ1, suggesting that a cis-urethane confor- 11 and 12
mation is the major species. In addition, a shoulder at 1735
Reaction of the N-acetylated amino acid 8 with 1-
cmϪ1 is observed indicating the presence of another species
hydroxybenzotriazole (HOBt) in the presence of 1,3-di-
in CH2Cl2 solution. In THF solution, however, a different
cyclohexylcarbodiimide (DCC) leads to the formation of
pattern is observed: 1735 (s), 1716 (s) and 1563 (s) cmϪ1
.
the isolable ferrocenoyl benzotriazole ester 11 (Scheme 5).
This reaction is similar to that of ferrocene carboxylic acid
with HOBt/DCC.[40] In the absence of HOBt 8 reacts with
DFT calculations on 10 with a trans-orientated urethane
group predict a comparable pattern: 1715 (0.78), 1694
(0.67), 1569 (0.73) cmϪ1 (see Supporting Information).
Thus, 10 prefers the cis-conformation in CH2Cl2 solution
and in the crystal and the trans-conformation in THF.[38,39]
In all cases the acid group appears to be hydrogen bonded
via carboxylic acid dimers. In the NH/OH region of the IR
absorption spectrum bands are observed at 3266, 3316 and
3425 cmϪ1 in CH2Cl2 and at 3269, 3504 and 3573 cmϪ1 in
THF. Thus hydrogen bonding involving the NH group ex-
ists in CH2Cl2 and is absent in THF. NMR spectroscopy
supports this interpretation: in CD2Cl2 solution two reson-
ances[38,39] assigned to the NH protons are observed at δ ϭ
6.95 (free NH group; trans conformation; ∆δNH could not
be determined as the signal moves into the multiplet for
the fluorenyl protons) and δ ϭ 7.99 (hydrogen-bonded NH
group; cis conformation; ∆δNH ϭ Ϫ7 ppb KϪ1) with equal
intensity, together with a doubled signal set for all Cp pro-
tons and the CH2 group, while in THF solution only a sin-
gle signal set for the NH, Cp and CH2 protons is observed
(Table 2). Based on the experimental data, the proposed dy-
namic solution structure of 10 is depicted in Scheme 4. The
cis-orientated species which has the opportunity to form
hydrogen bonds is the dominant species in CH2Cl2, while
the trans-orientated conformer without NH hydrogen
bonds is the major species in THF. These bonding motifs
can be derived from the crystal structure of 10 (Figure 6)
by cleaving one and two NϪH···O hydrogen bonds, respec-
tively, concomitant with a cis/trans rearrangement. A simi- Scheme 5
Scheme 4
2980
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Main Chain Ferrocenyl Amides from 1-Aminoferrocene-1Ј-carboxylic Acid
FULL PAPER
DCC to give 1-[1Ј-(acetylamino)ferrocenylcarbonyl]-1,3-di- are shifted to 3428, 3363 (amide A), 1787 (COester), 1689
cyclohexylurea (12) in a reaction similar to that of ferro- (amide I) and 1536 (amide II) cmϪ1 (Table 5). These data
cenecarboxylic acid with DCC.[41Ϫ43]
show that in the solid state and in solution hydrogen bond-
The activated ester 11 crystallises in the monoclinic space ing involving the NH part of the amide group occurs. DFT
group P21/n as discrete molecules (Table 1). The benzotria- calculations suggest that the solution structure is identical
zole substituent is rotated out of the ester plane by 88.6°, to the crystal structure (Figure 8, see Supporting Infor-
similar to Fc-COOBt (96.6°[40]) but pointing in the opposite mation). This intramolecular hydrogen-bonded system is
direction. This orientation allows for an intramolecular hy- stabilised by 19 kJ molϪ1 relative to the open form accord-
drogen bond from the amide NH to the central nitrogen ing to DFT calculations. The activation barrier for the hy-
atom of the Bt group (N1 to N3 distance: 3.06 A, Figure 7). drogen-bond dissociation is calculated to be 27 kJ molϪ1
.
˚
This interpretation is supported by NMR spectroscopy: the
signal for the amide proton appears at δ ϭ 7.42 in CD2Cl2
suggesting the presence of hydrogen bonding in dilute solu-
tion (Table 2). The signal is temperature dependent, with
∆δNH ϭ Ϫ3.4 ppb KϪ1 when excluding intermolecular hy-
drogen bonding (a larger temperature dependence is ex-
pected when intermolecular hydrogen bonding is in-
cluded[13,18]). In the VT-1H NMR spectra the proton signals
for the cyclopentadienyl rings H-2/5, H-3/4, H-7/10 and H-
8/9 disappear at low temperature with a coalescence tem-
perature (TC) of 223, 213, 213 and 203 K, respectively, and
reappear as separate signals with ∆ν ϭ 168, 57, 39 and 9 Hz
at lower temperature (Figure 8). This finding can be inter-
preted as a ‘‘frozen’’ interconversion of the enantiomeric
hydrogen-bonded structures of 11 rendering the protons
pairs H-2/5, H-3/4, H-7/10 and H-8/9 magnetically different
(Figure 8). The activation barrier for this process can be
Figure 7. Molecular structure of 11 in the crystal
estimated to be ∆G϶(TC) ϭ 43 kJ molϪ1
.
