Organometallic β-turn mimetics. A structural and spectroscopic study of inter-strand hydrogen bonding in ferrocene and cobaltocenium conjugates of amino acids and dipeptides

Article abstract of DOI:10.1039/b208363a

By using organometallic turn-mimetics, we have investigated the influence of a positive charge on the structure and stability of peptide turn structures which are stabilized by hydrogen bonds. Starting from metallocene mono- (1) or di-carboxylic acid (2), 11 amide derivatives were prepared, namely CpMC ₅H₄-CO-Phe-OMe (3), CpMC₅H₄-CO- AlaPhe-OMe (4), CpMC₅H₄-CO-NH-CH(CH₃)-Ph (5), M(C₅H₄-CO-Phe-OMe)₂ (6), M(C₅H ₄-CO-Ala-Phe-OMe)₂ (7), and Fe(C₅H ₄-CO-NH-CH(CH₃)-Ph)₂ (8a) with Cp = η-C₅H₅ and M = Fe (ferrocene, a) or M = Co⁺ (cobaltocenium, b). All compounds were characterized by elemental analysis, MS, IR, electrochemistry, Moessbauer spectroscopy (a only) and NMR spectroscopy. Solid state structures of 4a, 6a, 7a, 3b, and 5b were determined by single crystal X-ray diffraction. ¹H NMR data (δ(NH) and Δδ(NH) with T) as well as solution IR spectra were evaluated in order to determine intramolecular hydrogen bond interactions in solution. No intramolecular hydrogen bonds form in the monosubstituted derivatives 3-5 and in 8a. For 7, a strong intramolecular hydrogen bond is observed between the NH_Ala, and CO_Ala. of the other ring, forming an 11-membered ring in solution as well as in the solid state. The situation is most complex for 6, which forms an intramolecular 8-membered ring by hydrogen bonds NH_Phe ... CO_Cp in the solid state (6a), but a symmetrical 11-membered ring structure with NH_Phe ... CO _Phe, bonds in solution. A comparison of the uncharged ferrocene derivatives with the iso-structural but positively charged cobaltocenium derivatives reveals only minor differences. Apparently, the presence of a positive charge does not significantly influence hydrogen bonds in peptide turn structures. Our results are related to geometries and amino acid sequences in protein turn structures and a nomenclature for turn mimetics with a parallel orientation of the two peptide strands is proposed. The Royal Society of Chemistry 2003.

Full text of DOI:10.1039/b208363a

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Organometallic ꢀ-turn mimetics. A structural and spectroscopic
study of inter-strand hydrogen bonding in ferrocene and
cobaltocenium conjugates of amino acids and dipeptides†
Dave R. van Staveren,a,b Thomas Weyhermüllera and Nils Metzler-Nolte*b
a Max-Planck-Institut für Strahlenchemie, Stiftstraße 34-36, D-45470 Mülheim/Ruhr, Germany
b Institut für Pharmazie und Molekulare Biotechnologie, Universität Heidelberg,
Im Neuenheimer Feld 364, D-69120 Heidelberg, Germany.
E-mail: Nils.Metzler-Nolte@urz.uni-heidelberg.de
Received 28th August 2002, Accepted 20th November 2002
First published as an Advance Article on the web 9th December 2002
By using organometallic turn-mimetics, we have investigated the influence of a positive charge on the structure and
stability of peptide turn structures which are stabilized by hydrogen bonds. Starting from metallocene mono- (1) or
di-carboxylic acid (2), 11 amide derivatives were prepared, namely CpMC5H4-CO-Phe-OMe (3), CpMC5H4-CO-Ala-
Phe-OMe (4), CpMC5H4-CO-NH-CH(CH3)-Ph (5), M(C5H4-CO-Phe-OMe)2 (6), M(C5H4-CO-Ala-Phe-OMe)2 (7),
and Fe(C5H4-CO-NH-CH(CH3)-Ph)2 (8a) with Cp = η-C5H5 and M = Fe (ferrocene, a) or M = Coϩ (cobaltocenium,
b). All compounds were characterized by elemental analysis, MS, IR, electrochemistry, Mössbauer spectroscopy (a
only) and NMR spectroscopy. Solid state structures of 4a, 6a, 7a, 3b, and 5b were determined by single crystal X-ray
diffraction. 1H NMR data (δ(NH) and ∆δ(NH) with T ) as well as solution IR spectra were evaluated in order to
determine intramolecular hydrogen bond interactions in solution. No intramolecular hydrogen bonds form in the
monosubstituted derivatives 3–5 and in 8a. For 7, a strong intramolecular hydrogen bond is observed between the
NHAla and COAla’ of the other ring, forming an 11-membered ring in solution as well as in the solid state. The
situation is most complex for 6, which forms an intramolecular 8-membered ring by hydrogen bonds NHPhe ؒ ؒ ؒ COCp
in the solid state (6a), but a symmetrical 11-membered ring structure with NHPhe ؒ ؒ ؒ COPhe’ bonds in solution. A
comparison of the uncharged ferrocene derivatives with the iso-structural but positively charged cobaltocenium
derivatives reveals only minor differences. Apparently, the presence of a positive charge does not significantly
influence hydrogen bonds in peptide turn structures. Our results are related to geometries and amino acid sequences
in protein turn structures and a nomenclature for turn mimetics with a parallel orientation of the two peptide strands
is proposed.
of ferrocene of about 3.3 Å is close to the N ؒ ؒ ؒ O distance
in β-sheets, this ordered conformation is a mimic for this
secondary structural element. More recently, Hirao and co-
Introduction
α-Helices and β-sheets are important secondary structural
elements in peptides.1 Extended structures are formed from
workers prepared several disubstituted dipeptide derivatives,
these primary elements resulting in helix bundles or extended
which contain a similar ordered structure.6–9
sheets. In particular, β-turns induce an extended sheet structure
Compared to purely organic scaffolds, ferrocene derivatives
from two consecutive β-sheets, typically in an anti-parallel
offer very favourable redox properties which were used in other
fashion. β-Turns and extended β-sheets are stabilized by
types of molecular receptors.10 Although the electrochemical
hydrogen bonds. This structural motif has important implic-
reversibility of ferrocene oxidation is excellent under almost
all circumstances, the one-electron oxidized ferrocenium com-
ations for the biological function.2 Consequently, β-turns have
become target structures for medicinal research and a number
pounds are generally not readily isolated and studied, especially
of β-turn mimetics based on rigid organic molecules were
in protic media. This precludes studies on the influence of
designed.3,4 Ferrocene derivatives were proposed as an organo-
metallic scaffold for β-turns. In 1996, Herrick et al. reported
compounds of the general type Fe(C5H4-CO-Xaa-OMe)2
charge on the structure and stability of β-turn mimetics based
on ferrocene.
In this work, we present a series of novel cobaltocenium
(with Xaa = amino acid) to have an ordered structure in organic
organometallic β-turn mimetics. Cobaltocenium derivatives are
solvents such as CH2Cl2 and CHCl3.5 This ordered structure is
structurally very similar to ferrocene compounds, but the stable
stabilized by two symmetrically equivalent hydrogen bonds
between the amide NH and the methyl ester carbonyl moiety
of another strand (Scheme 1). Because the inter-ring separation
18-electron form naturally possesses a positive charge.11
A
comparison to the iso-structural, but neutral, ferrocene
derivatives makes it possible to assess the influence of charge
on structure and stability of β-turns. In addition, a number
of amine and peptide derivatives were synthesized where
only some but not all of the hydrogen bonds that would
stabilize a β-turn can form and their properties were investi-
gated and compared to the full organometallic turn mimetics.
Experimental
Scheme 1
All reactions were carried out in ordinary glassware and
solvents. Chemicals were obtained from Aldrich or from
Novabiochem. Enantiomerically pure -amino acids were used.
The dipeptide Boc-Ala-Phe-OMe was prepared according to
† Dedicated to Professor Wolfgang Beck, Ludwig-Maximilians-
Universität München, on the occasion of his 70th birthday.
D a l t o n T r a n s . , 2 0 0 3 , 2 1 0 – 2 2 0
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
210

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standard peptide chemistry techniques from Boc-Ala-OH and
H-Phe-OMeؒHCl, employing isobutylchloroformate as the
coupling reagent.12 The Boc-protecting group of the dipeptide
was removed by reaction with CH2Cl2/CF3CO2H (1 : 1, v/v) for
1 h at room temperature, followed by removal of the solvent
in vacuo, yielding the dipeptide H-Ala-Phe-OMeؒCF3CO2H
as a white hygroscopic solid. The compounds [Co(Cp)(C5H4-
CO2H)]PF6 (1b, Cp = η-C5H5) and [Co(C5H4-CO2H)2]PF6 (2b)
were synthesised according to literature methods.13
band that eluted was the desired compound. Yields were 0.34 g
(87%) for 3a, 0.34 g (74%) for 4a, 0.21 g (63%) for 5a, 0.46 g
(77%) for 6a, 0.57 g (77%) for 7a, and 0.25 g (52%) for
8a. Crystals suitable for X-ray analysis of 6a were grown by
pentane diffusion into an ethyl acetate solution at room
temperature. X-Ray quality crystals of 4aؒ0.25CH2Cl2 were
grown by slow evaporation of a CH2Cl2–hexane solution,
whereas crystals suitable for X-ray structure determination of
7aؒ0.5CHCl3 were obtained by slow evaporation of a CHCl3–
heptane solution.
Elemental analyses were performed by H. Kolbe, Micro-
analytisches Laboratorium, Mülheim an der Ruhr, Germany.
Infrared spectra were recorded on a Perkin-Elmer FT-IR
spectrophotometer 2000 as KBr disks and/or in CH2Cl2
solution, with a spectral resolution of 4.0 cmϪ1. Mass spectra
were recorded on a Finnigan MAT 8200 instrument (EI, 70 eV)
or on a Hewlett-Packard HP 5989 mass spectrometer (ESI and
HR-MS; solvent and detection mode are given in parentheses).
Cyclic voltammograms (CV) and square wave voltammograms
(SWV) were recorded in CH2Cl2, with NBu4PF6 as supporting
electrolyte, by using an EG&G Potentiostat/Galvanostat 273A.
