Preparation and structural characterisation of a novel ferrocene-amino acid conjugate

Article abstract of DOI:10.1016/j.inoche.2009.10.038

A new type of ferrocene-amino acid conjugate, 2-[(methoxycarbonyl)methyl]-2-aza[3]ferrocenophane (1), was obtained in a rather low yield via condensation reaction of 1,1′-bis(hydroxymethyl)ferrocene and glycine methyl ester in the presence of [RuCl₂(PPh₃)₃] as a catalyst. The compound was characterised by combustion analysis and by spectroscopic method, and its solid-state structure was established by single-crystal X-ray diffraction analysis. Compound 1 is reluctant towards alkylation with MeI but readily forms a stable picrate salt. Cyclic voltammetry experiments on 1 (in CH₃CN at Pt electrode) revealed the compound to undergo a one-electron reversible oxidation attributable to ferrocene/ferrocenium couple (E^o′ = -5 mV vs. ferrocene itself), which shifts towards more positive potentials upon protonation with HCl.

Full text of DOI:10.1016/j.inoche.2009.10.038

Inorganic Chemistry Communications 13 (2010) 149–152
Contents lists available at ScienceDirect
Inorganic Chemistry Communications
journal homepage: www.elsevier.com/locate/inoche
Preparation and structural characterisation of a novel ferrocene–amino
acid conjugate
*
ˇ
ˇ
ˇ
Jirí Tauchman, Petr Štepnicka
Department of Inorganic Chemistry, Faculty of Science, Charles University in Prague, Hlavova 2030, 12840 Prague, Czech Republic
a r t i c l e i n f o
a b s t r a c t
Article history:
A new type of ferrocene–amino acid conjugate, 2-[(methoxycarbonyl)methyl]-2-aza[3]ferrocenophane
(1), was obtained in a rather low yield via condensation reaction of 1,10-bis(hydroxymethyl)ferrocene
and glycine methyl ester in the presence of [RuCl2(PPh3)3] as a catalyst. The compound was characterised
by combustion analysis and by spectroscopic method, and its solid-state structure was established by sin-
gle-crystal X-ray diffraction analysis. Compound 1 is reluctant towards alkylation with MeI but readily
forms a stable picrate salt. Cyclic voltammetry experiments on 1 (in CH3CN at Pt electrode) revealed
the compound to undergo a one-electron reversible oxidation attributable to ferrocene/ferrocenium cou-
Received 8 September 2009
Accepted 27 October 2009
Available online 30 October 2009
Keywords:
Ferrocene
Glycine
Ferrocenophane
Structure elucidation
Cyclic voltammetry
ple (Eo = ꢀ5 mV vs. ferrocene itself), which shifts towards more positive potentials upon protonation
0
with HCl.
Ó 2009 Elsevier B.V. All rights reserved.
Ferrocenylated amino acids and peptides have been intensely
studied in the recent past mainly due to their attractiveness as re-
dox-active biomolecular probes and structural models for peptides
[1]. Most typically such compounds have been obtained by con-
densation between an appropriate organometallic reagent (usually
ferrocenecarboxylic acid or its derivative) and free (terminal) ami-
no group of an amino acid or a peptide chain to give the respective
N-ferrocenecarbonyl derivative (type I in Scheme 1). By contrast,
other methods including ferrocenylmethylation at the N-terminus
or preparation of amino acids bearing the ferrocenyl moiety in the
side chain (structures II and III in Scheme 1, respectively) remain
considerably less explored [1].
Compound 1 was prepared [8] by following the literature meth-
od consisting in thermally induced condensation of 1,10-
bis(hydroxymethyl)ferrocene [10] with glycine methyl ester [11]
at 170 °C in the presence of [RuCl2(PPh3)3] (3.5 mol.%) using N-
methylpyrrolidone as the solvent (Scheme 3). Isolation by column
chromatography afforded analytically pure 1 as an air-stable or-
ange crystalline solid in 10% yield. Apart from for 1, only small
amount of 2-oxa[3]ferrocenophane, which is evidently the product
of dehydration of the starting diol, was isolated from the crude
reaction mixtures. Attempts at improving the yield of 1 failed
probably because of competitive decomposition pathways operat-
ing under the relatively harsh reaction conditions.