In the solid state the characteristic IR absorption bands
of 11 appear at 3359 (amide A), 1764 (COester), 1682 (amide
In the UV/Vis spectrum the absorption band for the fer-
I) and 1548 (amide II) cmϪ1, while in solution these bands rocene unit of 11 appears at 457 nm (probably admixed
Figure 8. Partial VT-1H NMR spectra of 11 (CD2Cl2, 500 MHz) and proposed interconversion of the enantiomeric hydrogen-bonded
structures of 11
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K. Heinze, M. Schlenker
FULL PAPER
with a charge-transfer component); the absorption band for drogen bonding in the crystal structure (Table 5). In solu-
the benzotriazole group is observed at 370 nm (Table 4). In tion two absorption bands are observed for the NH stretch-
the cyclic voltammogram the oxidation potential of the fer- ing vibrations at 3426 and 3291 cmϪ1. The former is as-
rocene moiety is 670 mV (Table 4).
signed to the non-hydrogen-bonded NH group of the urea
The urea derivative 12 crystallises in the monoclinic space moiety and the latter to the hydrogen-bonded NH group of
group P21/c (Table 1). An intramolecular hydrogen bond the N-acetyl group. Three signals assigned to the carbonyl
from the amide proton (N1H1) to the carbonyl oxygen vibrations appear at 1697, 1677 and 1619 cmϪ1. The low-
˚
atom O2 is observed (N1···O2 distance: 3.02 A, Figure 9). energy vibration is assigned the hydrogen-bonded carbonyl
This intramolecular hydrogen bond in the crystal structure group C13ϪO2. Thus, the IR absorption data suggest a
of 12 proves that such strongly bent connections are indeed solution structure with an intramolecular hydrogen bond
possible (cf. proposed solution structures of 11 and 13 and N1ϪH1···O2 similar to that found in the crystal (Figure 9).
the crystal structure of 11). The molecules of 12 are connec- The IR spectroscopic data are also in agreement with the
ted through two different intermolecular hydrogen-bonding DFT-calculated frequencies of the hydrogen-bonded struc-
motifs (Figure 10): a centrosymmetric dimeric aggregate ture (see Supporting Information). NMR experiments con-
through double hydrogen bonds N1H1···O2 (N1···O2 2.96 firm this proposed structure as two signals for the amide
A), resulting in bifurcated hydrogen bonds at O2 and H1 protons are observed at δ ϭ 5.88 (H6, NOE correlation to
˚
and a connection of molecules along the b-axis through the cyclohexyl protons) and δ ϭ 7.78 (H1), with temperature
NH group of urea (N3H6) and the carbonyl oxygen atom dependences of ∆δNH ϭ Ϫ13 and Ϫ5.7 ppb KϪ1, respec-
of the N-acetyl group (O1) with a donor acceptor distance tively. The large ∆δNH observed for the urea proton H6 is
˚
N3···O1 of 2.95 A.
probably due to the start of intermolecular association at
The characteristic IR absorption bands in the solid state lower temperatures. A static structure as found for 11 was
arise from the hydrogen-bonded NH groups (3319 cmϪ1), not observed for 12 in the NMR experiments at lower tem-
CH2 and CH groups of the cyclohexyl rings (2934, 2886 peratures implying that the activation barrier for the anal-
cmϪ1), CO groups (1699, 1672, 1625 cmϪ1) and CN groups ogous interconversion of hydrogen-bonded structures of 12
(1569, 1543 cmϪ1); this is consistent with the observed hy- is smaller than 40 kJ molϪ1
.
C) Amide Formation, Crystal and Solution Structure of 13
In the activated ester 11 the CϪO ester bond to the
˚
benzotriazole is very long (1.423 A), therefore allowing a
facile reaction with amines. Thus, 11 cleanly reacts with am-
inoferrocene 5 to give the biferrocene 13 (Scheme 6).
