The synthesis and structural characterization of N-ortho-ferrocenyl benzoyl amino acid esters. The X-ray crystal structure of N-{ortho-(ferrocenyl)benzoyl} -l-phenylalanine ethyl ester

Article abstract of DOI:10.1016/j.jorganchem.2005.09.019

A series of N-ortho-ferrocenyl benzoyl amino acid ethyl esters 3-9 have been prepared by coupling ortho-ferrocenyl benzoic acid 2 to the amino acid ethyl esters of glycine, l-alanine, l-leucine, l-phenylalanine, β-alanine, 4-aminobutyric acid and (±)-2-aminobutyric acid using the conventional 1,3-dicyclohexylcarbodiimide, 1-hydroxybenzotriazole protocol. The compounds were fully characterized by a range of NMR spectroscopic techniques and by mass spectrometry (MALDI-MS, ESI-MS). The X-ray crystal structure of the l-phenylalanine derivative 6 has been determined.

Full text of DOI:10.1016/j.jorganchem.2005.09.019

Journal of Organometallic Chemistry 691 (2006) 463–469
www.elsevier.com/locate/jorganchem
The synthesis and structural characterization of N-ortho-ferrocenyl
benzoyl amino acid esters. The X-ray crystal structure of
N-{ortho-(ferrocenyl)benzoyl}-L-phenylalanine ethyl ester
a
a
b
b
b
David Savage , Gwen Malone , Steven R. Alley , John F. Gallagher , Alok Goel ,
b
c
b,
*
Paula N. Kelly , Helge Mueller-Bunz , Peter T.M. Kenny
a
School of Chemical Sciences, Dublin City University, Dublin 9, Ireland
National Institute for Cellular Biotechnology, Dublin City University, Dublin 9, Ireland
b
c
Department of Chemistry, University College Dublin, Belfield, Dublin 4 Ireland
Received 11 July 2005; received in revised form 30 August 2005; accepted 5 September 2005
Available online 19 October 2005
Abstract
A series of N-ortho-ferrocenyl benzoyl amino acid ethyl esters 3–9 have been prepared by coupling ortho-ferrocenyl benzoic acid 2 to
the amino acid ethyl esters of glycine, L-alanine, L-leucine, L-phenylalanine, b-alanine, 4-aminobutyric acid and ( )-2-aminobutyric acid
using the conventional 1,3-dicyclohexylcarbodiimide, 1-hydroxybenzotriazole protocol. The compounds were fully characterized by a
range of NMR spectroscopic techniques and by mass spectrometry (MALDI-MS, ESI-MS). The X-ray crystal structure of the L-phen-
ylalanine derivative 6 has been determined.
ꢀ 2005 Elsevier B.V. All rights reserved.
Keywords: Ferrocene; Amino acid esters; Bioorganometallic chemistry; MALDI; X-ray crystal structure
1. Introduction
amino acid and peptide derivatives has been reported
[10–26]. A review on bioorganometallic chemistry of ferro-
cene has recently been published [27]. We now report the
synthesis and structural characterization of a series of
N-ortho-ferrocenyl benzoyl amino acid esters 3–9. These
unusual materials are composed of three key moieties,
namely, (i) an electroactive core, (ii) a conjugated linker
that can act as a chromophore and (iii) an amino acid
derivative that can interact with other molecules via hydro-
gen bonding. The amino acids employed in the synthesis
were glycine, L-alanine, L-leucine, L-phenylalanine, b-ala-
nine, 4-aminobutyric acid and ( )-2-aminobutyric acid.
The compounds were fully characterized by 1H NMR,
13C NMR and by MALDI and ESI mass spectrometry.
In addition the X-ray crystal structure of the L-phenylala-
nine derivative 6 is also reported.
Research in the area of bioorganometallic chemistry has
seen an increase in attention over the past decade. The
incorporation of ferrocene in novel materials has been re-
ported primarily due to its stability, spectroscopic proper-
ties, electrochemical properties and ease of use [1,2]. As a
direct consequence of these factors, research in the area
of ferrocenyl derivatives has seen an increase in attention,
primarily for the preparation of novel sensor compounds,
peptide mimetic models and unnatural drugs [3–9]. The
incorporation of a ferrocene group onto proteins has shown
the mediation of electron transfer between electrodes and
the protein redox site [3,4]. The synthesis and structural
characterization of novel N-ferrocenoyl and N-ferrocenyl
We have already reported the synthesis and structural
characterization of a series of N-para and N-meta-ferroce-
nyl benzoyl amino acid ester derivatives [28–30].
*
Corresponding author. Tel.: +353 1 7005689; fax: +353 1 7005503.
E-mail address: peter.kenny@dcu.ie (P.T.M. Kenny).