While seeking for an alternative ‘‘ferrocenylation” method
applicable to amino acids, we became inspired with ferroceno-
phane amines of the type IV (Scheme 2). Such compounds have
been originally synthesised by condensation of 1,10-bis(hydroxy-
methyl)ferrocene with isocyantes (IV: R = C6H4X-4, where X = H,
OMe, NO2 [2]), by twofold alkylation of an amine (RNH2) with
1,10-bis(bromomethyl)ferrocene (IV: R = C6H4NO2-4 [3]) or 1,10-
bis(N-pyridiummethyl)ferrocene dichloride (IV: R = Me [4]) and, fi-
nally, by reductive ammination of ferrocene-1,10-dicarbaldehyde
Compound 1 was characterised by the conventional spectro-
scopic methods and by combustion analysis [12]. In 1H NMR spec-
tra, it showed a pair of apparent triplets due to symmetrically 1,10-
disubstituted ferrocene moiety (i.e., due to two identical AA0BB0
spin systems) and resonances attributable to the modifying substi-
tuent, namely a singlet for the equivalent, ferrocene-bound CH2
groups (dH 3.10) and two additional singlets for the glycine residue
(dH 3.66 and 3.75 for CH2 and CH3 group, respectively). 13C NMR
spectra were also in accordance with the formulation, displaying
two ferrocene CH resonances and one down-field shifted Cipso sig-
nal (dC 83.15) as it is typical for alkyl-substituted ferrocenes. Sig-
nals of the amino acid moiety were observed in the expected
region (dC 58.77 and 51.42 for CH2 and CH3 groups, respectively);
the glycine C@O was found at dC 171.65. Finally, IR spectra of 1
confirmed the presence of the terminal ester group, showing a
(IV: R =
x-[(7-chloro-4-quinolyl)amino]alkyl [5]). More recently,
Osakada and co-workers devised a practical synthetic route to fer-
rocenophanes IV based on Ru-catalysed condensation of 1,10-
bis(hydroxymethyl)ferrocene with amines [6]. We decided to
make use of this approach in the preparation of a novel ferro-
cene–glycine conjugate 1 (Scheme 2) [7].
strong mC
@ .
O
band at 1739 cmꢀ1
Solid-state structure of 1 was determined by single-crystal X-
* Corresponding author. Fax: +420 221 951 253.
ˇ
ˇ
E-mail address: stepnic@natur.cuni.cz (P. Štepnicka).
ray diffraction [13]. A view of the molecular structure is presented
1387-7003/$ - see front matter Ó 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.inoche.2009.10.038

ˇ ˇ
J. Tauchman, P. Štepnicka / Inorganic Chemistry Communications 13 (2010) 149–152
150
C14 bond (N–C13–C14–O1 = 9.1(3)°), which lowers the overall
O
R
molecular symmetry. As a consequence, the {C13, C14, O1, O2,
C15} plane [16] is practically perpendicular to the {C11, N, C12}
plane (dihedral angle = 83.6(2)°) but, simultaneously, inclined to-
wards the Cp2 ring as evidenced by the dihedral angles of the
{C13, C14, O1, O2, C15} plane and the Cp1/Cp2 rings being
4.5(1)/15.8(1)° (Fig. 2).