Figure 9. Molecular structure of 12 in the crystal
Scheme 6
The diamide 13 crystallises in the polar orthorhombic
space group P212121 as a twinned racemic crystal (Fig-
ure 11). The individual molecules are connected through in-
termolecular hydrogen bonds between the NH-acetyl group
and the amide carbonyl oxygen atom (N1···O2 distance:
˚
3.04 A) and between the NH-amide group and the carbonyl
˚
oxygen atom of the acetyl group (N2···O1 distance: 3.03 A)
Figure 10. Hydrogen bonding of 12 in the crystal
2982
resulting in a sheet structure (Figure 12).
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Main Chain Ferrocenyl Amides from 1-Aminoferrocene-1Ј-carboxylic Acid
FULL PAPER
Figure 11. Molecular structure of 13 in the crystal
Figure 13. IR spectrum of 13 in CH2Cl2
(Table 5). In solution, however, one signal set for a hydro-
gen-bonded NHCO group (3292, 1660, 1559 cmϪ1) and one
set for a non-hydrogen-bonded NHCO group (3430, 1679,
1529 cmϪ1) is observed (Table 5, Figure 13). These findings
can be accounted for by one of the intramolecularly hydro-
gen-bonded structures 13a/13b, as shown in Figure 14, or
by a mixture of both structures which are indistinguishable
by IR spectroscopy.
1
In the H NMR spectrum of 13 in CD2Cl2 two NH res-
onances are observed at δ ϭ 7.13 and 8.33 with temperature
dependences of ∆δNH ϭ Ϫ6.6 and Ϫ11 ppb KϪ1, respec-
tively (Table 2). The former signal is assigned to the proton
of the NH-acetyl group (NOESY correlation peak between
CH3 and NH) and the latter to the NH proton of the amide
Figure 12. Hydrogen bonding of 13 in the crystal
In the solid-state IR absorption spectrum of 13 the bond. The chemical shifts and their temperature depen-
characteristic absorption bands confirm a hydrogen-bonded dences suggest that both protons are involved in dynamic
structure involving all NH protons and all carbonyl groups hydrogen bonding. This can be rationalised by a flipping
Figure 14. Interconversion of the two hydrogen-bonded structures of 13 (13a/b) and the extended form 13c (DFT: B3LYP, LanL2DZ)
Eur. J. Inorg. Chem. 2004, 2974Ϫ2988
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K. Heinze, M. Schlenker
FULL PAPER
process that occurs between the two hydrogen-bonded Experimental Section
structures 13a and 13b, as shown in Figure 14. This equilib-
Unless noted otherwise, all manipulations were carried out under
argon by means of standard Schlenk techniques. All solvents were
dried by standard methods and distilled under argon prior to use.
Iodoferrocene 3 was prepared by a literature method.[26] All other
reagents were used as received from commercial sources. NMR
spectra were recorded on Bruker Avance DPX 200 at 200.15 MHz
(1H), 50.323 MHz (13C) at 303 K; chemical shifts (δ) in ppm with
respect to residual solvent peaks as internal standards: CD2Cl2 (1H:
δ ϭ 5.32; 13C: δ ϭ 53.5 ppm), CDCl3 (1H: δ ϭ 7.24; 13C: δ ϭ 77.0
ppm), [D]6DMSO (1H: δ ϭ 2.49; 13C: δ ϭ 39.7 ppm), [D]8THF
(1H: δ ϭ 1.73, 3.58; 13C: δ ϭ 25.5, 67.7), D2O (1H: δ ϭ 4.65 ppm).
Proton NMR spectra were measured at a concentration of 10 m.
Assignments are based on 2D NMR spectra and by comparison
with spectra of similar compounds. IR absorption spectra were re-
corded on a BioRad Excalibur FTS 3000 spectrometer using CaF2
cells (concentration Ͻ 10 m) or CsI discs. UV/Vis/NIR spectra
were recorded on a PerkinϪElmer Lambda 19, 0.2 cm cells
(Hellma, suprasil). Cyclic voltammetry was performed using a
glassy carbon electrode, a platinum electrode and a SCE electrode,
10Ϫ3  in 0.1  nBu4NPF6/CH3CN, potentials are given relative to
that of SCE. Mass spectra were recorded on a Finnigan MAT 8400
spectrometer, 4-nitrobenzyl alcohol (FAB). Elemental analyses
were performed by the microanalytical laboratory of the Organic
Chemistry Department, University of Heidelberg. Melting points
were determined with a Gallenkamp capillary melting point appar-
atus MFB 595 010 and are uncorrected.
rium is fast on the NMR time scale, averaging the NMR
signals for free and hydrogen-bonded amide protons. DFT
calculations on these two conformers confirm that both are
minima on the potential energy surface with 13b slightly
higher in energy than 13a. The activation barrier for the
flipping process 13a Ǟ 13b is calculated to be only 8 kJ
molϪ1, supporting the interpretation of a fast equilibrium
(Figure 14, see Supporting Information). High-temperature
NMR and IR studies show that the folded structures are
stable up to 55 °C in chloroform. DFT calculations confirm
the stability of 13a/13b towards unfolding into the extended
structure 13c (Figure 14, ∆E13a/13c ϭ 10 kJ molϪ1). From
these energies, equilibrium compositions of 100:11:2
(13a:13b:13c) at 20 °C and 100:13:3 (13a:13b:13c) at 55 °C
can be estimated which explain the experimental findings.