0022-328X/$ - see front matter ꢀ 2005 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2005.09.019

464
D. Savage et al. / Journal of Organometallic Chemistry 691 (2006) 463–469
2. Results and discussion
2.1. Synthesis
(MALDI) for compounds 3, 4, 7, 8, and 9, or electrospray
ionization mass spectrometry (ESI) for compounds 5 and
6. Crystals of sufficient quality for X-ray diffraction studies
were also obtained for compound 6.
ortho-Ferrocenyl benzoic acid 2 was prepared using con-
ventional diazonium salt chemistry. Treatment of ethyl-2-
aminobenzoate with sodium nitrite in the presence of
hydrochloric acid yielded the diazonium salt, which was
then reacted with ferrocene in situ to yield the ortho-substi-
tuted ferrocenyl ethyl benzoate 1. Prior to coupling with
the C-protected amino acids, the ester group was cleanly
cleaved by treatment with 10% sodium hydroxide to yield
1
2.2. H and 13C NMR spectroscopic analysis
All the proton and carbon chemical shifts for com-
pounds 3–9 were unambiguously assigned by a combina-
tion of DEPT-135 and H–13C-COSY (HMQC). The H
and 13C NMR spectra for compounds 3–9 showed peaks
in the ferrocene region characteristic of a mono substituted
ferrocene moiety [10,28–30]. The protons of the ortho-
disubstituted benzoyl group appear in the region d 6.88–
7.81. For example, in the case of the L-alanine derivative
1
1
1
ortho-ferrocenyl benzoic acid 2. The H NMR spectrum
showed signals for the aromatic ring protons at d 7.83
(d), d 7.44 (t), d 7.37 (d) and d 7.27 (t), integrating for
one proton each, characteristic of a ortho-disubstituted
aromatic ring. The carboxylic acid proton was present at
d 12.8. The ferrocenyl ortho and meta protons on the (g5-
C5H4) ring were observed at d 4.55 and d 4.32, respectively,
and an intense singlet was present at d 4.08 for the (g5-
C5H5) ring. ortho-Ferrocenyl benzoic acid 2 was coupled
under basic conditions to the free N-terminal amino acid
esters of glycine, L-alanine, L-leucine, L-phenylalanine, b-
alanine, 4-aminobutyric acid and ( )-2-aminobutyric acid
in the presence of dicyclohexylcarbodiimide (DCC) and
1-hydroxybenzotriazole (HOBt) as outlined in Scheme 1.
The N-ortho-ferrocenyl benzoyl amino acid esters 3–9 were
obtained as yellow/orange coloured crystals. The yields ob-
tained ranged between 55% and 68% and all gave analytical
and spectroscopic data in accordance with the proposed
structures. The compounds are reasonably stable however
they can slowly decompose over a period of time. The per-
centage yields obtained are comparable to those obtained
for both the para and meta analogues [28–30]. The N-
ortho-ferrocenyl benzoyl derivatives 3–9 were characterized
4 the (g5-C5H5) ring appears as a singlet in the H NMR
1
spectrum at d 4.03 whereas the meta and ortho protons
on the (g5-C5H4) ring are present at d 4.27 and 4.63,
respectively. The NH proton appears as a doublet at d
8.75 and another doublet at d 1.31 integrating for three
protons corresponds to the side chain methyl group. The
aromatic ring protons are present in the region d 7.21–7.79.
The 13C NMR spectra of compounds 3–9 show signals
in the region d 68.5–85.7 indicative of a monosubstituted
ferrocene subunit. The ipso carbon of the (g5-C5H4) ring
appears in the range of d 84.5 to 85.7. This signal is absent
in the DEPT-135 spectra. The carbon atoms of the phenyl
spacer group are non-equivalent and therefore six signals
are visible in the region d 125.8–137.9. The two quaternary
carbon atoms of this phenyl group were identified by
DEPT-135. In the case of the L-alanine derivative 4 the sig-
nals were present at d 136.8 and 136.2 and were absent in
the DEPT-135 spectrum. The four other aromatic peaks
appeared at d 130.4, 129.2, 127.8 and 125.8, respectively.
The signal due to the ipso carbon of the ferrocenyl group
was at d 84.7 and absent in the DEPT 135 spectrum. Up-
field from the ferrocenyl ipso carbon signal the (g5-C5H5)
ring appears at d 69.6 whereas the signals due to the meta
and ortho carbons are present at d 69.6 and 68.6, respec-
tively. The methylene carbon of the ethyl ester group ap-
pears at d 60.9 and displays a negative peak in the DEPT
135 spectrum. The a-carbon is present at d 48.3. The
methyl groups of the alanine side chain and the ethyl ester
are present at d 17.0 and 14.5, respectively. All the methy-
lene carbon atoms of the derivatives 3–9 were also identi-
1
by a combination of H NMR, 13C NMR, DEPT-135 and
1H–13C COSY (HMQC) spectroscopy, and by either ma-
trix assisted laser desorption ionization mass spectrometry
i
H2N
Fe
Fe
O
OC2H5
O
OC2H5
1
1
ii
fied by DEPT-135. A complete assignment of the H and
13C NMR spectra of compound 4 is presented in Table 1.
2.3. Mass spectrometry
iii
Fe
R
Fe
Since the introduction of soft ionization techniques such
as matrix assisted laser desorption ionization (MADLI)
and electrospray ionization (ESI), a wide range of thermo-
labile and non-volatile compounds can be subjected to
mass spectrometric analysis [31–33]. Compounds 3–9 were
not amenable to electron ionization studies, therefore
MADLI and ESI were employed in the analysis. Both
OC2H5
O
N
O
OH
H
O
3-9
2
Scheme 1. Synthesis of the N-ortho-ferrocenyl benzoyl amino acid esters
3–9; Gly(OEt) 3, Ala(OEt) 4, Leu(OEt) 5, Phe(OEt) 6, b-Ala(OEt) 7, 4-
Abat(OEt) 8, 2-Aba(OEt) 9. (i) NaNO2, HCl, 5 ꢁC, (ii) NaOH/MeOH,
H2O, (iii) DCC, HOBt, Et3N, amino acid ester.