A three-electrode cell was employed with a glassy-carbon work-
ing electrode, a platinum wire auxiliary electrode and a Ag/
AgNO3 reference electrode (0.01 M AgNO3 in MeCN). For
determination of the redox potentials, ferrocene was added as
an internal standard. 57Fe Mössbauer spectra were recorded on
an Oxford Instruments Mössbauer spectrometer in the con-
stant acceleration mode, by using 57Co/Rh as the radiation
source. The measurements were performed at 80 K on solid
samples containing a natural abundance of 57Fe. The minimum
experimental line-width was 0.24 mm sϪ1. Isomer shifts were
determined relative to α-Fe at 300 K. 1H and 13C NMR spectra
were recorded on Bruker ARX 250 (1H at 250.13 MHz), Bruker
DRX 400 (1H at 400.13 MHz) and Bruker DRX 500 (1H at
500.35 MHz) instruments. 1H and 13C NMR spectra were
referenced to TMS, using the 13C or residual protio signals of
the deuterated solvents as internal standards (CDCl3 ≡ 7.24
(1H) and 77.0 (13C), DMSO ≡ 2.49 (1H) and 39.5 (13C)). Variable
Fe(Cp)(ꢁ-C5H4-CO-Phe-OMe) (3a). 1H NMR (400.13 MHz;
CDCl3; 293 K; 2 × 10Ϫ2 M): δ 7.32 (2H, mult, HAr), 7.26
(1H, mult, HAr), 7.18 (2H, mult, HAr), 6.00 (1H, br, NH), 5.01
(1H, mult, CαH), 4.62 (1H, HCp), 4.59 (1H, HCp), 4.33
(2H, HCp), 4.12 (5H, s, HCp), 3.76 (3H, s, OCH3), 3.20 (1H,
mult, CβH), 3.14 (1H, mult, CβH). 13C NMR (100.6 MHz;
CDCl ): δ 172.3 (C᎐O ), 170.0 (C᎐Oamide), 136.1 (CAr, Phe),
᎐
᎐
3
ester
129.2 (CAr, Phe), 128.7 (CAr, Phe), 127.2 (CAr, Phe), 75.3 (CCp, q), 70.5
(CCp), 69.7 (5C, CCp), 68.3, 68.0 (CCp), 52.8 (Cα), 52.3 (OCH3),
38.0 (Cβ). IR (KBr): 3299 (w, sh), 3266 (m, br, νNH), 1756 (s),
1736 (s, νC᎐O, ester), 1631 (s), 1620 cmϪ1 (s, νC᎐O, amide); IR (CH2Cl2):
᎐
᎐
3426 (w, νNH), 1741 (s, νC᎐O, ester), 1659 cmϪ1 (s, νC᎐O, amide). MS
᎐
᎐
(EI): m/z = 391 (100) [M]ϩ, 331 (2) [M Ϫ Cp]ϩ, 213 (45). Anal.
calc. for C21H21NO3Fe (391.25 g molϪ1): C, 64.47; H, 5.41; N,
3.58. Found: C, 64.41; H, 5.53; N, 3.64%.
Fe(Cp)(ꢁ-C5H4-CO-Ala-Phe-OMe) (4a). 1H NMR (400.13
MHz; CDCl3; 293 K; 2 × 10Ϫ2 M): δ 7.21 (3H, mult, HAr), 7.07
(2H, mult, HAr), 6.53 (1H, d, 3JHH = 7.8 Hz, NHAla), 6.18 (1H, d,
3JHH = 7.5 Hz, NHPhe), 4.83 (1H, mult, Cα, PheH), 4.68 (1H, HCp),
4.63 (1H, HCp), 4.59 (1H, mult, Cα, AlaH), 4.35 (2H, HCp), 4.17
(5H, s, HCp), 3.71 (3H, s, OCH3), 3.13 (1H, mult, Cβ, PheH), 3.07
(1H, mult, Cβ, PheH), 1.41 (3H, d, J = 7.0 Hz, CH3, Ala). 13C NMR
(100.6 MHz; CDCl ): δ = 172.3 (br), 171.5 (C᎐O, only two
᎐
3
resonances of C᎐O carbon atoms were observed), 135.6 (CAr, q),
᎐
129.4 (CAr), 128.6 (CAr), 126.9 (CAr), 74.9 (CCp, q), 70.8, 70.7,
69.2, 68.8 (all CCp), 70.1 (5H, CCp), 53.4, 52.5 (OCH3 ϩ Cα, Phe),
49.2 (br, Cα, Ala), 38.1 (Cβ, Phe), 19.6 (br, CH3, Ala). IR (KBr): 3301
1
temperature H NMR spectra were recorded on the Bruker
DRX 400 NMR spectrometer. For these VT NMR experi-
ments, CDCl3 was dried over activated molecular sieves (3 Å)
and the NMR tubes were thoroughly dried before use. High
performance liquid chromatography (HPLC) purifications
were performed by using a Macherey & Nagel Nucleosil 7-C-18
column (250 × 21 mm). As an eluent a 3 : 1 (v/v) mixture of
MeCN and H2O, the latter containing 0.05 mol LϪ1 NaPF6 was
used.
(m, br, νNH), 1746 (s, νC᎐O, ester), 1654 (s), 1625 cmϪ1 (vs, νC᎐O, amide);
᎐
IR (CH2Cl2): 3424 (m, νNH, Phe ϩ νNH, Ala), 1744 (s, νC᎐O, este᎐r), 1683
(s), 1651 cmϪ1 (s, νC᎐O, amide). MS (EI): m/z = 462 ᎐(100) [M]ϩ.
᎐
Anal. calc. for C24FeH26N2O4 (462.33 g molϪ1): C, 62.35; H,
5.67; N, 6.06. Found: C, 62.19; H, 5.61; N, 6.05%.
Fe(Cp)(ꢁ-C5H4-CO-NH-CH(CH3)-Ph) (5a). 1H NMR
(400.13 MHz; CDCl3; 293 K; 2 × 10Ϫ2 M): δ 7.37 (4H, mult,
HAr), 7.27 (1H, mult, HAr), 5.82 (1H, d, J = 7.6 Hz, NH), 5.28
(1H, mult, NCH), 4.67 (1H, pseudo-d, HCp), 4.61 (1H, pseudo-
d, HCp), 4.31 (2H, pseudo-t, HCp), 4.11 (5H, s, HCp), 1.56 (3H, d,
J = 6.9 Hz, CH3). 13C NMR (62.9 MHz; CDCl ): δ 169.3 (C᎐O),
General synthesis of the ferrocene derivatives
Ferrocene carboxylic acid 1a (230 mg, 1 mmol) or 1,1Ј-ferro-
cene dicarboxylic acid 2a (274 mg, 1 mmol) were dissolved in
DMF (15 mL) and NEt3 (1.5 mL, 1.09 g, 10.8 mmol) was
added. To this mixture were added stoichiometric amounts (i.e.
1 mmol for the synthesis of 3a–5a and 2 mmol for the synthesis
of 6a–8a) of phenylalanine methyl ester hydrochloride (for 3a
and 6a), S-1-phenylethylamine (for 5a and 8a) or the dipeptide
H-Ala-Phe-OMeؒCF3CO2H (for 4a and 7a). After addition of
stoichiometric amounts of TBTU (O-(1H-benzotriazol-1-yl)-
N,N,NЈ,NЈ-tetramethyluronium tetrafluoroborate, 1 mmol for
3a, 4a and 5a; 2 mmol for 6a, 7a and 8a), the mixture was
stirred for 30 minutes at room temperature and subsequently
evaporated to dryness in vacuo. The residue was suspended in
CH2Cl2 (150 mL) and filtered to remove insoluble material,
followed by washing of the CH2Cl2 solution with 2 M aqueous
NaHCO3 (100 mL), 1 M HCl (100 mL) and water (100 mL).
The organic phase was dried over MgSO4, filtered and evapor-
ated to dryness under reduced pressure to yield an orange solid.
Only in the case of 5a and 8a it was necessary to purify this
solid by column chromatography over silica by using ethyl acet-
ate–hexane (3 : 1, v/v) as the eluent. The first orange coloured
᎐
3
143.6 (CAr, q), 128.7, 126.2, 127.4, 76.0 (CCp, q), 70.4, 70.4, 68.4,
67.8 (all CCp), 69.2 (5C, CCp), 48.5 (CH), 21.7 (CH3). IR (KBr):
3294 (w, br, νNH), 1621 cmϪ1 (s, νC᎐O); IR (CH2Cl2): 3440 (w, νNH),
᎐
1654 cmϪ1 (s, νC᎐O). MS (EI): m/z = 333 (100) [M]ϩ. Anal. calc.
᎐
for C19FeH19NO (333.21 g molϪ1): C, 68.49; H, 5.75; N, 4.20.
Found: C, 67.86; H, 5.65; N, 4.11%.
Fe(ꢁ-C5H4-CO-Phe-OMe)2 (6a). 1H NMR (400.13 MHz;
CDCl3; 293 K; 1 × 10Ϫ2 M): δ 7.75 (2H, d, J = 8.4 Hz, NH), 7.29
(6H, mult, HAr), 7.21 (4H, mult, HAr), 5.06 (2H, mult, CαH) 4.78
(2H, pseudo-t, HCp), 4.66 (2H, pseudo-t, HCp), 4.49 (2H,
pseudo-t, HCp), 4.28 (2H, pseudo-t, HCp), 3.84 (6H, s, OCH3),
3.18 (2H, mult, CβH), 2.95 (2H, mult, CβH). 13C NMR (CDCl3;
100.6 MHz): δ 175.4 (C᎐O ), 170.3 (C᎐Oamide), 136.7, 128.9,
᎐
᎐
ester
128.6, 127.0 (all CAr, Phe), 75.9 (CCp, q), 71.9, 71.3, 70.4, 70.0
(all CCp), 54.0 (Cα), 52.8 (O–CH3), 37.0 (Cβ). IR (KBr): 3284
(w), 3219 (w, νNH), 1759 (m), 1740 (s, νC᎐O, ester), 1630 cmϪ1
᎐
(s, νC᎐O, amide); IR (CH2Cl2): 3380 (w, νNH), 1729 (s, νC᎐O, ester), 1652
cmϪ1 (s, νC᎐O, amide). MS (EI): m/z = 596 (100) [M]ϩ, 326 (15) [M Ϫ
᎐
D a l t o n T r a n s . , 2 0 0 3 , 2 1 0 – 2 2 0
211

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CpCONPhe-OMe]ϩ. Anal. calc. for C32FeH32N2O6 (596.46 g
molϪ1): C, 64.44; H, 5.41; N, 4.70. Found: C, 64.44; H, 5.51; N,
4.62%.
ester),
1654
cmϪ1
(s,
νC᎐O,
amide).