In addition to the folding characteristics imposed by the
amide groups, the biferrocene compound 13 shows metal
specific properties: (i) 13 absorbs at 451 nm with a small
bathochromic shift relative to e.g. 12 (Table 4) and (ii) 13
can be oxidised in two reversible steps at 285 and 590 mV
(Table 4). These values are different from the oxidation po-
tentials of comparable mononuclear complexes e.g. 6 and
12 (Table 4). The constant for the comproportionation equi-
librium KC can be estimated to be 1.4 ϫ 105, showing that
13؉ is stable towards disproportionation into 13 and 132؉
.
Computational Method: Density functional calculations were car-
ried out with the Gaussian98/DFT[45] series of programs. The
B3LYP formulation of density functional theory was used em-
ploying the LanL2DZ basis set.[45] Harmonic vibrational frequenc-
ies and infrared intensities were calculated by numerical second de-
rivatives using analytically calculated first derivatives. Frequencies
are not scaled.
Conclusion
The optimised synthesis of the non-natural amino acid 9
reported here offers the possibility to incorporate ferrocenes
in the main chain of peptides. Standard reactions of peptide
Crystallographic Structure Determinations: The measurements were
carried out on an EnrafϪNonius Kappa CCD diffractometer using
synthesis (N-protection with Fmoc and acid activation with graphite monochromated Mo-Kα radiation. The data were pro-
cessed using the standard Nonius software.[46] All calculations were
performed with the SHELXT PLUS software package. Structures
HOBt/DCC) have been applied to this ferrocene amino
acid. The crystal structures of NHC(ϭO)R-substituted fer-
rocenes 6Ϫ13 have been determined by X-ray crystallogra-
were solved using direct or Patterson methods with the SHELXS-
97 program and refined with the SHELXL-97 program.[47] Graphi-
phy in order to elucidate hydrogen-bonding motifs. In most
cal handling of the structural data during refinement was per-
cases hydrogen bonding is found to be intermolecular, ex-
formed using XMPA[48] and WinRay[49]. Atomic coordinates and
cept in the case of the active ester 11 (only intramolecular)
and the urea derivative 12 (both types). The solution struc-
anisotropic thermal parameters of the non-hydrogen atoms were
refined by full-matrix least-squares calculations. Data relating to
tures have been investigated by a combination of IR and
NMR spectroscopy, together with DFT calculations. In
solution 6 and 7 are monomeric and non-hydrogen-bonded,
8 and 10 with C(ϭO)OH groups at the 1Ј position form
dimers via OϪH···O and NϪH···O hydrogen bonds, the ac-
tive ester 11 forms an intramolecular hydrogen bond to the
the structure determinations are collected in Table 6 and Table 7.
CCDC-225594Ϫ225602 contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge at www.ccdc.cam.ac.uk/conts/retrieving.html [or from the
Cambridge Crystallographic Data Centre, 12 Union Road, Cam-
bridge CB2 1EZ, UK; Fax: (internat.) ϩ44-1223-336-033; E-mail:
benzotriazole substituent, and 12 and 13 with C(ϭO)NRRЈ deposit@ccdc.cam.ac.uk].
groups at the 1Ј position form intramolecular NϪH···O hy-
drogen bonds. The structure of the diamide 13 in solution
and in the crystal is reminiscent of the typical structures of
Copper Phthalimide: (modified literature procedure)[27,28] A solu-
tion of potassium phthalimide (20 g, 107 mmol) in water (50 mL)
was added to an aqueous solution of CuSO4·5H2O (8 g, 32 mmol)
peptides built from α-amino acids, i.e. α-helix and β-sheet in water (50 mL). The mixture was stirred for 30 min and the re-
sulting light blue precipitate was filtered, washed with water and
ethanol and dried in vacuo. Yield: 10.8 g (93%).
structures, respectively.