D. Savage et al. / Journal of Organometallic Chemistry 691 (2006) 463–469
465
Table 1
by soft ionization techniques such as MALDI furnish pro-
tonated molecular ion species as a result of proton transfer
reactions between the analyte and matrix or cation adduc-
tion. However, it has been reported that the molecular rad-
ical cation of ferrocene and not the protonated molecular
ion is generated during analysis by MALDI [34]. More
interestingly, in contrast to the related para and meta deriv-
atives an important fragment ion at m/z [M ꢀ 65]+Å result-
ing from loss of the unsubstituted (g5-C5H5) ring, was
observed in all the mass spectra and this ion is unique for
the ortho series. The formation of this fragment ion is prob-
ably due to steric interactions between the unsubstituted
(g5-C5H5) ring and the ortho benzoyl substituents. In the
case of the glycine derivative 3 the molecular ion was pres-
ent at m/z 391 and the fragment ion at m/z 326. For the ala-
nine and b-alanine derivatives 4 and 7 this fragment ion
was shifted 14 mass units higher to m/z 340 and for the
amino butyric acid derivatives 8 and 9 to m/z 354. Com-
pounds 5 and 6 were analyzed by electrospray ionization
mass spectrometry (ESI-MS). The ESI mass spectra dis-
played both radical cation and [M + H]+ species and in-
tense adducts due to sodium and potassium were present
22 and 38 Da higher than the protonated molecular ion
species.
1H and 13C spectroscopic data for 4
12
13
3
2
11
14
19
1
4
5
Fe
CH3
16
17
15
21 22
OCH2CH3
20
6-10
18
O
N
H
O
4
Site
1H NMR
13C NMR
84.7
HMQC
1
2,5
3,4
6–10
11
12
13
14
15
16
17
18
19
20
21
22
a,b
4.63
4.27
4.03
68.6
69.6
69.8
136.8a
7.11–26
7.11–26
7.41
130.4
129.2a
127.8b
125.8
7.79
136.2b
169.8
4.36
1.31
48.3
17
172.9
4.12
1.22
60.9
14.4
Signals may be reversed.
2.4. X-ray crystallographic studies of 6
MALDI and ESI confirmed the correct relative molecular
mass for all the compounds and examination of the mass
spectra revealed the presence of intense radical-cations.
Cation adducts due to sodium and potassium were also
present. The vast majority of analytes subjected to analysis
The single crystal X-ray structure of 6 has been deter-
mined (Fig. 1) with selected bond lengths and angles listed
in Table 2 with crystallographic details given in the foot-
note. There is an increasing number of metallocene based
amino acid/peptide structures on the Cambridge Structural
b
C27
a
c
C26
C25
C28
C21
C20
C23
C24
C22
O3
C19
C18
O2
C8
Fe
N
C9
N
H
O
C
?
C7
C2
C10
C17
C6
C11
Fe
C16
O1
C1
C5
C15
C14
C12
C4
C13
C3
Fig. 1. Molecular drawing using ORTEP: displacement ellipsoids are drawn at the 50% probability level.

466
D. Savage et al. / Journal of Organometallic Chemistry 691 (2006) 463–469
Table 2
with the amino acid esters using conventional organic pep-
tide synthetic protocols. The compounds were fully charac-
terized by a range of NMR spectroscopic techniques and
by mass spectrometry. The mass spectra of compounds
3–9 show a diagnostic fragment ion at m/z [M ꢀ 65]+Å
which is absent in the mass spectra of the corresponding
para and meta analogues. In addition the X-ray crystal
structure of compound 6 has been determined.
˚
Selected bond lengths (A) and angles (ꢁ) for 6
Fe. . .Cg1
Fe. . .Cg2
Cg1. . .Fe. . .Cg2
N–C(17)
N–C(18)
O–(1)–C(17)
O–(2)–C(19)
O–(3)–C(19)
O–(3)–C(20)
1.647(2) O(1)–C(17)–N
1.646(2) N–C(17)–C(16)
123.30(15)
115.11(13)
108.99(11)
110.07(12)
112.80(12)
125.15(15)
124.32(14)
110.52(12)
114.06(12)
7.8(2)
178.24(2)
N–C(18)–C(19)
1.347(2) N–C(18)–C(22)
1.454(2) C(19)–C(18)–C(22)
1.225(2) O(2)–C(19)–O(3)
1.202(2) O(2)–C(19)–C(18)
1.332(2) O(3)–C(19)–C(18)
1.456(2) C(23)–C(22)–C(18)
4. Experimental
C–(15)–C(16)–C(17) 116.09(14) C(10)–C(11)–C(16)–C(17)
C–(11)–C(16)–C(17) 124.07(14)
4.1. General procedures
Where Cg1 and Cg2 are the centroids of substituted and unsubstituted
cyclopentadienyl rings, respectively.