MS
(ESI-pos.;
CH3OH):
m/z
=
394
[3b-BPh4]ϩ. Anal. calc. for BC45CoH41NO3 (713.57 g molϪ1): C,
75.74; H, 5.75; N, 1.96. Found: C, 75.58; H, 5.74; N, 2.01%.
Fe(ꢁ-C5H4-CO-Ala-Phe-OMe)2 (7a). 1H NMR (400.13 MHz;
CDCl3; 293 K; 1 × 10Ϫ2 M): δ 8.33 (2H, d, J = 7.1 Hz, NHAla),
7.32 (4H, mult, HAr), 7.27 (2H, mult, HAr), 7.20 (4H, mult, HAr),
6.31 (2H, d, J = 7.7 Hz, NHPhe), 4.88 (2H, HCp), 4.84 (2H, mult,
Cα, PheH), 4.81 (2H, HCp), 4.61 (2H, mult, Cα, AlaH) 4.46 (2H,
HCp), 4.29 (2H, HCp), 3.66 (6H, s, OCH3), 3.19 (2H, mult,
Cβ, PheH), 3.16 (2H, mult, Cβ, PheH), 1.33 (6H, d, J = 7.1 Hz,
CH3, Ala). 13C NMR (100.6 MHz; CDCl ): δ 174.5 (C᎐Oester),
[Co(Cp)(C5H4-CO-Ala-Phe-OMe)]BPh4 (4b). 1H NMR
(400.13 MHz; DMSO-d6): δ 8.69 (1H, d, J = 6.9 Hz, NH), 8.53
(1H, d, J = 7.1 Hz, NH), 7.26 (13H, mult, HAr), 6.93 (8H,
mult, HAr), 6.79 (4H, mult, HAr), 6.40 (1H, HCp), 6.24 (1H,
HCp), 5.86 (2H, pseudo-d, HCp), 5.79 (5H, s, HCp), 3.58 (3H, s,
OCH3), Cα, AlaH obscured by the H2O signal, 3.02 (2H, mult,
C
β, PheH), 1.35(3H, d, J=7.0Hz, CH3, Ala). 13CNMR(100.6MHz;
DMSO-d ): δ 172.21, 171.9 (C᎐O), 163.3 (q, 2JBC = 49 Hz, Cq, Ph),
᎐
3
᎐
6
171.6, 170.4 (br, C᎐O), 135.5 (CAr, q), 129.5, 128.6, 127.1 (all CAr),
᎐
137.1 (Cq, Phe), 135.5 (CAr, Ph), 129.1, 128.3, 126.6 (all CAr, Phe),
125.3, 121.5 (both CAr, Ph), 92.6 (CCp, q), 86.0, 85.7, 84.5, 83.6 (all
CCp),86.0(5C,CCp),53.9,51.4(OCH3 ϩCα, Phe),36.5(Cβ, Phe),17.5
(CH3, Ala). IR (KBr): 3416 (m), 3381 (w, νNH), 1724 (s, νC᎐O, ester),
75.6 (CCp, q), 72.0, 71.3, 70.5, 70.4 (all CCp), 53.9, 52.3 (OCH3 ϩ
Cα, Phe), 49.5 (br, Cα, Ala), 37.9 (Cβ, Phe), 17.5 (br, CH3, Ala). IR
(KBr): 3277 (m, br, νNH), 1750 (s, νC᎐O, ester), 1669 (s), 1625 cmϪ1
(s, νC᎐O, amide); IR (CH2Cl2): 3414 (m,᎐νNH, Phe), 3322 (m, νNH, Ala),
1744᎐(s, νC᎐O, ester), 1677 (s), 1644 cmϪ1 (s, νC᎐O, amide). MS (EI): m/z
1679 cmϪ1 (vs, νC᎐O, amide). MS (ESI-pos; MeOH): m/z = 465 [4b Ϫ
᎐
BPh4]ϩ. Anal. calc. for BC48H46CoN2O4 (784.65 g molϪ1): C,
73.48; H, 5.91; N, 3.57. Found: C, 73.33; H, 5.86; N, 3.61%.
᎐
᎐
= 738 (100) [M]ϩ. Anal. calc. for C38FeH42N4O8 (738.62 g
molϪ1): C, 61.79; H, 5.73; N, 7.59. Found: C, 61.57; H, 5.78; N,
7.65%.
Synthesis of [Co(Cp)(C5H4-CO-S-NH-CH(CH3)-Ph)2]BPh4
(5b). This compound was prepared analogously as described for
the other mono-substituted cobaltocenium compounds 3b and
4b by using S-1-phenylethylamine. After addition of a meth-
anolic NaBPh4 solution, about 10 mg of X-ray quality crystals
separated the first time the synthesis was performed. The X-ray
crystal structure confirms the identity of this compound.
However, it could not be reproduced because when tried again,
the precipitate that formed upon addition of NaBPh4 was
found to be contaminated with S-1-phenylethylammonium
salts, which were not readily removed. BC43CoH39NO (655.5 g
molϪ1). Anal. calc. C, 78.79; H, 6.00; N, 2.14. Found: C, 76.32;
Fe(ꢁ-C5H4-CO-NH-CH(CH3)-Ph)2 (8a). 1H NMR (400.13
MHz; CDCl3; 293 K; 1 × 10Ϫ2 M): δ 7.42 (4H, mult, HAr), 7.34
(4H, mult, HAr), 7.25 (2H, mult, HAr), 6.93 (2H, d, J = 7.9 Hz,
NH), 5.25 (2H, mult, N–CH), 4.45 (2H, pseudo-t, HCp), 4.32
(2H, pseudo-t, HCp), 4.24 (2H, pseudo-t, HCp), 4.21 (2H, mult,
HCp), 1.61 (6H, d, J = 7.0 Hz, both CH3). 13C NMR (62.9 MHz;
CDCl ): δ 169.3 (C᎐O), 143.9 (C q), 128.5, 126.4, 127.2, 78.2
᎐
3
Ar,
(CCp, q), 72.3, 71.1, 70.7, 69.2 (all CCp), 49.2 (CH), 21.9 (CH3).
IR (KBr): 3392 (w), 3382 (m, νNH), 1637 cmϪ1 (s, νC᎐O); IR
(CH2Cl2): 3435 (w, νNH), 1638 cmϪ1 (s, νC᎐O). MS (EI): m/᎐z = 480
᎐
(100) [M]ϩ, 268 (10) [M Ϫ Cp-CO-NH-CH(CH3)-Ph]. Anal.
calc. for C28FeH28N2O2 (480.39 g molϪ1): C, 70.01; H, 5.87; N,
5.83. Found: C, 68.37; H, 6.08; N, 5.68%.
H, 5.82; N, 2.06%. IR (KBr): 3384m (νNH), 1667s (νC᎐O) cmϪ1
.
᎐
MS (ESI-pos., MeOH): m/z = 336 [5b Ϫ BPh4]ϩ.
General synthesis of the disubstituted cobaltocenium complexes
General synthesis of the monsubstituted cobaltocenium
complexes
To a solution of [Co(C5H4-CO2H)2]PF6 2b (217 mg, 0.5 mmol)
in DMF (6 mL) was added NEt3 (1.0 mL, 0.73 g, 7 mmol)
and O-(1H-benzotriazol-1-yl)-N,N,NЈ,NЈ-tetramethyluronium
hexafluorophosphate (HBTU, 182 mg, 0.5 mmol) and either
phenylalanine methyl ester hydrochloride (216 mg, 1.0 mmol,
for 6b) or H-Ala-Phe-OMeؒCF3CO2H (1 mmol, 364 mg, for
7b). The mixture was stirrred for 30 minutes and subsequently
evaporated to dryness in vacuo. The residue was suspended in
CH2Cl2 (100 mL) and filtered to remove insoluble material. The
resulting clear yellow solution was washed with 2 M NaHCO3
(50 mL), 1 M HCl (50 mL) and water (50 mL). The CH2Cl2 was
dried over MgSO4 and subsequently removed under reduced
pressure. The resulting sticky residue was dried for several
hours in vacuo, yielding a hygroscopic yellow foam-like solid.
This solid was purified by preparative HPLC, employing a 3 : 1
mixture of MeCN and H2O (the latter containing 0.05 M
NaPF6) as the eluent. The work-up consisted of concentration
of the eluent to about a quarter of its volume under reduced
pressure. The remaining solution was extracted with CH2Cl2 (3
× 50 mL) and the CH2Cl2 was dried over MgSO4. Removal of
the CH2Cl2 in vacuo afforded the desired compounds in highly
pure form. Yield: 110 mg (32%) for 6b and 50 mg (11%) for 7b.
To a solution of [Co(Cp)(C5H4-CO2H)]PF6 1b (379 mg, 1.0
mmol) in DMF (10 mL) was added NEt3 (1.0 mL, 0.73 g, 7
mmol) and TBTU (323 mg, 1.0 mmol) and either phenylalanine
methyl ester hydrochloride (216 mg, 1.0 mmol, for 3b) or H-
Ala-Phe-OMeؒCF3CO2H (1 mmol, 364 mg, for 4b). The
mixture was stirrred for 30 min and subsequently evaporated to
dryness in vacuo. The residue was suspended in CH2Cl2 (100
mL) and filtered to remove insoluble material. The resulting
clear yellow solution was washed with 2 M NaHCO3 (50 mL), 1
M HCl (50 mL) and water (50 mL). The CH2Cl2 was dried over
MgSO4 and subsequently removed under reduced pressure,
yielding a sticky yellow residue. This was dissolved in MeOH
(10 mL), followed by addition of a NaBPh4 (0.25 g, 0.73 mmol)
solution in MeOH (10 mL). Upon standing overnight, a yellow
precipitate formed, which was isolated by filtration and washed
with MeOH (5 mL) and air dried. Yields were 0.26 g (36%) for
3b and 0.10 g (13%) for 4b. X-Ray quality crystals of 3b were
grown by slow evaporation of a MeOH solution.