This chemistry is currently extended to build ferrocene
containing peptides in order to study their folding, electron-
transfer and anion-sensing properties.[44]
2-Ferrocenylisoindole-1,3-dione (4): Copper phthalimide (20 g) and
iodoferrocene (7 g, 22 mmol) were made into a powder and heated
2984
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Inorg. Chem. 2004, 2974Ϫ2988

Main Chain Ferrocenyl Amides from 1-Aminoferrocene-1Ј-carboxylic Acid
Table 6. X-ray crystallographic data of complexes 4, 5, 6 and 7
FULL PAPER
4
5
6
7
Formula
C18H13FeNO2
331.14
C10H11FeN
201.05
C12H10FeNO
240.06
C19H15Cl2FeNO2
416.07
Molecular mass
Crystal dimension /mm
Crystal system
Space group (no.)
0.15 ϫ 0.05 ϫ 0.05
monoclinic
P21/n (14)
5.740(1)
18.406(4)
13.078(3)
96.91(3)
1371.7(5)
4
0.15 ϫ 0.10 ϫ 0.05
tetragonal
I41/a (88)
23.632(3)
23.632(3)
5.931(1)
90.0
3312.3(9)
16
1.754
0.10 ϫ 0.03 ϫ 0.03
monoclinic
P21/n (14)
5.913(1)
7.488(2)
23.405(6)
92.44(3)
1035.3(4)
4
0.15 ϫ 0.05 ϫ 0.05
monoclinic
P21/c (14)
16.027(3)
9.023(2)
11.917(2)
100.55(3)
1694.2(6)
4
˚
a /A
˚
b /A
˚
c /A
β /°
3
˚
Cell volume /A
Molecular units per cell
µ /mmϪ1
1.105
1.604
200
1.424
1.540
200
1.218
1.631
200
Density (calcd.) /g cmϪ3
T /K
1.613
200
Scan range (2Θ)
3.8Ϫ54.9
20
5748
3091
1984
251
0.55/Ϫ0.53
3.4Ϫ55.1
20
3488
1912
1202
153
0.31/Ϫ0.37
5.7Ϫ55.0
40
3740
2229
1112
154
1.92/Ϫ0.75
5.2Ϫ55.0
30
6587
3862
2366
267
0.46/Ϫ0.43
Scan speed /sec frameϪ1
Measured reflections
Unique reflections
Obs. reflections (I Ն 2σ)
Parameters refined
Max. residual electron
Ϫ3
˚
density/e A
Agreement factors
R1 ϭ 6.0%
Rw ϭ 15.0%
R1 ϭ 4.9%
Rw ϭ 11.3%
R1 ϭ 15.8%
Rw ϭ 40.3%
R1 ϭ 5.4%
Rw ϭ 12.2%
(F2 refinement)
Table 7. X-ray crystallographic data of complexes 8, 10, 11, 12 and 13
10
8
11
12
13
Formula
Molecular mass
C13H13FeNO3·CH3OH C26H21FeNO4·0.5CH2Cl2 C19H16FeN4O3
C26H35FeN3O3
493.43
C23H22Fe2N2O2
470.13
319.14
509.75
404.21
Crystal dimension /mm 0.05 ϫ 0.02 ϫ 0.02
0.30 ϫ 0.20 ϫ 0.20
monoclinic
P21/c (14)
16.785(2)
16.287(2)
17.149(2)
106.918(2)
4485.2(8)
8
0.30 ϫ 0.20 ϫ 0.02 0.35 ϫ 0.15 ϫ 0.06 0.20 ϫ 0.15 ϫ 0.02
Crystal system
orthorhombic
Pbca (61)
27.396(6)
10.228(2)
9.5500(19)
90.0
monoclinic
P21/n (14)
9.667(2)
16.146(3)
11.253(2)
101.85(3)
1719.0 (6)
44
monoclinic
P21/c (14)
15.867(1)
7.7275(6)
19.824(2)
103.496(2)
2363.6(3)
4
orthorhombic
P212121 (19)
7.489(2)
10.286(2)
24.761(5)
90.0
1907.4(7)
4
1.544
Space group (no.)