All chemicals were purchased from Sigma/Aldrich and
used as received. Commercial grade reagents were used
without further purification, however, solvents were puri-
fied prior to use. Melting points were determined using a
Griffin melting point apparatus and are uncorrected. Infra-
red spectra were recorded on a Nicolet 405 FT-IR spec-
trometer and UV–Vis spectra on a Hewlett–Packard
8452A diode array UV–Vis spectrophotometer. NMR spec-
tra were obtained on a Bruker AC 400 NMR spectrometer
Database (CSD) [35], but compounds incorporating the
Fc-C6H4- moiety are relatively rare in comparison to the
Fc systems, where Fc = (g5-C5H5)Fe(g5-C5H4).
2.4.1. Molecular and crystal structure study of 6
Compound 6 crystallizes with one molecule in the asym-
metric unit of space group P212121 (No. 19). The key geo-
1
metric parameters are amide C@O 1.225(7) A, OC–NH
operating at 400 MHz for H NMR and 100 MHz for 13C
˚
˚
˚
1.347(2) A, HN–CH 1.454(2) A and ester C@O/C–O
NMR. The 1H and 13C NMR chemical shifts (ppm) are rel-
ative to TMS and all coupling constants (J) are in Hertz.
Matrix assisted laser desorption ionization mass spectra
were obtained on a Bruker Ultraflex TOF/TOF mass spec-
trometer employing a nitrogen laser at 337 nm. Electro-
spray ionization mass spectra were performed on either a
Bruker Esquire ion trap mass spectrometer or a Micromass
Q-ToF Ultima quadrupole time of flight mass spectrometer.
˚
1.202(2)/1.332(2) A, respectively, which are similar to the
previously reported L-alanine and glycine derivatives
[28,29]. Cyclopentadienyl rings (Cp1 and Cp2) are slightly
staggered with C1n. . .Cg1. . .Cg2. . .C2n torsion angles
(n = 1–5) in the 7.80(2)–8.30(2)ꢁ range. Centroids Cg1
and Cg2 of the Cp rings are equidistant from the iron core,
Fe. . .Cg1/Cg2 distances are 1.647(2)/1.646(2) with
178.24(2)ꢁ Cg1. . .Fe. . .Cg2 angle.
Crystal data were collected at 113(2) K using a Bruker
¨
There is an intermolecular hydrogen bond N–H. . .O@C
SMART APEX CCD area detector diffractometer. A full
sphere of the reciprocal space was scanned by /–x scans.
Pseudo-empirical absorption correction based on redun-
dant reflections was performed by the program SADABS
[36]. The structures were solved by direct methods using
SHELXS-97 [37] and refined by full matrix least-squares on
F2 for all data using SHELXL-97 [38]. All hydrogen atoms
were located in the difference fourier map and allowed to re-
fine freely with isotropic temperature factors. Anisotropic
temperature factors were used for all non-hydrogen atoms.
˚
(ester), with H. . .O 2.28(2) A, N–H. . .O 169(2)ꢁ, similar to
the L-alanine derivative and in contrast to amide. . .amide
intermolecular interactions found in glycine and ( )-2-ami-
nobutyric acid derivatives [29]. There is also a significant
intermolecular contact between a methylene hydrogen
(H22) and a (Cp1) ring hydrogen (H7), contact distance
˚
being 2.26(2) A. These two interactions generate a one-
dimensional chain along the b-axis and the packing along
the chain comprises alternating Ôhead to tailÕ arrangement
of identical molecules.
ortho-Ferrocenyl and amide groups of the central phenyl
ring are significantly twisted. The angle between the central
phenyl and the Cp ring planes is 37.8(2)ꢁ, whereas the angle
between the phenyl ring and the O@C–N plane is 49.65(2)ꢁ.
The torsion angle C10–C11–C16–C17 between the two
substituents is 7.8ꢁ. Although conjugating groups are usu-
ally planer to the phenyl ring and provide extended conju-
gation, steric effects force these groups out of plane in the
solid state.
4.2. General procedure for the synthesis of the starting
materials 1 and 2
4.2.1. ortho-Ferrocenyl ethyl benzoate 1
Concentrated hydrochloric acid (6 ml) was added with
intermittent cooling to a solution of ethyl-2-aminobenzoate
(3 g, 18.2 mmol) in 15 ml of water. A solution of sodium ni-
trite (1.4 g, 20.3 mmol) in 15 ml of water was then added
slowly to this mixture with stirring keeping the temperature
below 5 ꢁC furnishing a pale yellow solution. The resulting
diazo salt was added to a solution of ferrocene (3.8 g,
20.4 mmol) in diethyl ether (90 ml) and allowed to react
for 12 h. The reactant mixture was then washed with water;
the ether layer was dried over MgSO4 and the solvent was
3. Conclusions
The N-ortho-ferrocenyl benzoyl amino acid esters 3–9
were prepared by coupling ortho-ferrocenyl benzoic acid

D. Savage et al. / Journal of Organometallic Chemistry 691 (2006) 463–469
467
removed in vacuo to yield the crude product. The crude
product was purified using column chromatography {elu-
ant 2:3 petroleum ether (40–60 ꢁC): diethyl ether}.
1H NMR (400 MHz) d (DMSO): 7.88 (1H, d, J = 8 Hz,
ArH), 7.50 (1H, t, J = 8 Hz, ArH), 7.39 (1H, d, J = 8 Hz,
ArH), 7.30 (1H, t, J = 8 Hz, ArH), 4.46 {2H, s, ortho on
(g5-C5H4)}, 4.33 {2H, s, meta on (g5-C5H4)}, 4.14 (2H,
q, J = 7.2 Hz, –OCH2CH3), 4.09 {5H, s, (g5-C5H5)}, 1.13
(3H, t, J = 7.2 Hz, –OCH2CH3).