1
[Co(Cp)(C5H4-CO-Phe-OMe)]BPh4 (3b). H NMR (400.13
MHz; CDCl3; 293 K; 2 × 10Ϫ2 M): δ 7.48 (8H, mult, HAr), 7.30
(2H, mult, HAr), 7.15 (2H, mult, HAr), 7.05 (8H, mult, HAr), 6.90
(5H, mult, HAr), 6.11 (1H, d, J = 7.9 Hz, NH), 4.99 (2H, app. s,
HCp), 4.85 (2H, app. s, HCp), 4.80 (5H, s, HCp), 4.54 (2H, app. s,
HCp), 4.50 (2H, app. s, HCp), 3.77 (3H, s, OCH3), 3.28 (1H, mult,
CβH), 3.06 (1H, mult, CβH). 13C NMR (125.8 MHz; CD3OD): δ
173.1 (C᎐Oester), 165.3 (q, 2JBC = 49 Hz, Cq, Ph), 163.8 (C᎐Oamide),
[Co(C5H4-Phe-OMe)2]PF6 (6b). 1H NMR (400.13 MHz;
CDCl3; 293 K; 1 × 10Ϫ2 M): δ 7.79 (2H, d, J = 8.3 Hz, NH), 7.33
(6H, mult, HAr), 7.25 (2H, mult, HAr), 6.12 (2H, pseudo-t, HCp),
5.82 (6H, mult, HCp), 3.83 (6H, s, OCH3), 3.35 (2H, mult, CβH),
3.05 (2H, mult, CβH). 13C NMR (CDCl3; 100.6 MHz): δ 171.8
᎐
᎐
138.5 (CAr, Phe, q), 137.3 (CAr, Ph), 130.1 (CAr, Phe), 129.8 (CAr, Phe),
128.2 (CAr, Phe), 126.4 (CAr, Ph), 122.7 (CAr, Ph), 94.1 (CCp, q), 87.4
(CCp), 87.3 (5C, CCp), 85.3 (CCp), 85.0 (CCp), 55.5 (Cα), 53.1
(O–CH3), 37.7 (Cβ). IR (KBr): 3404 (w, νNH), 1735 (s, νC᎐O, ester),
1674 cmϪ1 (s, νC᎐O, amide); IR (CH2Cl2): 3403 (w, νNH), 1744 ᎐(s, νC᎐O,
(C᎐O ), 162.2 (C᎐Oamide), 137.2 (CAr, q), 129.2, 128.5, 127.4
᎐ ᎐
ester
(all CAr), 92.9 (CCp, q) 88.2, 87.3, 86.6, 84.9 (all CCp), 54.9 (Cα),
52.6 (OCH3), 36.3 (Cβ). IR (KBr): 3216 (m, br, νNH), 1742
(s, νC᎐O, ester), 1670 cmϪ1 (s, νC᎐O
, amide); IR (CH2Cl2): 3403 (w), 3362
᎐
(w, νNH), 1743 (s), 1721 cmϪ1᎐(s, νC᎐O, ester). MS (ESI-pos.; MeOH):
᎐
᎐
᎐
D a l t o n T r a n s . , 2 0 0 3 , 2 1 0 – 2 2 0
212

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m/z = 599 [6b Ϫ PF6]ϩ. Anal. calc. for C32CoF6H32N2O6P
(744.51 g molϪ1): C, 51.62; H, 4.33; N, 3.76. Found: C, 51.46; H,
4.40; N, 3.72%.
[Co(C5H4-Ala-Phe-OMe)2]PF6 (7b). 1H NMR (400.13 MHz;
CDCl3; 5 × 10Ϫ3 M; 293 K): δ 8.79 (2H, d, J = 6.4 Hz, NHAla),
7.32 (4H, mult, HAr), 7.28 (2H, mult, HAr), 7.22 (4H, mult, HAr),
6.57 (2H, br, NH), 6.32 (2H, br, HCp), 6.26 (2H, br, HCp), 6.02
(2H, br, HCp), 5.87 (2H, br, HCp), 4.83 (2H, mult, Cα, PheH), 4.57
(2H, mult, Cα, AlaH), 3.70 (s, 6H, OCH3), 3.16 (4H, mult,
C
β, PheH), 1.36 (6H, d, J = 7.4 Hz, CH3, Ala). 13C NMR (62.9 MHz;
CDCl ): δ 173.7 (C᎐O ), 171.6 (C᎐O ), 161.2 (C᎐OCp), 135.9
᎐
᎐
Ala
᎐
3
ester
(CAr, q), 129.3, 128.6, 127.1 (all CAr), 92.1 (CCp, q), 87.9, 87.5, 86.0,
85.4 (all CCp), 54.0, 52.4 (OCH3 and Cα, Phe), 49.9 (Cα, Ala), 37.6
(Cβ, Phe), 16.9 (CH3, Ala). IR (CH2Cl2): 3405 (w, νNH, Phe), 3296
(w, νNH, Ala), 1744 (s, νC᎐O, ester), 1660 cmϪ1 (s, νC᎐O, amide). MS (ESI-
᎐
᎐
pos.; MeOH): m/z = 741 [7b Ϫ PF6]ϩ; exact mass: 741.2332;
C38CoH42N4O8 requires 741.2335.
X-Ray crystallographic data collection and refinement of the
structures
Scheme 2
Yellow single crystals of 3b, 5b, 7a, and yellow brownish
crystals of 4a and 6a were coated with perfluoropolyether.
Suitable crystals were picked up with a glass fiber and were
immediately mounted in the nitrogen cold stream of the dif-
fractometer to prevent the loss of solvent. Intensity data were
collected at 100 K using graphite monochromated Mo-Kα
radiation (λ = 0.71073 Å). Final cell constants were obtained
from a least squares fit of a subset of several thousand strong
reflections. Data collection was performed by hemisphere runs
taking frames at 0.3Њ (Siemens SMART, 4a, 5b and 6a) and
0.5Њ (Nonius Kappa-CCD, 3b and 7a) in ω. A semiempirical
absorption correction using the program SADABS14 was
performed on the data sets of 4a, 5b, 6a. The program DelRefAbs
which is part of the PLATON9915 program suite was used to
account for absorption of a crystal needle of 7a since data
redundancy was not sufficient for a semiempirical correction.
Intensity data of 3b were not corrected.
triazol-1-yl)-N,N,NЈ,NЈ-tetramethyluronium tetrafluoroborate
(TBTU) and excess NEt3. After work-up, the compounds were
obtained as orange solids. Only in the case of the S-1-phenyl-
ethylamine derivatives 5a and 8a, an extra purification step by
column chromatography over silica was necessary because
small amounts of unreacted amine were found to be present in
the isolated solids. Yields varied from 52 to 87%. Compounds
3a and 6a have been reported before, but were not fully
characterised.5,17
The synthesis and constitution of the cobaltocenium
compounds (b) are also depicted in Schemes 2 and 3. The cobalt-
ocenium acids (mono-, 1b, or 1,1Ј-di, 2b) are, in contrast to
their ferrocene analogues, not commercially available and were
synthesised according to a published procedure.13 The first part
of the synthesis of the mono cobaltocenium derivatives 3b
and 4b was performed analogously to that of the ferrocene
derivatives, but oily residues were obtained after the extractive
work-up and removal of the solvent. After dissolution in
MeOH and addition of a NaBPh4 solution in methanol, the
compounds precipitated in pure form as their tetraphenylborate
salts. The yield of the cobaltocenium compounds 3b and 4b was
lower than of their ferrocene analogues. This may be attributed
to the overall positive charge of the cobaltocenium complexes,
which makes them more water-soluble, resulting in significant
losses during extractive work-up.
The di-substituted cobaltocenium derivatives 6b and 7b were
obtained by reacting cobaltocenium di-carboxylic acid 2b with
either H-Phe-OMe or H-Ala-Phe-OMe in DMF with TBTU as
the coupling reagent. After extractive work-up, the oily residue
was dried in vacuo for a few hours, yielding the compounds as
hygroscopic powders, with purity around 90–95% as concluded
from their 1H NMR spectra. Unfortunately, the complexes
could not be purified by crystallisation and also did not precipi-
tate from MeOH upon addition of anions which are unable to
act as hydrogen bond acceptors, such as BF4Ϫ and tetraphenyl-
borate. Instead, analytically pure samples were obtained by
preparative HPLC purification (see Materials and methods).
Our interest also concerned the S-1-phenylethylamine cobal-
tocenium derivatives. However, the work-up of the reaction of
[Co(C5H4-CO2H)2]PF6 with two equivalents of S-1-phenyl-
ethylamine did not proceed smoothly, because the organic layer
was invariably colourless after the washing steps. Also the
mono S-1-phenylethylamine derivative 5b was difficult to
obtain. By using an identical procedure as for the compounds
3b and 4b, a small amount of X-ray quality crystals of [Co(Cp)-
(C5H4-CO-S-NH-CH(CH3)-Ph)]BPh4 (5b) was obtained.
However, when tried again, the precipitates were contaminated
The ShelXTL software package16 was used for solution,
refinement and artwork of the structure. The structures were
readily solved by direct methods and difference Fourier
techniques. Absolute structure parameters were checked by
refining the inverse structure and are reliable. Solvent molecules
in 4a and 7a were found to be disordered and not fully
occupied. A split atom model with restrained C–Cl and Cl–Cl
distances and
a reduced occupancy factor satisfactorily
described the disorder of the chloroform molecule in 7a. The
occupancy factor of the CH2Cl2 molecule in 4a was reduced to
0.25 and C–Cl distances were restrained to be equal within
a certain error. All non-hydrogen atoms, except C atoms in
disordered solvent molecules, were refined anisotropically.