˚
a /A
˚
b /A
˚
c /A
β /°
3
˚
Cell volume /A
Molecular units per cell
µ /mmϪ1
2676.0(9)
8
1.139
0.827
1.510
0.906
0.665
Density (calcd.) /g cmϪ3 1.584
1.562
1.327
1.637
T /K
200
3.0Ϫ55.0
173
3.5Ϫ56.6
20
200
4.5Ϫ54.1
60
103
4.2Ϫ61.0
20
200
4.3Ϫ55.4
50
Scan range (2Θ)
Scan speed /sec frameϪ1 30
Measured reflections
Unique reflections
Obs. reflections (I Ն 2σ) 1773
Parameters refined 249
6102
3074
47935
11134
8535
780
6127
3728
1920
251
27762
7206
5011
438
3031
3012
1897
267
Max. residual electron 0.56/Ϫ0.32
density /e A
0.43/Ϫ0.29
0.57/Ϫ0.30
1.58/Ϫ1.19
0.54/Ϫ0.52
Ϫ3
˚
Agreement factors
R1 ϭ 5.3%
Rw ϭ 13.9%
R1 ϭ 3.4%
Rw ϭ 7.3%
R1 ϭ 6.5%
Rw ϭ 13.4%
R1 ϭ 5.2%
Rw ϭ 15.2%
6.6
17.7
(F2 refinement)
in vacuo at 135Ϫ140 °C for two hours. After cooling to room tem-
perature, the mixture was washed with petroleum ether (boiling
range 40Ϫ60 °C) to remove unchanged iodoferrocene. The residue
was extracted with diethyl ether (5 ϫ). The combined extracts were
evaporated in vacuo to give an orange solid. Yield: 6 g, 18 mmol
(82%). C18H13NO2Fe (331.15): calcd. C 65.29, H 3.96, N 4.23;
ν˜ ϭ 1780 (w, COsym), 1720 (vs, COasym), 1484 (s, CN) cmϪ1. MS
(FAB): m/z (%) ϭ 331 (100) [Mϩ], 266 (64) [Mϩ Ϫ C5H5]. M.p.
148Ϫ151 °C.
1-Aminoferrocene (5): Compound 4 (3.57 g, 11 mmol) was dis-
solved in dry ethanol (50 mL). Hydrazine monohydrate (20 mL)
found C 64.88, H 4.06, N 4.87. IR (CsI): ν˜ ϭ 3095 (w, CH), 1778 was added and the mixture was heated under reflux for two hours.
(w, COsym), 1717 (vs, COasym), 1479 (s, CN) cmϪ1. IR (CH2Cl2): After cooling to ambient temperature, water (80 mL) was added
Eur. J. Inorg. Chem. 2004, 2974Ϫ2988
www.eurjic.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2985

K. Heinze, M. Schlenker
FULL PAPER
and the mixture was extracted with diethyl ether (3 ϫ). The com-
bined organic phases were dried over Na2SO4, filtered and the sol-
vents evaporated to dryness under reduced pressure to give a yellow
solid which darkens on storage. Yield: 2.2 g, 10.9 mmol (99%).
C10H11NFe (201.05): calcd. C 59.74, H 5.51, N 6.97; found C 59.64,
(15 mL) for 30 minutes. The mixture turned to a clear brown solu-
tion. After filtration, the solvents were evaporated to dryness and
the brown residue was washed with tetrahydrofuran and diethyl
ether to obtain the product as a light brown solid. Yield: 0.55 g,
1.96 mmol (98%). C11H11NO2Fe (245.06)·2HCl·0.5H2O: calcd. C
H 5.46, N 7.07. IR (CsI): ν˜ ϭ 3400, 3336 (w, NH), 3085 (w, CH), 40.41, H 4.32, N 4.28; found C 39.98, H 4.52, N 4.78. IR (CsI):
1621 (br., NH2def), 1500 (s, CN) cmϪ1. IR (CH2Cl2): ν˜ ϭ 3425, ν˜ ϭ 3366 (vs, OH), 3177, 3135, 3030 (m, NH3ϩ), 1628 (m, CO)
3354 (w, NH), 1616 (br., NH2def), 1497 (s, CN) cmϪ1. MS (EI):
m/z (%) ϭ 201 (100) [Mϩ], 121 (26) [Mϩ Ϫ CpNH2], 80 (24)
[C5H6Nϩ].M.p. 153Ϫ155 °C.
cmϪ1. MS (FAB): m/z (%) ϭ 245 (100) [Mϩ], 228 (24) [Mϩ Ϫ NH4].
M.p. 165 °C (dec.).
1-[(Fluoren-9-yl)methyloxycarbonylamino]ferrocene-1Ј-carboxylic
Acid (10): 1-Aminoferrocene-1Ј-carboxylic acid, hydrochloride
9·HCl (1.1 g, 3.9 mmol) was dissolved in phosphate buffer (20 mL)
and the pH was adjusted to 7. 9-Fluorenylmethyl chloroformate
(1.03 g, 3.98 mmol) dissolved in dioxane (10 mL) was added to the
solution. A bright orange solid separated from the solution im-
1-(Acetylamino)ferrocene (6): Compound 5 (2.2 g, 10.9 mmol) was
treated with acetic anhydride (20 mL) in the presence of sodium
acetate (0.1 g, 1.2 mmol) for 18 hours. After removal of the solvent,
the crude pale brown product was purified by recrystallisation from
diethyl ether/petroleum ether (40:60) to give a golden powder.