J = 8 Hz, ArH), 7.20–7.28 (2H, m, ArH), 4.68 {2H, t,
J = 2 Hz, ortho on (g5-C5H4)}, 4.28 {2H, t, J = 2 Hz, meta
on (g5-C5H4)}, 4.16 (2H, q, J = 7.2 Hz, –OCH2CH3), 4.05
{5H, s, (g5-C5H5)}, 3.92 (2H, d, J = 6.4 Hz, –NHCH2CO–),
1.24 (3H, t, J = 7.2 Hz, –OCH2CH3).
13C NMR (100 MHz) d (DMSO): 170.6, 170.2, 136.8,
136.0, 130.4, 129.3, 127.8, 125.8, 84.5, 69.8, 69.1, 68.6,
60.9 (-ve DEPT), 41.4 (-ve DEPT), 14.4.
13C NMR (100 MHz) d (DMSO): 170.3, 138.7, 132.6,
131.7, 130.5, 128.8, 126.3, 86.6, 70.1, 69.7, 68.8, 61.5 (-ve
DEPT), 14.2.
4.3.2. N-{ortho-(Ferrocenyl)benzoyl}-L-alanine ethyl ester 4
L-Alanine ethyl ester hydrochloride (0.3 g, 2.0 mmol)
was used. Recrystallization from petroleum ether (40–
60 ꢁC): ethyl acetate furnished the title compound as a yel-
low solid (0.39 g, 60%).
4.2.2. ortho-Ferrocenyl benzoic acid 2
25
Sodium hydroxide (0.3 g, 7.5 mmol) was added to ortho-
ferrocenyl ethyl benzoate 1 (2.4 g, 7.2 mmol) in a 1:1
mixture of water/methanol and was refluxed for 3 h. Con-
centrated HCl was added until pH 2 was reached. The solu-
tion was allowed to cool and the product was isolated by
filtration.
m.p. 54–56 ꢁC, E00 = 111 mV, ½aꢁD ¼ þ9ꢂ (c = 2,
CH2Cl2).
Analysis: found: C, 65.24; H, 6.00; N, 3.43.
C22H23N1O3Fe requires: C, 65.20; H, 5.72; N, 3.46.
Mass spectrum: found: [M]+Å 405.104.
C22H23N1O3Fe requires: 405.103.
m.p. 124–126 ꢁC.
IR mmax (KBr) :3323, 1757, 1635, 1530, 1459 cmꢀ1
.
IR mmax (KBr): 1693, 1607, 1402, 1227 cmꢀ1
.
UV–Vis kmax MeCN: 330 (e 1130), 450 (e 290) nm.
UV–Vis kmax CH2Cl2: 356 (e 1310), 450 (e 430) nm.
1H NMR (400 MHz) d (DMSO): 12.8 (1H, s, –COOH),
7.83 (1H, d, J = 8 Hz, ArH), 7.44 (1H, t, J = 8 Hz, ArH),
7.37 (1H, d, J = 8 Hz, ArH), 7.27 (1H, t, J = 8 Hz, ArH),
4.55 {2H, s, ortho on (g5-C5H4)}, 4.32 {2H, t, meta on
(g5-C5H4)}, 4.08 {5H, s, (g5-C5H5)}.
1H NMR (400 MHz)
d
(DMSO): 8.75 (1H, d,
J = 6.8 Hz, –CONH–), 7.79 (1H, d, J = 8 Hz, ArH), 7.41
(1H, t, J = 8 Hz, ArH), 7.21–7.26 (2H, m, ArH), 4.63
(2H, d, J = 1.6 Hz, ortho on (g5-C5H4)), 4.36 {1H, t, J =
8 Hz, –CH(CH3)}, 4.27 {2H, d, J = 1.6 Hz, meta on (g5-
C5H4)}, 4.12 (2H, q, J = 6.4 Hz, –OCH2CH3), 4.03 {5H,
s, (g5-C5H5)}, 1.31 {3H, d, J = 7.2 Hz, –CH(CH3)}, 1.22
(3H, t, J = 6.4 Hz, –OCH2CH3).
13C NMR (100 MHz) d (DMSO): 171.2, 137.0, 133.4,
131.1, 129.9, 127.8, 126.1, 85.4, 69.9, 69.2, 68.6.
13C NMR (100 MHz) d (DMSO): 172.9, 169.8, 136.8,
136.2, 130.4, 129.2, 127.8, 125.8, 84.7, 69.8, 69.6, 68.7,
68.6, 68.5, 60.9 (-ve DEPT), 48.3, 17.0, 14.4.