Hydrogen atoms were placed at calculated positions and
refined as riding atoms with isotropic displacement parameters.
Crystallographic data of the compounds are collected in Table 1.
CCDC reference numbers 180589–180593.
See http://www.rsc.org/suppdata/dt/b2/b208363a/ for crystal-
lographic data in CIF or other electronic format.
Results and discussion
Synthesis
The synthesis and constitution of the ferrocene derivatives are
depicted in Schemes 2 and 3. The ferrocene compounds (a) were
synthesised by reacting ferrocene mono- (1a) or 1,1Ј-di-carb-
oxylic acid (2a) with stoichiometric amounts of S-1-phenyl-
ethylamine (PEA), S-phenylalanine methyl ester or the
dipeptide H-Ala-Phe-OMe in DMF in the presence of
equimolar amounts of the coupling reagent O-(1H-benzo-
D a l t o n T r a n s . , 2 0 0 3 , 2 1 0 – 2 2 0
213

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Table 1 Summary of crystallographic data for 6a, 4aؒ0.25CH2Cl2, 7aؒ0.5CHCl3, 3b and 5b
6a
4aؒ0.25CH2Cl2
7aؒ0.5CHCl3
3b
5b
Chemical formula
C32H32FeN2O6
C24H26FeN2O4ؒ
0.25CH2Cl2
483.55
1.28 × 0.70 × 0.60
Tetragonal
P43212
17.2236(14)
17.2236(14)
16.9834(12)
90
90
90
5038.2(7)
8
1.275
C38H42FeN4O8ؒ
0.5CHCl3
798.29
0.60 × 0.18 × 0.12
Monoclinic
P21
12.7711(8)
16.4209(10)
18.269(12)
90
93.44(1)
90
C45H41BCoNO3
C43H39BCoNO
FW
596.45
0.53 × 0.18 × 0.18
Hexagonal
P65
22.332(2)
22.332(2)
10.3690(7)
90
90
120
4478.4(5)
6
1.327
713.53
655.49
Crystal size/mm
Crystal system
Space group
a/Å
b/Å
c/Å
α/Њ
β/Њ
0.36 × 0.22 × 0.10
Orthorhombic
P21212
13.992(2)
39.148(7)
13.195(2)
90
90
90
7228(2)
8
1.311
0.50 × 0.38 × 0.08
Triclinic
P1
9.493(1)
9.925(1)
9.947(1)
97.90(3)
92.80(3)
115.51(3)
831.7(2)
1
γ/Њ
V/Å3
3824(3)
4
1.386
Z
D (calcd.), g/cm3
T /K
1.309
100(2)
100(2)
100(2)
100(2)
100(2)
λ/Å
0.71073
0.551
0.0532
0.1567
4974 /1/372
1.039
0.71073
0.682
0.0703
0.2124
9122/2/300
1.079
0.71073
0.556
0.0516
0.1551
14096/31/986
1.022
0.71073
0.518
0.0713
0.1480
11283/0/919
0.922
0.71073
0.552
0.0434
0.0942
5814/3/427
1.014
Absorption coefficient/mmϪ1
R1 [I > 2σ(I )]a
wR2 (all data)b
Data/restraints/parameters
GooF on F 2 c
Flack parameter
Ϫ0.01(2)
0.02(2)
Ϫ0.012(14)
0.02(2)
0.022(11)
2
2
a R1 = Σ||Fo| Ϫ |Fc||/Σ|Fo|. b wR2 = [Σ[w(Fo2 Ϫ Fc2)2]/Σ[w(Fo )2]1/2, where w = 1/σ2(Fo ) ϩ (aP)2 ϩ bP, P = (Fo2 ϩ 2Fc2)/3. c GooF = [Σ[w(Fo2 Ϫ Fc2)2]/(n Ϫ
p)]1/2 where n = no. of reflections and p = no. of refined parameters.
Scheme 3
with S-1-phenylethylammonium salts. Since the corresponding
cobaltocenium di-S-phenylethylamine derivative 8b could not
be obtained at all, the purification as well as the total charac-
terisation of 5b was not pursued further.
S-1-Phenylethylamine (PEA) appears to be much less
reactive towards coupling reactions with the organometallic
acids than amino acids or dipeptides. The disubstituted PEA
cobaltocenium derivative could not be obtained at all, and also
the yield for the other PEA compounds is significantly lower
compared to the amino acid or dipeptide derivatives.
tances will be presented because none of these values is
exceptional and they show only statistical variations between
the structures presented. However, a number of more elusive
structural parameters, such as the tilt and other specific angles
will be presented below (see Table 2 and Scheme 4).
Scheme 4
Solid state structures
An ORTEP projection for the cationic part of [Co(Cp)(C5H4-
CO-S-NH-CH(CH3)-Ph)]BPh4 (5b) is shown in Fig. 1. The
cation does not display any unusual structural features, and
the unit cell consists of an isolated complex cation and a tetra-
phenylborate anion. Hydrogen bonds are not present in the
solid state. This is consistent with the observation of the amide
In order to determine intramolecular hydrogen bonding inter-
actions, the X-ray single crystal structures of 4aؒ0.25CH2Cl2,
6a, 7aؒ0.5CHCl3, 3b and 5b were determined. Details on how
the crystals were obtained are given in the Materials and
methods section. In this discussion, no metal–C(Cp) bond dis-
D a l t o n T r a n s . , 2 0 0 3 , 2 1 0 – 2 2 0
214

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Table 2 Summary of specific angles (Њ) for the X-ray crystal structuresa
b
Anglea
6a
4aؒ0.25CH2Cl2
7aؒ0.5CHCl3
3bb
5b
θc
βd
ωf
4.7
1.1
6.1
1.3
1.5
3.3
10.5
1.9
9.9
0.7
5.5
31.4/15.1e
68.9
4.1/5.8e
3.7/10.3e
70.3
68.9
a Angles are visualised in Scheme 4. b Two independent molecules in the unit cell; first value(s) correspond(s) to molecule A. c The dihedral angle
between the two Cp rings. d The dihedral angle between the plane of the Cp ring and the C(ipso)-C᎐O bond. e Disubstituted derivatives; first value for
᎐
β corresponds to the C᎐O moiety with the lower atomic label. f The torsion angle is defined as C(ipso)–Cp(centroid)–Cp(centroid)–C(ipso).
᎐
Fig. 1 ORTEP plot of the cation of 5b. Thermal ellipsoids are
depicted at 50% probability.
νNH stretch vibration at 3384 cmϪ1 in the infrared spectrum of
5b as a KBr pellet.
The unit cell of 3b consists of two crystallographically
Fig. 3 ORTEP plot of the asymmetric unit of 6a. Thermal ellipsoids
independent complex cations and two tetraphenylborate
anions. ORTEP diagrams of both cations are depicted in Fig. 2.
In cation A (left) the phenyl ring of the phenylalanine substitu-
ent is directed towards the unsubstituted Cp-ring and the
methyl ester is pointing downwards. In cation B (right) on the
other hand, the substituents have more or less exchanged
positions relative to cation A, i.e. the phenyl ring is located away
from the substituted Cp-ring and the methyl ester is directed
towards the unsubstituted Cp-ring.18 No hydrogen bonds are
present in the solid state, which is consistent with the observ-
ation of the amide νNH stretch vibration at 3404 cmϪ1 in the
infrared spectrum of 3b (KBr).
An ORTEP plot for the asymmetric unit in 6a is shown in
Fig. 3. The compound crystallises in the hexagonal space group
P65, which implies the presence of a left-handed six-fold screw
axis in the unit-cell. The molecules are arranged in a helical
fashion around this six-fold screw axis, linked together via
intermolecular hydrogen bond interactions between N(27) and
O(6) of another molecule (N ؒ ؒ ؒ O contact 2.935 Å). The
structure is stabilized by an intramolecular hydrogen bond
between N(7) and O(26) (N ؒ ؒ ؒ O contact 2.832 Å). The helix
has a pitch of 10.3690(7) Å, which is equivalent to the length of
the crystallographic c-axis. Per definition, the six-fold screw axis
is aligned parallel to this axis in the hexagonal space group P65.
are depicted at 50% probability.
The X-ray crystal structure of a different bis-amino acid
methyl ester ferrocene derivative, namely Fe(C5H4-CO-Val-
OMe)2, has been reported.19 This valine derivative has the
ordered conformation depicted in Scheme 1 in the solid state
and shows two very weak symmetry-related hydrogen bond
interactions between the amide NH group and the methyl ester
carbonyl oxygen atom with N ؒ ؒ ؒ O contacts of 3.247 Å. In
contrast to Fe(C5H4-CO-Val-OMe)2, 6a does not have intra-
molecular hydrogen bonds between the ester carbonyl oxygen
atom and the amide NH moiety. Apparently, the presence of
bulky phenyl rings in 6a compared to the smaller iso-propyl side
chains in Fe(C5H4-CO-Val-OMe)2 induces a different packing
in the solid state. The crystal structure of another bis-amino
acid ferrocene derivative with C-terminal amide protecting
groups, namely Fe(C5H4-CO-Gly-NH2)2 has been reported as
well.20 Like Fe(C5H4-CO-Val-OMe)2, this glycinamide com-
pound has the ordered conformation shown in Scheme 1, with
N ؒ ؒ ؒ O contacts of 2.88 Å. The shorter N ؒ ؒ ؒ O contacts for
Fe(C5H4-CO-Gly-NH2)2 compared to Fe(C5H4-CO-Val-OMe)2
are attributed to the better hydrogen acceptor properties of
amide carbonyl oxygen atoms compared to methyl ester
carbonyl oxygen atoms.
Fig. 2 ORTEP plot of the two independent cations of 3b (A: left and B: right). Thermal ellipsoids are depicted at 50% probability.