Alkylation of 1 with an excess of methyl iodide [17] met with no
success, leading only to a complete recovery of unchanged 1. On
the other hand, treatment of 1 with 2,4,6-trinitrophenol in ethyl
acetate and subsequent crystallisation [18] yielded picrate 2 as a
red crystalline solid (Scheme 3), which was characterised by melt-
ing point and by spectroscopic methods [19]. Ions constituting salt
2 were clearly seen in electrospray mass spectra. Likewise, the 1H
NMR spectrum of 2 showed signals attributable to cation [1H]+ and
characteristic resonance due to the picrate protons at dH 8.94. The
presence of the picrate anion was further manifested in IR spectra
OH
N
H
Fc
O
I
Fc
R
Y
OH
OH
N
H
H N
2
Fc
O
O
II
III
Scheme 1. Selected examples of ferrocenylated amino acids (Fc = ferrocenyl, Y = an
organic spacer).
CO Me
2
Fe
Fe
R
via the diagnostic bands at 1556/1567
(masNO2), 1321/1364
N
N
(m
sNO2), 1615/1629 ( )
m
C–C), and at 1270 cmꢀ1 (phenoxide mC–O
[20]. A band due to glycine C@O group (mC@O) was observed at
IV
1
1751 cmꢀ1, shifted by 12 cmꢀ1 to higher energies compared to 1.
Cyclic voltammogram of compound 1 recorded in acetonitrile at
a platinum electrode [21] displayed a diffusion-controlled, one-
Scheme 2. [3]Ferrocenophane amines (IV) and the amino acid derivative under
study (1).
electron reversible oxidation [22] at Eo = –0.005 V vs. ferrocene/
0
ferrocenium reference (Fig. 3). Addition of MeI (10 equiv.,
30 min) to the analysed solution left the redox response un-
changed which is, indeed, in line with the observed reluctance of
1 towards alkylation. On the other hand, addition of HCl (as a
methanol solution) led to immediate protonation at the nitrogen
atom, which in turn resulted in a pronounced shift of the ferro-
cene/ferrocenium wave towards more positive potentials (ca.
275 mV with 5 equiv., and ca. 300 mV with 10 equiv. of added
HCl), while not affecting its overall reversibility (Fig. 3) [23].
In summary, we have succeeded in preparing of a new type of
ferrocene–amino acid conjugate starting from simple precursors
in Fig. 1 together with selected distances and angles. The bridged
cyclopentadienyl rings in the molecule of 1 are mutually eclipsed
and symmetrically tilted by ca. 12° (the variation in the Fe-ring
centroid distances being statistically insignificant), and the geom-
etry of the ferrocenophane part does not differ much from the
structural data reported for the N-methyl analogue (IV, R = Me
[4]). The CNC bridge in 1 is bent at the nitrogen atom with the
C11–N–C12 angle being 113.8(1)°, and symmetrically incorporates
the glycine unit (the C11/C12–N–C13 angles differ by only 1°).
However, the pendant moiety it is slightly twisted at the C13–
OH
O N
2
CO Me
CO Me
2
2
H NCH CO Me
Hpic
2
2
2
O
NO
2
Fe
Fe
Fe
N
N
cat. [Ru]
N-methylpyrrolidone
H
O N
2
OH
1
2
Scheme 3. Preparation of ferrocenophane 1 and its picrate salt 2 (Hpic = 2,4,6-trinitrophenol).
C3
C2
C1
C4
C11
N
C5
O1
C15
C13
Fe
C7
C14
O2
C6
C8
C12
C10
C9
Fig. 1. View of the molecule of 1 showing displacement ellipsoids at the 30% probability level. Selected distances and angles: Fe–Cg1 1.6370(7), Fe–Cg2 1.6353(8), C1–C11
1.499(2), C6–C12 1.496(2), N–C11 1.471(2), N–C12 1.475(2), N–C13 1.454(2), C13–C14 1.518(2), C14–O1 1.201(2), C14–O2 1.332(2), O2–C15 1.445(2); \Cp1, Cp2 11.9(1),
C11–N–C12 113.8(1), N–C13–C14 116.7(1), O1–C14–O2 123.5(2), C14–O2–C15 116.0(1). Definition of ring planes: Cp1 = C(1–5), Cp2 = C(6–10); Cg1 and Cg2 are the
respective centroids.