4.3. General procedure for the synthesis of N-{ortho-
(ferrocenyl)benzoyl} amino acid esters 3–9
4.3.1. N-{ortho-(ferrocenyl)benzoyl} glycine ethyl ester 3
Glycine ethyl ester hydrochloride (0.3 g, 2.2 mmol) and
triethylamine (0.5 ml) were added to a solution of ortho-
ferrocenyl benzoic acid (0.5 g, 1.6 mmol), 1-hydroxybenzo-
triazole (0.3 g, 2.2 mmol) and 1,3-dicyclohexylcarbodi-
imide (0.45 g, 2.2 mmol) in CH2Cl2 (50 ml) at 0 ꢁC. After
30 min the solution was raised to room temperature and al-
lowed to proceed for 48 h. The precipitated N,N0-dic-
yclohexylurea was removed by filtration and the filtrate
was washed with water, 10% potassium hydrogen carbon-
ate, 5% citric acid and dried over MgSO4. Recrystallization
from petroleum ether (40–60 ꢁC): ethyl acetate furnished
N-{ortho-(ferrocenyl)benzoyl} glycine ethyl ester 3 as or-
ange needles (0.38 g, 62%).
4.3.3. N-{ortho-(Ferrocenyl)benzoyl}-L-leucine ethyl ester 5
L-Leucine ethyl ester hydrochloride (0.3 g, 1.5 mmol)
was used. Recrystallization from petroleum ether (40–
60 ꢁC): ethyl acetate yielded the title compound as an or-
ange solid (0.46 g, 64%).
20
m.p. 88–90 ꢁC, E00 = 106 mV, ½aꢁD ¼ þ3ꢂ (c = 1.2,
CH2Cl2).
Analysis: found: C, 67.16; H, 6.64; N, 3.21.
C25H29N1O3Fe requires: C, 67.12; H, 6.53; N, 3.13.
Mass spectrum: found: [M]+Å 447.2.
C25H29N1O3Fe requires: 447.15.
IR mmax (KBr): 3324, 3266, 1744, 1644 cmꢀ1
.
UV–Vis kmax CH2Cl2: 334 (e 1140), 448 (e 260) nm.
1H NMR (400 MHz)
d
(DMSO): 8.69 (1H, d,
m.p. 99–101 ꢁC, E00 = 109 mV.
J = 7.6 Hz, –CONH–), 7.81 (1H, d, J = 8 Hz, ArH), 7.41
(1H, t, J = 8 Hz, ArH), 7.26 (1H, t, J = 8 Hz, ArH), 7.16
(1H, d, J = 8 Hz, ArH), 4.60 {2H, s, ortho on (g5-
C5H4)}, 4.30–4.36 [1H, m, –CH{CH2CH(CH3)2}], 4.28
{1H, s, meta on (g5-C5H4)}, 4.12 {1H, s, meta on (g5-
C5H4)}, 4.11 (2H, q, J = 6.4 Hz, –OCH2CH3), 4.05 {5H,
s, (g5-C5H5)}, 1.57–1.81 [3H, m, –{CH2CH(CH3)2}], 1.22
(3H, t, J = 6.4 Hz, –OCH2CH3), 0.87 [6H, d, J = 6.4 Hz,
–CH{CH2CH(CH3)2}].
Analysis: found: C, 64.35; H, 5.47; N, 3.80.
C21H21N1O3Fe requires: C, 64.47; H, 5.41; N, 3.58.
Mass spectrum: found: [M]+Å 391.089.
C21H21N1O3Fe requires: 391.087.
IR mmax (KBr): 3298, 1740, 1643, 1529 cmꢀ1
.
UV–Vis kmax CH2Cl2: 340 (e 1060), 446 (e 340) nm.
1H NMR (400 MHz) d (DMSO): 8.76 (1H, d, J = 5.6 Hz
–CONH–), 7.81 (1H, d, J = 8 Hz, ArH), 7.43 (1H, t,

468
D. Savage et al. / Journal of Organometallic Chemistry 691 (2006) 463–469
13C NMR (100 MHz) d (DMSO): 172.8, 170.3, 136.6,
136.3, 130.5, 129.1, 127.7, 125.8, 84.7, 69.8, 69.6, 68.5,
68.4, 60.9 (-ve DEPT), 51.0, 39.5 (-ve DEPT), 24.6, 23.3,
21.4, 14.4.
4.3.6. N-{ortho-(ferrocenyl)-benzoyl}-4-amino butyric acid
ethyl ester 8
4-Amino butyric acid ethyl ester hydrochloride (0.3 g,
1.8 mmol) was used. Recrystallization from diethyl ether
yielded the title compound as a brown solid (0.42 g, 62%).
m.p. 62–63 ꢁC, E00 = 108 mV.
4.3.4. N-{ortho-(ferrocenyl)benzoyl}-L-phenylalanine ethyl
ester 6
Mass spectrum: found: [M]+Å 419.108.
L-Phenylalanine ethyl ester hydrochloride (0.3 g,
1.3 mmol) was used. Recrystallization from petroleum
ether (40–60 ꢁC): ethyl acetate yielded the title compound
as red needles. The crystals were of sufficient quality for
an X-ray diffraction study. (0.43 g, 68%).
C23H25N1O3Fe requires: 419.118.
IR mmax (KBr): 3389, 3086, 2925, 1752, 1647, 1542, 1406,
1196 cmꢀ1
.
UV–Vis kmax MeCN: 325 (e 1640), 445 (e 280) nm.