D a l t o n T r a n s . , 2 0 0 3 , 2 1 0 – 2 2 0
215

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An ORTEP representation for the asymmetric unit of 4aؒ
0.25CH2Cl2 is shown in Fig. 4. The compound crystallises in the
The helix has a pitch of 16.9834(12) Å, which is equal to the
length of the crystallographic c-axis, and a helical rise of 4.0
units. This type of helix is very interesting, because two hydro-
gen bond donors and two acceptors exist per molecule. Three
other ferrocenyl dipeptides have been structurally characterised
by X-ray crystallography, namely Fe(Cp)(C5H4-CO-Pro-Pro-
OBzl),21 Fe(Cp)(C5H4-CO-Gly-Pro-OEt)9 and Fe(Cp)(C5H4-
CO-Ala-Pro-OEt).6 All these compounds contain at least one
Pro residue which cannot form amide hydrogen bonds. Con-
sequently, hydrogen bonding is different compared to 4a, with
the compounds Fe(Cp)(C5H4-CO-Ala-Pro-OEt) and Fe(Cp)-
(C5H4-CO-Gly-Pro-OEt) showing a zigzag hydrogen bonding
arrangement, and of course no hydrogen bonds are present in
the case of Fc(Cp)(C5H4-CO-Pro-Pro-OBzl) due to the absence
of amide NH groups. We have recently observed a zigzag
orientation induced by intermolecular hydrogen bonding in
ferrocene alkyne derivatives.22
Fig. 4 ORTEP plot of the asymmetric unit of 4a. Thermal ellipsoids
are depicted at 50% probability.
tetragonal space group P43212, which implies the presence of a
left-handed four-fold screw axis in the unit cell. The molecules
are arranged in a helical fashion around this screw axis, as
shown in Fig. 5. Intermolecular hydrogen bond interactions are
present between N(7) and O(6) of a neighbouring molecule
(N ؒ ؒ ؒ O contact 2.936 Å) and between N(10) and O(9) of the
same neighbouring molecule (N ؒ ؒ ؒ O contact 2.862 Å).
X-Ray crystallography revealed the presence of two
crystallographically independent molecules in the unit cell of
7aؒ0.5CHCl3, which display only slightly different bond lengths
and angles. An ORTEP diagram for one of the crystallo-
graphically independent molecules is depicted in Fig. 6. There
Fig. 5 Packing diagram for 4a, indicating intermolecular hydrogen bond interactions and visualizing the helical arrangement of the molecules.
Fig. 6 ORTEP plot of one of the crystallographically independent molecules of 7a. All geometrical parameters of the second independent molecule
are very similar. Thermal ellipsoids are depicted at 50% probability.
D a l t o n T r a n s . , 2 0 0 3 , 2 1 0 – 2 2 0
216

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Table 3 Summary of spectroscopic data for the NH hydrogen atoms
in 3a–7b
are two intramolecular hydrogen bonds between the alanine
NH group and the alanine carbonyl moiety of the other strand.
In molecule A (depicted in Fig. 6), the N ؒ ؒ ؒ O contacts are
2.921 and 2.924 Å (N(1) ؒ ؒ ؒ O(6) and N(3) ؒ ؒ ؒ O(2), respec-
tively), whereas these N ؒ ؒ ؒ O contacts are slightly shorter in
the other independent molecule (molecule B, not depicted,
2.901 and 2.893 Å).
a
c
Compound
νNH
δNHb
3JHH
∆δd
3a
4a
3436e
3424e
6.00e
6.53e
6.18
n.r.h,i
7.8
7.5
7.6
8.4
7.1
7.7
7.9
Ϫ1.4
Ϫ5.4
Ϫ3.6
Ϫ2.2
Ϫ5.2
Ϫ4.5
Ϫ2.4
Ϫ7.2
Ϫ0.7
3440e
3380f
3322f
3414
5.82e
7.75f
8.33f
6.31
In addition to intramolecular hydrogen bonds, there are also
intermolecular hydrogen bond interactions between the
5a
6a
7a
phenylalanine NH groups and the ferrocenyl C᎐O moieties of
᎐
two neighbouring molecules that belong to the same crystallo-
graphic type. Each dipeptide strand forms intermolecular
hydrogen bonds to a different molecule of the same type, result-
ing in infinite chains of molecules A and B throughout the
lattice. Between molecules A, the N ؒ ؒ ؒ O contacts are 2.834
and 2.844 Å (N(4) ؒ ؒ ؒ O(1) and N(2) ؒ ؒ ؒ O(5), respectively),
whereas they are 2.830 and 2.836 Å for the intermolecular
hydrogen bonds between molecules B. The hydrogen bonds
are arranged in such way that a 14-membered ring forms, as
visualised in Fig. 7. A similar arrangement has recently been
8a
3b
4b
6b
3435f
3404e
3404g
3362f
3403k
3296f
3405
6.93f
6.11e
n.d.n
7.79m
7.9
n.d.n
8.3
n.d.n
Ϫ8.6
7b
8.82
6.58
6.8
Ϫ4.7
n.r.h,i
n.r.h,o
a In cmϪ1; in CH2Cl2. b In dry CDCl3; T = 293 K; in ppm. c In Hz.
d Temperature range: 223–323 K; in ppb KϪ1. e 2 × 10Ϫ2 M. f 1 × 10Ϫ2 M.
g 5 × 10Ϫ3 M. h n.r. = not reliable. i Broad NH resonance observed.
k Second νNH vibration observed. See text for explanation. m Value not
reliable because the complex is very hygroscopic. n Insoluble in CDCl3.
o Resonance becomes very broad at T < 293 K.
1,2Ј-conformation either by intramolecular hydrogen bonds or
by steric constraints of the rigid macrocycle. In the case of
difunctionalised ferrocenes without such constraints, the
substituents will be arranged in such way as to minimize steric
interactions. Consequently, ω angles much larger than 80Њ are
observed for disubstituted ferrocene derivatives of that type.
Solution structures
Although solid state structures provide reliable and accurate
data about the molecular constitution, the molecular conform-
ation in solution is decisive for biological function. Hydrogen
bonds in the turn region determine the stability and biological
function of β-turns. It was therefore crucial to investigate the
presence and strength, at least qualitatively, for the β-turn
mimetics under investigation in this study. To this end, at least
two spectroscopic techniques have been established, namely
infrared and 1H NMR spectroscopy. Amide NH hydrogen
atoms that are not hydrogen bonded display νNH stretch
vibrations in the infrared spectrum at wavenumbers higher than
3400 cmϪ1 and show resonances in between 5.5 and 7.0 ppm in
the 1H NMR spectrum in solvents which themselves do
not form hydrogen bonds, such as CDCl3 or CD2Cl2. NH
stretching vibrations below 3400 cmϪ1 in the infrared spectrum
are diagnostic of hydrogen bonded amide NH hydrogen
atoms.28,29 In addition, amide NH hydrogen atoms involved
in hydrogen bond interactions have a chemical shift higher than
7.5 ppm. The temperature dependence ∆δ1H of the amide
proton resonance is another criterium. Small values of ∆δ1H
between Ϫ2 to Ϫ4 ppb KϪ1 are diagnostic for amide protons
which are either not hydrogen bonded at all or fixed in a very
strong locked hydrogen bond. Peptide amide protons in a
dynamic hydrogen bond produce larger effects.30
Fig.
7
Visualisation of the 14-membered ring that forms via
intermolecular hydrogen bonds between two molecules of 7a.
observed for the packing of Fe(C5H4-CO-Gly-Phe-OMe)2.8 In
contrast to this compound, the unit cell of 7a contains two
crystallographically independent molecules.
Structural parameters for the five X-ray crystal structures are
summarised in Table 2, and the corresponding angles are
visualised in Scheme 4. The Cp rings in all structures are almost
coplanar. The largest deviation from coplanarity is observed for
6a. The tilt of 4.7Њ in 6a is likely due to the rigid hydrogen
bonded helical arrangement of the complex molecules. This
deviation is slightly larger than what is usually observed for
disubstituted ferrocenes bearing carboxyl substituents.23,24 For
comparison, a large value of 16.4Њ for θ was reported for an
imine-bridged [3]ferrocenophane.25
The amide moieties in all structures, except in 6a, are almost
coplanar with the Cp-rings (β ≈ 0), resulting in a maximum
π-overlap between the cyclopentadienyl and amide π systems.
The large β angle for 6a of 31.4Њ is due to the intramolecular
hydrogen bond interaction, which forces one of the amide
moieties to rotate significantly out of the Cp plane. Because of
a cosine dependence, an angle of 31.4Њ still corresponds to
about 86% of the maximum overlap between the amide π
orbitals and the cyclopentadienyl π system.26 This deviation
from planarity of the amide functionality in 6a is not
exceptional: twists of 45.7 and even 50.2Њ have been observed
Relevant infrared and 1H NMR spectroscopic data for 3a–7b
are summarised in Table 3. The mono-substituted ferrocenes
3a, 4a and 5a and cobaltocenium complexes 3b and 4b display
νNH stretching vibrations at wavenumbers higher than 3400
cmϪ1 and chemical shifts of the NH hydrogen atoms between
5.8 and 6.5 ppm in CDCl3 (Table 3). This indicates that the NH
hydrogen atoms of these compounds do not form hydrogen
bonds in solution, as expected and observed previously for 3a5
and several other mono substituted ferrocene amino acid and
dipeptide conjugates.6–9
previously
for
constrained
disubstituted
ferrocene
compounds.25,27
The observed ω angles for 6a and both independent
molecules of 7a are close to the ideal value for a 1,2Ј-
conformation (360/5 = 72Њ). Similar ω values were found for
Fe(Cp-CO-Ala-Pro-OR)2 (R = Me, Et or Bzl) and several other
disubstituted ferrocenes that are part of a macrocycle.7,23 The
substituted Cp rings of these derivatives are forced into this
The ferrocene di-phenylalanine methyl ester derivative 6a
shows a νNH stretch vibration at 3380 cmϪ1 and a chemical shift
of 7.75 ppm for the NH hydrogen atoms.5 In the case of the
D a l t o n T r a n s . , 2 0 0 3 , 2 1 0 – 2 2 0
217

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Table 4 Reversible one-electron transitions for 3a–7ba
di-S-1-phenylethylamine derivative 8a, the νNH stretch vibration
is located at 3435 cmϪ1 and the NH hydrogen atom resonates at
6.93 ppm. The differences between 6a and 8a can only be
explained by the presence of two intramolecular hydrogen
bonds between the amide NH and the methyl ester carbonyl
moiety in 6a. Because there is no ester group in 8a, no hydrogen
bonds can form. The differences between the mono PEA
derivative 5a and its disubstituted analogue 8a is small,
suggesting that only weak hydrogen bonds of 8a exist in
solution. If the amide group twists to a small extent out of the
Cp-plane, a weak hydrogen bond may be possible between the
b
b
Compound
E1/2
Compound
E1/2
3a
ϩ0.19
ϩ0.19
ϩ0.17
Ϫ1.36c
Ϫ1.13
Ϫ1.13
6a
ϩ0.40
ϩ0.34
ϩ0.35
Ϫ1.34d
Ϫ0.93
Ϫ1.00
4a
7a
5a
8a
[Co(Cp)2]PF6
[Co(Cp)2]PF6
3b
4b
6b
7b
a In CH2Cl2; NBu4PF6 as supporting electrolyte. b In V; vs. Fc/Fcϩ.