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J. Tauchman, P. Štepnicka / Inorganic Chemistry Communications 13 (2010) 149–152
151
and is a part of long-term research projects supported by the Min-
istry of Education, Youth and Sports of the Czech Republic (Project
Nos. MSM 0021620857 and LC 06070).
(a)
(b)
References
[1] (a) N. Metzler-Nolte, M. Salmain, The bioorganometallic chemistry of
ˇ
ˇ
ferrocene, in: P. Štepnicka (Ed.), Ferrocenes: Ligands, Materials and
Biomolecules, Wiley, Chichester, 2008, pp. 499–639 (Chapter 13);
(b) T. Moriuchi, T. Hirao, Top. Organomet. Chem. 17 (2006) 143;
(c) H.-B. Kraatz, J. Inorg. Organomet. Polym. Mater. 15 (2005) 83;
(d) D.R. van Staveren, N. Metzler-Nolte, Chem. Rev. 104 (2004) 5931;
(e) T. Moriuchi, T. Hirao, Chem. Soc. Rev. 33 (2004) 294.
[2] H.-J. Lorkowski, P. Kieselack, Chem. Ber. 99 (1966) 3619.
[3] A.S. Georgopoulou, D.M.P. Mingos, A.J.P. White, D.J. Williams, B.R. Horrocks, A.
Houlton, J. Chem. Soc., Dalton Trans. (2000) 2969.
Fig. 2. Projections of the molecule of 1 along (a) the C1–C6 vector, and (b) the C13–
N bond (for atom labelling, see Fig. 1).
[4] H. Plenio, J. Yang, R. Diodone, J. Heinze, Inorg. Chem. 33 (1994) 4098.
[5] C.M. N’Diaye, L.A. Maciejewski, J.S. Brocard, C. Biot, Tetrahedron Lett. 42 (2001)
7221.
[6] K. Osakada, T. Sakano, M. Horie, Y. Suzaki, Coord. Chem. Rev. 250 (2006) 1012.
and references cited therein.
[7] Synthesis of
a ferrocenophane-based c-amino acid has been recently
communicated by Erker and coworkers: L. Tebben, K. Bussmann, M.
Hegemann, G. Kehr, R. Fröhlich, G. Erker, Organometallics 27 (2008) 4269.
[8] A solution of [RuCl2(PPh3)3] (27 mg, 0.03 mmol, 3.5 mol.%) in dry 1-methyl-2-
pyrrolidone (1.5 mL) was added to solid 1,1-bis(hydroxymethyl)ferrocene
(200 mg, 0.81 mmol) and [H3NCH2CO2Me]Cl (110 mg, 0.88 mmol). After
stirring at room temperature under Ar atmosphere for 5 min, triethylamine
(0.2 mL, 1.76 mmol) was introduced and the mixture was heated at 170 °C in
the dark for 24 h. Then, the volatiles were removed under vacuum and the dark
residue was extracted with ethyl acetate. Some insoluble by-products were
separated by filtration and the extract was purified by column
chromatography (silica gel, hexane:ethyl acetate, 5:1 v/v). The second band
was collected and evaporated to afford analytically pure 1 as a yellow solid
(24 mg, 10%). The first minor band contains mostly 2-oxa[3]ferrocenophane
according to NMR spectra [9].
[9] M.A. Carroll, A.J.P. White, D.A. Widdowson, D.J. Williams, J. Chem. Soc., Perkin
Trans. 1 (2000) 1551.
[10] V.K. Aggarwal, D. Jones, M.L. Turner, H. Adams, J. Organomet. Chem. 524
(1996) 263.
[11] Glycine methyl ester is formed in situ from glycine methyl ester hydrochloride
and triethylamine.
Fig. 3. Cyclic voltammograms of
1 before (solid line) and after (dashed line)
addition of 5 equiv. of HCl (recorded in acetonitrile on Pt electrode, 100 mV sꢀ1 scan
rate).