1H NMR (400 MHz)
(CDCl3): 7.78 (1H, d,
d
20
m.p. 110–112 ꢁC, E00 = 95 mV, ½aꢁD ¼ ꢀ6ꢂ (c = 2, CH2-
J = 7.6 Hz, ArH), 7.38–7.41 (2H, m, ArH), 7.25–7.28
(1H, m, ArH), 5.51 (1H, br.s, –CONH–), 4.53 {2H, s, ortho
on (g5-C5H4)}, 4.29 {2H, s, meta on (g5-C5H4)}, 4.06–4.10
{7H, m, –OCH2CH3, (g5-C5H5)}, 3.28 (2H, q, J =
6.4 Hz, –NHCH2CH2CH2–), 2.20 (2H, t, J = 7.2 Hz,
–NHCH2CH2CH2–), 1.70–174 (2H, m, –NHCH2CH2-
CH2–), 1.24 (3H, t, J = 7.6 Hz, –OCH2CH3).
Cl2).
Analysis: found: C, 69.67; H, 5.63; N, 2.96.
C28H27N1O3Fe requires: C, 69.86; H, 5.65; N, 2.91.
Mass spectrum: found: [M]+Å 481.1345.
C28H27N1O3Fe requires: 481.1340.
IR mmax (KBr): 2929, 1728, 1656, 1531 cmꢀ1
.
UV–Vis kmax CH2Cl2: 336 (e 5750), 448 (e 1440) nm.
1H NMR (400 MHz) d (DMSO): 8.75 (1H, d, J = 8 Hz,
–CONH–), 7.66 (1H, d, J = 7.2 Hz, ArH), 7.20–7.31 (6H,
m, ArH), 7.16 (1H, t, J = 7.2 Hz, ArH), 6.88 (1H, d,
J = 7.2 Hz, ArH), 4.54–4.60 {1H, m, –CH(CH2Ph)}, 4.49
{1H, s, ortho on (g5-C5H4)}, 4.03–4.10 {5H, m, meta on
(g5-C5H4), ortho on (g5-C5H4) and –OCH2CH3}, 3.76
{5H, s, (g5-C5H5)}, 2.83–2.89 {2H, m, –CH(CH2Ph)},
0.99 (3H, t, J = 7.2 Hz, –OCH2CH3).
13C NMR (100 MHz) d (CDCl3): 173.6, 170.9, 136.5,
136.3, 131.2, 129.7, 128.2, 126.7, 85.7, 70.2, 69.8, 69.0,
60.9 (-ve DEPT), 39.6 (-ve DEPT), 32.0 (-ve DEPT), 24.6
(-ve DEPT), 14.6.
4.3.7. N-{ortho-(ferrocenyl)-benzoyl} ( )-2-amino butyric
acid ethyl ester 9
( )-2-Amino butyric acid ethyl ester hydrochloride
(0.3 g, 1.8 mmol) was used. Recrystallization from diethyl
ether furnished the title compound as orange needles
(0.37 g, 55%).
13C NMR (100 MHz) d (DMSO): 171.9, 169.9, 137.9,
136.8, 136.1, 130.4, 129.5, 129.1, 128.6, 127.5, 126.9,
125.7, 84.4, 69.8, 69.0, 68.7, 68.5, 61.1 (-ve DEPT), 54.0,
31.1 (-ve DEPT), 14.4.
m.p. 67–69 ꢁC, E00 = 111 mV.
Mass spectrum: found: [M]+Å 419.107.
C23H25N1O3Fe requires: 419.118.
IR mmax (KBr): 3260, 2980, 1742, 1636, 1541, 1196,
4.3.5. N-{ortho-(ferroceny)l-benzoyl}-b-alanine ethyl
ester 7
1153 cmꢀ1
.
UV–Vis kmax MeCN: 323 (e 1590), 444 (e 360) nm.
1H NMR (400 MHz) d (CDCl3): 7.72 (1H, d, J = 8 Hz,
ArH), 7.31–7.35 (2H, m, ArH), 7.19 (1H, d, J = 8 Hz,
ArH), 5.86 (1H, d, J = 7.6 Hz, –CONH–), 4.46–4.55 {3H,
m, ortho on (g5-C5H4), –CH(CH2CH3)], 4.19 {2H, s, meta
on (g5-C5H4)}, 4.07 (2H, q, J = 7.2 Hz, –OCH2CH3), 3.96
{5H, s, (g5-C5H5)}, 1.68–1.73 {1H, m, –CH(CH2CH3)},
1.59–1.64 {1H, m, –CH(CH2CH3)}, 1.17 (3H, t,
J = 7.2 Hz, –OCH2CH3), 0.69 {3H, t, J = 7.2 Hz,
–CH(CH2CH3)}.
b-Alanine ethyl ester hydrochloride (0.3 g, 2.0 mmol)
was used. Recrystallization from petroleum ether (40–
60 ꢁC): ethyl acetate yielded the title compound as an or-
ange solid (0.39 g, 59%). E00 = 107 mV.
Analysis: found: C, 64.95; H, 5.96; N, 3.53.
C22H23N1O3Fe requires: C, 65.20; H, 5.72; N, 3.46.
Mass spectrum: found: [M]+Å 405.104.
C22H23N1O3Fe requires: 405.103.
IR mmax (KBr): 2932, 1735, 1670, 1520 cmꢀ1
.
UV–Vis kmax MeCN: 319 (e 1590), 446 (e 350) nm.