c Measured value in this work. d From ref. 44.
amide NH and the amide C᎐O of the other Cp-ring. The
᎐
resulting decrease in resonance energy between the planar
Cp-ring and the planar amide is compensated by the hydrogen
bond interaction at least to a certain extent. For the solid
8.4 Hz are not very informative, because they indicate dihedral
angles ꢀ of around 90Њ,33 which is a standard value for a
trans-configured amide.
state structure of 6a a rotation of the amide C᎐O moiety out
᎐
of the Cp plane has been observed crystallographically.
In the case of the di-substituted Ala-Phe-OMe ferrocene 7a
the hydrogen bond observed in the solid state between the
Variable temperature measurements over a range of about
100 K were made to investigate the temperature dependence
∆δ1H of the amide NH hydrogen atoms (Table 3). ∆δ1H values
between Ϫ2 to Ϫ4 ppb KϪ1 are generally considered diagnostic
for amide NH hydrogen atoms that are either locked in a very
strong hydrogen bond or not hydrogen bonded at all.30 Values
outside this range were associated with moderately strong
hydrogen bonds. The temperature dependence is explained by
reversible formation of the hydrogen bond, a process which is
evidently strongly influenced by temperature. However, no
quantitative expression that correlates ∆δ1H with the strength
of a hydrogen bond has been derived yet and this criterion is
basically used in a qualitative way. ∆δ1H values are tabulated in
Table 3. Although a trend in those values seems to prevail,
they are unfortunately not unambiguous. In compound 7a, two
different values of Ϫ4.5 and Ϫ2.4 ppb KϪ1 are observed. This is
in accordance with IR and δ1HNH data which suggest that the
first amide proton is hydrogen bonded, whereas the second
is not. Likewise, large negative values are observed for com-
pounds 6a, 6b and one proton of 7b, all of which do pre-
sumably form intramolecular hydrogen bonds. On the other
hand, a large negative value of Ϫ7.2 ppb KϪ1 for 8a seems to
suggest a hydrogen bond, which is at odds with IR and δ1H
data. Likewise, hydrogen bonds are not expected for compound
4a, leaving the ∆δ1H value of Ϫ5.4 ppb KϪ1 unexplained.34
Ala-NH group and the Ala-C᎐O moiety of the other strand is
᎐
also present in solution. This can be derived from the position
of the νNH stretch vibration at 3322 cmϪ1 and the chemical shift
of this NH hydrogen atom, which is located at 8.33 ppm. This
hydrogen bond in 7a is stronger than the one in the di-Phe-OMe
derivative 6a, which is consistent with the differences between
the hydrogen bond acceptor strengths of ester and amide carb-
onyl moieties. The νNH stretch vibration at 3322 cmϪ1 is in the
range reported for several other disubstituted ferrocene
derivatives bearing dipeptide substituents.6–9
The phenylalanine NH hydrogen atom is not involved in any
hydrogen bond interactions, as concluded from a νNH stretch
vibration at 3414 cmϪ1 and the chemical shift of 6.31 ppm. The
resonances of these alanine and phenylalanine amide NH
hydrogen atoms were assigned unambiguously by 2D NMR
techniques. Only the first NH hydrogen atom can form an
intramolecular hydrogen bond in solution, whereas the second
cannot because of spatial reasons, similar to what is observed
for the X-ray crystal structure of 7a.8,9
The disubstituted cobaltocenium Ala-Phe-OMe derivative 7b
has a conformation in solution identical to that of the ferrocene
analogue 7a, with the alanine NH moieties of this compound
being involved in two intramolecular hydrogen bonds. The νNH
stretch vibration of the alanine NH group in 7b is observed
about 25 cmϪ1 lower in energy compared to 7a. However, this
may be an intrinsic property of the charged cobaltocenium
derivatives, because the νNH stretching vibrations of the mono-
substituted derivatives 3b and 4b are also about 20–30 cmϪ1
lower than those for the corresponding ferrocene derivatives 3a
and 4a. The chemical shift of the alanine NH hydrogen atom in
7b is shifted significantly to higher field compared to that of the
ferrocene analogue 7a (8.82 ppm in 7b vs. 8.33 ppm in 7a). The
chemical shift difference between the NH hydrogen atoms in 3a
and 3b is significantly smaller (0.11 ppm). This value probably
reflects the intrinsic difference between uncharged ferrocene
and charged cobaltocenium amides. A much larger difference
between the resonances of the alanine NH hydrogen atoms in
7b and 7a then seems to indicate a stronger hydrogen bond in
the cobaltocenium derivative 7b.31
Electrochemistry
Redox potentials for the ferrocene and cobaltocenium
derivatives are tabulated in Table 4. The substituted ferrocene
derivatives display higher oxidation potentials than ferrocene
itself (by definition 0.00 V). The increase of the oxidation
potential upon substitution of the Cp ring by amide groups can
be explained by the withdrawal of electron density from the
ferrocene moiety by these substituents.24,35 The substituent
effects are roughly additive, with each amide group contri-
buting about 180 mV. A similar type of behaviour of the
redox potentials for mono and 1,1Ј-ferrocenes has been
observed previously.6,7,17,36 The size or nature of the substituent
on ferrocene does not have a significant influence on the
redox potentials. The variation of E1/2 is certainly too small to
differentiate between different substituents.36
The disubstituted Phe-OMe cobaltocenium derivative 6b
displays two amide NH stretching vibrations in the infrared
spectrum. The vibration at 3362 cmϪ1 is assigned as the NH
vibration of the hydrogen bonded NH moiety and the one at
3403 cmϪ1 is assigned to an NH stretching vibration originating
from a non-hydrogen bonded NH.28 In fact, the latter value is
identical to that of the mono phenylalanine derivative 3b,
which cannot be involved in any intramolecular hydrogen
bond interactions at all.
There is a fundamental difference between the electro-
chemical behaviour of ferrocene derivatives and their iso-
electronic cobaltocenium analogues in that the former can be
oxidised to yield a 17-electron species, whereas the latter can
only undergo a one-electron reduction to yield 19-electron
compounds. Reduction potentials for the cobaltocenium
derivatives 3b–7b are shown in Table 4. From this table, it is
observed that the reduction shifts to less negative potentials
upon substitution of a Cp-ring with an amide moiety. If both
Cp-rings are substituted, the shift of the reduction potential is
significantly larger. This shows that the e1g level is lowered in
energy, or in other words, becomes more accessible if electron-
Coupling constants 3J(CαH–NH) are important to determine
the conformation of a peptide in solution.32 The values of the
coupling constants for the compounds 3a–7b between 6.8 and
D a l t o n T r a n s . , 2 0 0 3 , 2 1 0 – 2 2 0
218

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Table 5 57Fe Mössbauer spectroscopic data at 80 K for ferrocene and
compounds 3a–8a
analysis and NH ؒ ؒ ؒ CO(ester) in solution. This behaviour
is in contrast to the previously reported compounds5,19,20 and
underscores the need for structural investigations in solution as
well as in the solid state.
a
Compound
δa
∆EQ
Γa
The peptides with an organometallic scaffold in this work
were designed such as to mimic structural properties in pep-
tides, in particular turn structures. A typical turn structure is
depicted schematically in Scheme 5. Ring constraints by
Fe(C5H5)2
0.53b
0.53
0.52
0.53
0.52
0.52
0.51
2.42b
2.37
2.32
2.32
2.27
2.27
2.27
3a
4a
5a
6a
7a
8a
0.34
0.28
0.30
0.27
0.32
0.30
a In mm sϪ1 b From ref. 38.
.
withdrawing substituents are present.11,26,37 The direction of the
observed shift upon substitution of a Cp-ring is the same as
observed for the ferrocene derivatives.
57Fe Mössbauer spectra
The results from 57Fe Mössbauer spectroscopic investigations
on 3a–8a are summarized in Table 5. The isomer shifts for
3a–8a are virtually identical to those of ferrocene.38 However,
they display a lower quadrupole splitting than ferrocene. The
values for the quadrupole splitting of the disubstituted
derivatives 6a, 7a and 8a are significantly lower than those of
the monosubstituted compounds 3a, 4a and 5a. It has been
noted before that the quadrupole splitting of ferrocene
decreases upon substitution of a Cp ring with an electron-
withdrawing substituent and even more when such a sub-
stituent is introduced on both Cp rings.39 This effect can be
explained by withdrawal of electron density from the orbital e1g,
the highest occupied orbital with Cp character.11,26,37 This
leads to a different field gradient along the molecular axis
and, thus, to a different value for the quadrupole splitting.
Scheme 5
hydrogen bonds define γ-turns (7-membered ring) or β-turns
(10-membered rings), whereas 13-membered rings are present
in α-helices.2 A classification of different β-turn geometries was
introduced by Venkatachalam depending on the angles Φn and
Ψn.40 Before and after the turn, the peptide extends as anti-
parallel strands, often in β-sheets. The organometallic scaffolds
used in this and previous work are diacids. As such, they
enforce a parallel orientation of the peptide strands and may
not seem “real” β-turn mimetics. Nevertheless, topological
similarities remain which will be discussed below.