[12] Analytical data for 1: 1H NMR (CDCl3, 400 MHz, SiMe4): d 3.10 (s, 4H, C5H4CH2),
3.66 (s, 2H, CH2CO2Me), 3.75 (s, 3H, OMe), 4.09 and 4.12 (2 ꢁ apparent t,
J0 ꢂ 1.8 Hz, 4H, C5H4). 13C{1H} NMR (CDCl3, 101 MHz, SiMe4):
d 51.20
(C5H4CH2), 51.42 (OMe), 58.77 (CH2CO2Me), 69.27 and 69.95 (CH of C5H4);
83.15 (Cipso of C5H4), 171.65 (CO2Me). IR (Nujol): mCH 3101 w, 3094 w, 3080 m;
and using the known synthetic protocol. Although validated only
for glycine, this method most likely represents a general approach
to structurally unique amino acid derivatives that contain the re-
dox-active ferrocene moiety.
mC@O 1739 vs; 1299 m, 1287 w, 1229 w, 1197 vs, 1174 vs, 1144 vs, 1113 m,
1039 s, 1026 s, 996 s, 931 m, 854 s, 849 s, 819 w, 812 w, 801 s, 773 s, 688 m,
569 m, 540 m, 510 vs cmꢀ1. ESI + MS: m/z 300 ([M + H]+), 322 ([M + Na]+).
Anal. Calc. for C15H17FeNO2: C, 60.22; H, 5.73; N, 4.68%. Found: C, 60.00; H,
5.61; N, 4.57%.
Ferrocenophane 1, was characterised by a combination of com-
bustion analysis and common spectroscopic methods, and its for-
mulation was corroborated by X-ray crystallography. Cyclic
voltammetry measurements have shown the compound to under-
go one-electron reversible electron oxidation, presumably at the
ferrocene moiety. Upon protonation, this oxidation expectedly be-
comes more difficult, which is reflected by a shift of the associated
redox wave towards more positive potentials. In the case of the re-
lated N-methyl derivative (IV, R = Me), a shift +380 mV was noted
for the ferrocene/ferrocenium wave upon protonation with H[BF4]
in the same solvent [4].
[13] Orange prism from hot heptane (0.05 ꢁ 0.25 ꢁ 0.25 mm3). The diffraction data
were collected with a Nonius KappaCCD diffractometer (Mo K
a radiation,
k = 0.71073 Å; hmax = 27.5°) at 150(2) K. Crystallographic data: C15H17FeNO2,
M = 299.15 g molꢀ1, orthorhombic, space group Pccn (no. 56), a = 12.1391(2) Å,
b = 20.8244(3) Å, c = 10.4905(3) Å; V = 2651.9(1) Å3, Z = 8, Total 36709
diffractions of which 3041 were unique (Rint = 4.6%) and 2598 observed
according to Io > 2r(Io) criterion. The structure was solved by direct methods
(SIR97 [14]) and refined on F2 (SHELXL-97 [15]). All non-hydrogen atoms were
refined with anisotropic displacement parameters; the hydrogens were
included in their calculated positions. Refinement parameters: R (observed
diffractions) = 2.93%,
R (all data) = 3.72%, wR (all data) = 7.35%, residual
electron density: 0.38, ꢀ0.37 e Åꢀ3
.
[14] A. Altomare, M.C. Burla, M. Camalli, G.L. Cascarano, C. Giacovazzo, A.
Guagliardi, A.G.G. Moliterni, G. Polidori, R. Spagna, J. Appl. Crystallogr. 32
(1999) 115.
[15] G.M. Sheldrick,
SHELXL97, Program for Crystal Structure Refinement from
Supplementary material
Diffraction Data, University of Göttingen, Germany, 1997.
[16] Atoms defining the {C13, C14, O1, O2, C15} plane are coplanar within 0.01 Å.
[17] Unchanged 1 was recovered after reacting with an excess of MeI in acetonitrile
overnight (5 mg (17
solvent).