13C NMR (100 MHz) d (CDCl3): 172.2, 170.3, 136.8,
136.1, 131.4, 129.8, 128.2, 126.6, 85.7, 70.2, 70.1, 69.6,
69.0, 69.0, 61.7 (-ve DEPT), 54.0, 25.8 (-ve DEPT), 14.6, 9.8.
1H NMR (400 MHz)
d
(CDCl3): 7.68 (1H, d,
J = 7.6 Hz, ArH), 7.29–7.33 (2H, m, ArH), 7.14–7.18
(1H, m, ArH), 5.80 (1H, t, J = 5.6 Hz, –CONH–), 4.42
{2H, t, J = 1.6 Hz, ortho on (g5-C5H4)}, 4.18 {2H, t,
J = 1.6 Hz, meta on (g5-C5H4)}, 3.94–4.04 {7H, m,
–OCH2CH3, (g5-C5H5)}, 3.43 (2H, q, J = 6.4 Hz,
–NHCH2CH2–), 2.37 (2H, t, J = 6.4 Hz, –NHCH2CH2–),
1.13 (3H, t, J = 7.2 Hz, –OCH2CH3).
4.4. Crystallographic footnotes for 6
Crystallographic data 6: chemical formula C28H27NO3-
Fe, red needles, molecular weight 481.36 g molꢀ1, crystal
size = 0.90 · 0.70 · 0.60 mm3, orthorhombic, space group
13C NMR (100 MHz) d (CDCl3): 172.6, 170.7, 136.5,
136.4, 131.2, 129.6, 128.1, 126.6, 85.7, 70.2, 69.7, 68.9,
61.0 (-ve DEPT), 35.3 (-ve DEPT), 34.0 (-ve DEPT),
14.6.
˚
P212121 (No. 19), unit cell dimensions a = 10.625(3) A
˚
˚
(a = 90ꢁ), b = 10.737(3) A (b = 90ꢁ), c = 19.966(5) A (c =
90ꢁ), V = 2277.9(9) A , Z = 4, density = 1.404 g cmꢀ3
,
3
˚

D. Savage et al. / Journal of Organometallic Chemistry 691 (2006) 463–469
469
l = 0.693 mmꢀ1, 39116 reflections collected in the range
2.04–28.29ꢁ, 5429 independent reflections, 406 parameters,
R factor = 0.028, wR2 = 0.067.
[10] H.-B. Kraatz, J. Lusztyk, G.D. Enright, Inorg. Chem. 36 (1997)
2400.
[11] P. Saweczko, H.-B. Kraatz, Coord. Chem. Rev. 192 (1999) 185.
[12] J.F. Gallagher, P.T.M. Kenny, M.J. Sheehy, Inorg. Chem. Commun.
2 (1999) 200.
[13] J.F. Gallagher, P.T.M. Kenny, M.J. Sheehy, Inorg. Chem. Commun.
2 (1999) 327.
5. Supplementary material
[14] H.-B. Kraatz, D.M. Leek, A. Houmam, G.D. Enright, J. Lusztyk,
D.D.M. Wayner, J. Organomet. Chem. 589 (1999) 38.
[15] T. Moriuchi, A. Nomoto, K. Yoshida, T. Hirao, J. Organomet.
Chem. 589 (1999) 50.
[16] O. Brosch, T. Weyhermuller, N. Metzler-Nolte, Eur. J. Inorg. Chem.
2 (2000) 323.
[17] A. Hess, J. Sehnert, T. Weyhermuller, N. Metzler-Nolte, Inorg.
Chem. 39 (2000) 5437.
[18] Y.M. Xu, H.-B. Kraatz, Tetrahedron Lett. 42 (2001) 2601.
[19] T. Moriuchi, K. Yoshida, T. Hirao, Organometallics 20 (2001) 3101.
[20] T. Moriuchi, K. Yoshida, T. Hirao, J. Organomet. Chem. 637 (2001)
75.
Crystallographic data for the structural analysis have
been deposited with the Cambridge Crystallographic
Data Centre as supplementary publication number
275972 for 6. Copies of the data can be obtained free
of charge from The Director, CCDC, 12 Union Road,
Cambridge, CB2 1EZ, UK [fax: +44 (0) 1223 336033
or e-mail: deposit@ccdc.cam.ac.uk].
Acknowledgments
[21] A. Wieckowska, R. Bilewicz, A. Misicka, M. Pietraszkiewicz, K.
Bajdor, L. Piela, Chem. Phys. Lett. 350 (2001) 447.
[22] H.-B. Kraatz, Y.M. Xu, P. Saweczko, J. Organomet. Chem. 637
(2001) 335.
[23] T. Moriuchi, A. Nomoto, K. Yoshida, A. Ogawa, T. Hirao, J. Am.
Chem. Soc. 123 (2001) 68.
[24] S. Maricic, U. Berg, T. Frejd, Tetrahedron 58 (2002) 3085.
[25] S. Maricic, T. Frejd, J. Org. Chem. 67 (2002) 7600.
[26] D.R. van Staveren, T. Weyhermuller, N. Metzler-Nolte, J. Chem.
Soc., Dalton Trans. (2003) 210.
D.S. thanks the Irish American Partnership and Dublin
City University for the funding of a studentship award
1999–2002. This research was partly supported by the Na-
tional Institute for Cellular Biotechnology under the Pro-
gramme for Research in Third Level Institutions (PRTLI,
round 3, 2001–2006).
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