Yield: 2.5 g, 10.3 mmol (95%). C12H13NOFe (243.09): calcd. C mediately after the addition. After stirring overnight, the precipi-
59.29, H 5.39, N 5.76; found C 58.80, H 5.41, N 5.81. IR (CsI): tate was collected by filtration and washed twice with diethyl ether.
ν˜ ϭ 3262, 3216 (m, NH), 3094, 2854 (w, CH), 1655 (s, CO), 1580 Recrystallisation from dichloromethane gave an orange powder.
(s, CN) cmϪ1. IR (CH2Cl2): ν˜ ϭ 3435 (m, NH), 1685 (s, CO), 1532
Yield: 1.5 g, 3.2 mmol (82%). C26H21NO4Fe (467.30)·0.5CH2Cl2:
(s, CN) cmϪ1. MS (FAB): m/z (%) ϭ 243 (100) [Mϩ]. M.p. calcd. C 62.44, H 4.35, N 2.75; found C 62.25, H 4.34, N 2.87. IR
169Ϫ171 °C.
(CsI): ν˜ ϭ 3263, 3153 (m, NH), 3400Ϫ2800 (br., OH), 1707 (s, CO),
1664 (s, CO), 1560 (w, CN) cmϪ1. IR (CH2Cl2): ν˜ ϭ 3425, 3316 (w,
NH), 3266 (w, OH), 1735 (s, CO), 1707 (s, CO), 1673 (s, CO), 1570,
1544 (m, CN) cmϪ1. IR (THF): ν˜ ϭ 3573, 3504 (w, NH), 3269 (w,
OH), 1735 (s, CO), 1717 (s, CO), 1563 (m, CN) cmϪ1. MS (FAB):
m/z (%) ϭ 467 (100) [Mϩ]. M.p. 118 °C.
1-(Acetylamino)-1Ј-(2,6-dichlorobenzoyl)ferrocene (7): A solution of
6 (4 g, 16 mmol) in dichloromethane (30 mL) was treated with 2,6-
dichlorobenzoyl chloride (2.56 mL, 16 mmol) and AlCl3 (3.06 g,
23 mmol) at 0 °C. The resulting blue solution was stirred for 30
minutes at 0 °C and for two hours at room temperature. The mix-
ture was cooled by carefully adding cold water (50 mL). The colour Benzotriazol-1-yl 1-(Acetylamino)ferrocene-1Ј-carboxylate (11): Di-
of the solution turned red immediately. The aqueous solution was
extracted with dichloromethane (3 ϫ) and the combined organic
phases were washed with water and 10% NaOH (aq.). After drying
over MgSO4 and filtering, the solution was evaporated under re-
duced pressure to obtain a red oil. Repeated washing with diethyl
ether gave a red microcrystalline product. Yield: 4.9 g, 11.8 mmol
cyclohexylcarbodiimide (0.86 g, 4.2 mmol) and N-hydroxybenztria-
zole (0.415 g, 4.2 mmol) was added to a solution of 8 (1.1 g,
3.8 mmol) in dichloromethane (10 mL). The mixture was stirred at
room temperature overnight. After filtering, the solution was
washed with aqueous NaHCO3, saturated NaCl (aq.) and 2% HCl
(aq.). After drying over MgSO4, the solvent was removed in vacuo
(74%). C19H15Cl2NO2Fe (416.09): calcd. C 54.85, H 3.63, N 3.37; and the crude product was purified by column chromatography on
found C 54.78, H 3.81, N 3.35. IR (CsI): ν˜ ϭ 3275, 3223 (m, NH), silica gel with ethyl acetate as eluent. After removal of the solvent
3105, 2853 (w, CH), 1659 (s, CO), 1638 (sh, CO), 1574 (s, CN)
cmϪ1. IR (CH2Cl2): ν˜ ϭ 3431 (w, NH), 1687 (s, CO), 1655 (s, CO), 1.23 g, 3.0 mmol (80%). C19H16N4O3Fe (404.21): calcd. C 56.46, H
1531 (s, CN) cmϪ1. MS (EI): m/z (%) ϭ 415 (100) [Mϩ], 373 (22)
3.99, N 13.86; found C 57.13, H 4.47, N 13.17. IR (CsI): ν˜ ϭ 3359
[Mϩ Ϫ C2H2O], 293 (16) [Mϩ Ϫ CpNHCOCH3], 178 (100) [Mϩ (m, NH), 1764 (s, CO), 1682 (s, CO), 1548 (s, CN), 1491 (m) cmϪ1
under reduced pressure an orange red powder was obtained. Yield:
.