[18] Compound 1 (5 mg, 17
CCDC 746701 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
lmol) of 1 and 14 mg (0.1 mmol) of MeI in 1 mL of dry
l
mol) and 2,4,6-trinitrophenol (Hpic; 4.5 mg, 20 mol)
l
were dissolved in ethyl acetate (1 mL). The mixture was layered with hexane
(2 mL) and allowed to crystallise at room temperature. The separated deep red
crystalline picrate 2 was filtered off, washed with pentane and dried under
vacuum. The yield was not determined.
[19] M.p. 170–172 °C (ethyl acetate–hexane). 1H NMR (CDCl3, 400 MHz, SiMe4): d
3.85 (s, 3H, OMe), 4.01 (br s, 4H, C5H4CH2 or C5H4), 4.21 (s, 2H, CH2CO2Me),
4.28 (br apparent t, J0 ꢂ 1.8 Hz, 4H, C5H4), 4.45 (br s, 4H, C5H4CH2 or C5H4), 8.94
(s, 2H, OC6H2(NO2)3). ESI MS (methanol): m/z 300 ([1 + H]+), 322 ([1 + Na]+);
228 (picꢀ), 479 ([(pic)2Na]ꢀ), 730 ([(pic)3Na2]ꢀ). IR (neat; diffuse reflectance):
Acknowledgements
ˇ
The authors are grateful to Dr. I. Císarová for recording the X-
ray diffraction data. This work was financially supported by the
Grant Agency of Charles University in Prague (Project No. 58009)
m
3115 w, 3096 w, 3085 m, 3078 w, 3007 m, 2995 w, 2970 w, 2947 m, ca.

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J. Tauchman, P. Štepnicka / Inorganic Chemistry Communications 13 (2010) 149–152
152
2850–2599 composite m, 1866 w, 1751 s, 1629 s, 1615 s, 1567 s, 1556 s, 1521
0.1 M Bu4N[PF6] (Fluka, puriss. for electrochemistry). The solutions were
deaerated with argon prior to the measurement and then kept under an argon
blanket. The redox potentials are given relative to ferrocene/ferrocenium
reference. Reactions with HCl and MeI were performed directly in the cell. The
reagents were added to the analysed solution (0.7 M HCl in MeOH, neat MeI)
and the mixture was stirred for 5 (HCl) or 30 min (MeI) to ensure complete
reaction.
m, 1493 s, 1457 m, 1447 w, 1432 s, 1364 m, 1321 vs, 1270 s, 1242/1235 m,
1212 m, 1161 s, 1075 s, 1044 m, 993 m, 964 m, 940 w, 931 s, 909 m, 865 w,
851 m, 811 m, 790 m, 747 m, 711 s cmꢀ1
.
[20] For recent references dealing with IR spectra of amino acid picrates, see: (a)
M.B. Mary, V. Sasirekha, V. Ramakrishnan, Spectrochim. Acta Part A 65 (2006)
414;
(b) S. Senthilkumar, M.B. Mary, V. Ramakrishnan, J. Raman Spectrosc. 38
(2007) 288.
[22] The ratio of the anodic and cathodic peak currents (ipa/ipc) remained close to
unity at scan rates (
increased with the square root of the scan rate ðipa
separation of the anodic and cathodic peaks (
Ep = 75 mV at 100 mV sꢀ1) was
m
) in the range 0.05–1 V sꢀ1, and the anodic peak current
[21] Electrochemical measurements were performed with
a
multipurpose
/
m1=2Þ. The observed
potentiostat AUTOLAB III (Eco Chemie) at room temperature using
l
a
D
standard three-electrode cell (platinum disc working electrode, platinum
sheet auxiliary electrode, and saturated calomel reference electrode) and
acetonitrile solutions (Aldrich, absolute) containing 1 mM of the analyte and
close to that of ferrocene itself under the same conditions (ca. 70 mV).
[23] Some ill-defined peaks were observed in the cathodic region of the
voltammogram.