First of all, let us compare the solid state structures of 6a and
7a. In 6a, an intramolecular hydrogen bond is formed between
O26 and N7. If connecting atoms are counted (H7–N7–C6–
C5–Fe1–C25–C26–O26), an 8-membered ring is formed.
Carbonyl groups may be counted as follows: C26–O26 (i),
C6–O6 (i ϩ 1), then N7 is the amide nitrogen atom of the
(i ϩ 2) amino acid. The situation is different for 7a. Two intra-
molecular hydrogen bonds N1 ؒ ؒ ؒ O6 and N3 ؒ ؒ ؒ O2 are
formed. Both define 11-membered rings between O (i) and N
(i ϩ 3) if a procedure as for 6a is applied. Because of the
approximate C2 symmetry of this molecule the same rules apply
to either Cp ring and their substituents. Taking these data
together, we conclude that the turn structure in 6a is γ-turn-like,
and the one found in 7a is β-turn-like. Because of the parallel
orientation induced by the diacid scaffold, we denote the turn
structures pseudo-γp and pseudo-βp.
Another important point is the overall charge of the turn
structure. Following an analysis by Hutchinson and Thornton,41
Asp is the only (negatively) charged amino acid that is
frequently found in β-turns (in the i position). The two
positively charged amino acids under physiological conditions
(Lys and Arg) are not frequently encountered at all in this type
of secondary structural element. This may seem astonishing in
light of the fact that additional hydrogen bonds (e.g. of Ser) are
indeed used to stabilize the turn structure. Furthermore, turn
structures are frequently involved in molecular recognition of a
protein by its receptor and are thus exposed to the (usually
hydrophilic) surface of the protein. In this work, a comparison
between uncharged ferrocene derivatives 6a and 7a and
positively charged cobaltocenium derivatives 6b and 7b is pre-
sented. Both pairs of compounds do presumably form very
similar structures as suggested by their analytical data. Indeed,
none of the data differ enough to infer a substantial difference
in either structure or strength of intramolecular hydrogen
bonds in solution. Hence, our work underscores that a nearby
positive charge does not influence hydrogen bonds that stabilize
a turn structure significantly.
Conclusions
In this work, we have prepared a number of di- and tetra-
peptides with a metallocene backbone. The length of the
peptide chains was systematically varied and the metal was
switched between Fe and Coϩ to change the overall charge
of the constructs. Both means were undertaken in order to
investigate the position and possibly strength of hydrogen
bonds. In each case, mono-substituted metallocene derivatives
were compared to their 1,1Ј-disubstituted analogues. Evidence
for strong intramolecular hydrogen bonding was found in
derivatives 6 and 7. Preliminary evidence for intramolecular
hydrogen bonding was reported by Herrick et al. for bis(amino
acid) ferrocene derivatives Fc(CO-Xaa-OMe)2 (see Scheme 1).5
An intramolecular hydrogen bond between amide NH and ester
CO was suggested by those workers based on NMR and IR
evidence and subsequently verified experimentally in two
related X-ray single crystal structures.19,20 In this work, we
rather find an intramolecular hydrogen bond between the amide
NH and ferrocene carbonyl CO for Xaa = Phe (6a) by X-ray
crystallography. There is evidence for NH hydrogen bonding in
solution for 6a, although this interaction appears to be less
strong than the one in the ferrocene bis(dipeptide) 7a. To
clarify this issue, we have prepared mono- and di-(S-1-phenyl-
ethylamine) ferrocene derivatives 5a and 8a. These compounds
are similar in their steric requirements to 6a but lack the ester
group altogether. NMR and IR data are very similar for both
compounds and give no indication for NH hydrogen bonds in
either 5a or 8a in solution. In 7a, on the other hand, a (strong)
intramolecular NH ؒ ؒ ؒ CO(amide) hydrogen bond is most
likely present in solution as well as in the solid state. We con-
clude that in our compound 6a different types of hydrogen
bonds form in the solid state and in solution, namely
NH ؒ ؒ ؒ CO(amide) in the solid state as confirmed by X-ray
D a l t o n T r a n s . , 2 0 0 3 , 2 1 0 – 2 2 0
219

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11 N. J. Long, Metallocenes, Blackwell Science, Oxford, 1998.
12 J. Meienhofer, The Mixed Carbonic Anhydride Method of Peptide
Synthesis, Academic Press, London, 1979.
13 J. E. Sheats and M. D. Rausch, J. Org. Chem., 1970, 35, 3245–3249.
14 G. M. Sheldrick, SADABS, University of Göttingen, 1994.
15 A. L. Spek, L. J. Farrugia, in PLATON99, Utrecht, 1999.
16 G. M. Sheldrick, ShelXTL, University of Göttingen, 1994.
17 W. Bauer, K. Polborn and W. Beck, J. Organomet. Chem., 1999, 579,
269–279.
18 D. R. van Staveren, T. Weyhermüller and N. Metzler-Nolte,
Organometallics, 2000, 19, 3730–3735.
19 M. Oberhoff, L. Duda, J. Karl, R. Mohr, G. Erker, R. Fröhlich and
M. Grehl, Organometallics, 1996, 15, 4005–4011.
20 A. S. Georgopoulou, D. M. P. Mingos, A. J. P. White, D. J. Williams,
B. R. Horrocks and A. Houlton, J. Chem. Soc., Dalton Trans., 2000,
2969–2974.
21 H. B. Kraatz, D. M. Leek, A. Houmam, G. D. Enright, J. Lusztyk
and D. D. M. Wayner, J. Organomet. Chem., 1999, 589, 38–49.
22 O. Brosch, T. Weyhermüller and N. Metzler-Nolte, Eur. J. Inorg.
Chem., 2000, 323–330.
The positional preference of certain amino acids in β-turns in
protein crystal structures has been studied by Thornton and
co-workers.41,42 To induce and stabilize a turn, Pro is the most
common amino acid at the (i ϩ 1) position (restriction of Φ
to about Ϫ60Њ). In organometallic mimics like ferrocene or
cobaltocene, a “turn-like” structure is inherent in the molecular
geometry of the two Cp rings. Thus, no special amino acid is
required to induce a turn. On the other hand, the two rings can
rotate against each other and situate substituents in 1 and 1Ј
position of the two rings into virtually any torsion angle ω
(see Table 2 and Scheme 4). As discussed above and shown in
Table 2, an angle of about 70Њ is present in both 6a and 7a.
Evidently, this is a favourable angle for turn structures and
stabilized by hydrogen bonds, much like β- or γ-turns in pro-
teins need additional stabilization through hydrogen bonds as
visualized in Scheme 5.
The torsional flexibility discussed above is a unique property
of the metallocene mimics proposed in this study. In com-
parison, most of the purely organic mimics are much more
rigid.4 The well-known phenoxathiine derivatives designed by
Feigel and co-workers are a pivotal example in which rigidity is
imposed by their tricyclic aromatic backbone.43 Recent studies
imply that some flexibility is indeed necessary for biological
activity. Upon binding to the receptor, changes in the geometry
of both the receptor and the small β-turn mimicking molecule
take place that optimize interactions and thus bonding
(“induced fit”). We believe that the torsional flexibility of the
turn mimetics proposed in this paper may bear some relevance
to the biological activity of β-turn mimetics with a metallocene
backbone. Studies along these lines are in progress in the
Heidelberg group.
23 M. C. Grossel, M. R. Goldspink, J. A. Hriljac and S. C. Weston,
Organometallics, 1991, 10, 851–860.
24 L. Lin, A. Berces and H.-B. Kraatz, J. Organomet. Chem., 1998, 556,
11–20.
25 T. Moriuchi, I. Ikeda and T. Hirao, Organometallics, 1995, 14,
3578–3580.
26 T. A. Albright, J. K. Burdett and M.-H. Whangbo, Orbital
Interactions in Chemistry, John Wiley & Sons, New York, 1985.
27 C. D. Hall, I. P. Danks, S. C. Nyburg, A. W. Parkins and
N. W. Sharpe, Organometallics, 1990, 9, 1602–1607.
28 G.-B. Liang, G. P. Dado and S. H. Gellman, J. Am. Chem. Soc.,
1991, 113, 3994–3995.
29 S. H. Gellman, G. P. Dado, G.-B. Liang and B. R. Adams, J. Am.
Chem. Soc., 1991, 113, 1164–1173.
30 C. N. Kirsten and T. H. Schrader, J. Am. Chem. Soc., 1997, 119,
12061–12068.
31 Although every effort was made to work under stringent conditions,
this result should be taken with appropriate care. Compound 7b is
very hygroscopic and the presence even of trace amounts of water
would already influence the measurements significantly.
32 G. C. K. Roberts, in NMR of Macromolecules – A Practical
Approach, ed. D. Rickwood, B. D. Hames, Oxford University Press,
Oxford, 1993.
Acknowledgements
The experimental part of this work was carried out at the
Max-Planck-Institut für Strahlenchemie. The authors are grate-
ful to the Max-Planck-Gesellschaft and Prof. K. Wieghardt for
support of this work. We are grateful to J. Bitter and K. Sand
for running numerous NMR spectra, H. Schucht for technical
assistance with the X-ray determinations, B. Mienert for
recording the Mößbauer spectra and M. Trinoga for HPLC
services. N. M. N. would like to acknowledge financial support
from the Fond der Chemischen Industrie and the Deutsche
Forschungsgemeinschaft (DFG).
33 H. Günther, NMR Spectroscopy, John Wiley & Sons, New York,
1980.
34 Intermolecular interactions can be excluded and reliable ∆δ1H
values are obtained only if the concentration of the solution is lower
than the self-association constant of the compound under
investigation. This work was carried out on approximately 10 mM
solutions, which is expected to be well beyond a self-association
constant. However, the self-association concentrations were not
determined and therefore, there is a slight chance that 10 mM
solutions were already too concentrated at least in some cases.
Furthermore, the presence of even small amounts of water is
expected to influence the ∆δ values to a large extent. Therefore, we
feel that the presence and the strength of hydrogen bonds can be
much better determined from the position of the νNH stretch
vibration in the infrared spectrum and the chemical shift of the
amide NH hydrogen atoms.
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