Ϫ CpCOAr]. M.p. 160 °C.
IR (CH2Cl2): ν˜ ϭ 3428, 3363 (w, NH), 1787 (s, CO), 1689 (s, CO),
1536 (s, CN),1485(m) cmϪ1. MS (FAB): m/z (%) ϭ 404 (100) [Mϩ].
M.p. 133 °C.
1-(Acetylamino)-ferrocene-1Ј-carboxylic Acid (8): A solution of 7
(3.5 g, 8.4 mmol) in 1,2-dimethoxyethane (20 mL) was added to a
slurry of potassium tert-butoxide (3.8 g, 33 mmol) and water (0.15
mL) while cooling under ice. The red solution was heated under
reflux for one hour. A colour change from red to brown was ob-
served. After cooling to ambient temperature, water (20 mL) was
1-[1Ј-(Acetylamino)ferrocenylcarbonyl]-1,3-dicyclohexylurea
(12):
Compound 8 (1.02 g, 3.5 mmol) was dissolved in tetrahydrofuran
(20 mL) and 1,3-dicyclohexylcarbodiimide (0.73 g, 3.5 mmol) was
added to the stirred solution. After standing overnight at room
added and the solution was washed with diethyl ether. The organic temperature, the solvent was removed in vacuo and the crude prod-
phase was back extracted with 10% NaOH (aq.) and water. The
combined aqueous phases were acidified with dilute HCl. The
crude product was obtained by extraction with ethyl acetate, drying
over MgSO4 and evaporation to dryness. After repeated washing
with diethyl ether, an orange-brown product was obtained. Yield:
1.7 g, 5.9 mmol (70%). C13H13NO3Fe (287.10): calcd. C 54.39, H
4.56, N 4.88; found C 54.38, H 4.55, N 4.83. IR (CsI): ν˜ ϭ 3322,
3225 (m, NH), 3300Ϫ2500 (br., OH), 1698 (sh, CO), 1666 (s, CO),
uct was purified by column chromatography on silica gel with ethyl
acetate as eluent. The solvent was removed under reduced pressure
and an orange-brown product was obtained. Yield: 1.46 g,
3.0 mmol (85%). C26H35N3O3Fe·0.18CH2Cl2 (493.43·0.18CH2Cl2):
calcd. C 61.80, H 7.00, N 8.26; found C 61.84, H 6.75, N 7.85. IR
(CsI): ν˜ ϭ 3319 (s, NH), 2934 (vs, CH2), 2856 (s, CH), 1699 (s,
CO), 1672 (vs, CO), 1625 (s, CO), 1569 (s, CN), 1541 (m, CN)
cmϪ1. IR (CH2Cl2): ν˜ ϭ 3426 (m, NH), 3291 (m, NH), 2936 (s,
1569 (s, CN) cmϪ1. IR (CH2Cl2): ν˜ ϭ 3303 (w, NH), 3235 (w, OH), CH2), 2858 (m, CH), 1697 (s, CO), 1677 (s, CO), 1619 (m, CO),
1715 (s, CO), 1691 (sh, CO), 1557 (s, CN) cmϪ1. MS (EI): m/z 1526 (s, CN), 1510 (s, CN) cmϪ1. MS (FAB): m/z (%) ϭ 493 (20)
(%) ϭ 287 (100) [Mϩ], 245 (4) [Mϩ Ϫ C2H2O], 178 (28) [Mϩ
CpCOOH], 165 (4) [Mϩ Ϫ CpNHCOCH3], 135 (22) [Mϩ
CpCOOHϪC2H2O]. M.p. 146Ϫ147 °C.
Ϫ
Ϫ
[Mϩ], 368 (93) [Mϩ Ϫ CyNCO], 178 (100) [FeCpNHAc]. M.p.
158 °C.
(CH3CONH؊C5H4)Fe(C5H4-CONH؊C5H4)Fe(C5H5) (13): Com-
1-Aminoferrocene-1Ј-carboxylic Acid, Hydrochloride (9·HCl): Com-
pound 11 (1.20 g, 2.9 mmol) and aminoferrocene 5 (0.59 g,
pound 8 (0.6 g, 2 mmol) was heated under reflux in 6  HCl (aq.) 2.9 mmol) were dissolved in tetrahydrofuran (10 mL) and stirred
2986
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjic.org
Eur. J. Inorg. Chem. 2004, 2974Ϫ2988

Main Chain Ferrocenyl Amides from 1-Aminoferrocene-1Ј-carboxylic Acid
FULL PAPER
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