Conformational analysis of heteroannularly substituted ferrocene oligoamides

Article abstract of DOI:10.1002/ejic.200601230

The main conformer of symmetrical conjugates of ferrocene-1,1′- dicarboxylic acid with natural amino acids - Fn(CO-AA_1-2-OMe) ₂ (type I, Fn = ferrocene-1,1′-diyl, AA = L-α-amino acid) - is supported by two hydrogen bonds between the peptide substituents. To compare intramolecular hydrogen bond patterns of type I conjugates with related asymmetrically substituted derivatives, type II (MeNHCO-Fn-CO-AA-OMe) and type III conjugates (MeNHCO-Fn-CO-AA-NHMe) were prepared in moderate-to-good yields in a few steps starting from 1′-(methoxycarbonyl)ferrocene-1-carboxylic acid by using the HOBt/EDC method (AA = Gly, Ala, Val). ¹H NMR spectroscopic variation ratio analysis suggests that an increase in the steric demand of the amino acid side chains favours conformations with hydrogen-bonded FnCONHMe groups. CD spectroscopy of chiral derivatives reveals that (P)-helical conformations predominate in solution. The experimental findings are in accordance with DFT calculations. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.

Full text of DOI:10.1002/ejic.200601230

FULL PAPER
DOI: 10.1002/ejic.200601230
Conformational Analysis of Heteroannularly Substituted Ferrocene
Oligoamides
Jasmina Lapic´,[a] Daniel Siebler,[b] Katja Heinze,*[b] and Vladimir Rapic´*[a]
Keywords: Conformation analysis / Density functional calculations / Hydrogen bonds / Metallocenes / Molecular modelling
The main conformer of symmetrical conjugates of ferrocene-
1,1Ј-dicarboxylic acid with natural amino acids – Fn(CO–
ylic acid by using the HOBt/EDC method (AA = Gly, Ala,
Val). H NMR spectroscopic variation ratio analysis suggests
1
AA1–2–OMe)2 (type I, Fn = ferrocene-1,1Ј-diyl, AA =
L-α-
that an increase in the steric demand of the amino acid side
amino acid) – is supported by two hydrogen bonds between chains favours conformations with hydrogen-bonded
the peptide substituents. To compare intramolecular hydro- FnCONHMe groups. CD spectroscopy of chiral derivatives
gen bond patterns of type I conjugates with related asymmet-
rically substituted derivatives, type II (MeNHCO–Fn–CO–
AA–OMe) and type III conjugates (MeNHCO–Fn–CO–AA–
NHMe) were prepared in moderate-to-good yields in a few
steps starting from 1Ј-(methoxycarbonyl)ferrocene-1-carbox-
reveals that (P)-helical conformations predominate in solu-
tion. The experimental findings are in accordance with DFT
calculations.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
Introduction
Symmetrically substituted bioconjugates of ferrocene-
1,1Ј-dicarboxylic acid Ϫ Fn(CO–AAn–OMe)2 (Fn = ferro-
cene-1,1Ј-diyl, AA = -α-amino acid, n = 1–2) (type I con-
jugates) Ϫ have been extensively studied, especially with the
focus on applications as turn mimetica. Depending on the
amino acid employed, these molecules adopt different con-
formations, A, B or C in the solid state, as well as in solu-
tion (Scheme 1).
In the solid state, the majority of type I conjugates form
two intramolecular hydrogen bonds, which results in two
10-membered rings (conformation A, β-turn, “Herrick con-
formation”). If these intramolecular hydrogen bonds are
sufficiently strong, conformation A is even retained in chlo-
roform solution.[1–11] The bis(phenylalanine) derivative
Fn(CO–Phe–OMe)2 crystallises in asymmetrical form B
characterised by a single seven-membered intramolecular
hydrogen-bonded ring (γ-turn, “van Staveren conforma-
tion”), whereas conformation A presumably predominates
in solution.[12] The derivatives Fn(CO–AA–OMe)2 (AA =
Pro, Cys(Bzl), Val) provide examples of open “Xu confor-
mations” C in the solid state.[13–16] However, conformations
Scheme 1. Intramolecular hydrogen bond patterns in symmetrical
ferrocene peptides (type I) [X = OMe, –AA–OMe].
found in the solid state can be substantially different from
solution conformations as intermolecular hydrogen bonds
are usually additionally present in the solid state. Therefore,
with respect to chemical reactivity, the conformations
adopted in solution are of importance. A systematic de-
scription of the structural motifs and a suitable nomencla-
ture of 1,1Ј-disubstituted ferrocenes has been recently put
forward.[17]
Having in mind the conformational characteristics of
type I conjugates, we aimed to investigate the hydrogen
bonding patterns of related asymmetrically substituted de-
rivatives of ferrocene-1,1Ј-dicarboxylic acid belonging to
[a] Department of Chemistry and Biochemistry, Faculty of Food
Technology and Biotechnology,
Pierottijeva 6, 10000 Zagreb, Croatia
Fax: +385-4836-082
E-mail: vrapic@pbf.hr
[b] Department of Inorganic Chemistry, University of Heidelberg,
Im Neuenheimer Feld 270, 69120 Heidelberg, Germany
Fax: +49-6221-545707
E-mail: katja.heinze@urz.uni-heidelberg.de
Supporting information for this article is available on the
WWW under http://www.eurjic.org or from the author.
2014
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Conformational Analysis of Heteroannularly Substituted Ferrocene Oligoamides
FULL PAPER
type II (MeNHCO–Fn–CO–AA–OMe) and type III be considered as half of a “Herrick’s” motive (Scheme 1,
(MeNHCO–Fn–CO–AA–NHMe) (AA = Gly, -Ala, -Val) A). These patterns represent γ- and β-turn structures, and
to understand individual conformational preferences in it is expected that their relative population depends on the
solution with respect to the amino acid employed (i.e. the
size of their side chains). Here we describe the conforma-
tional analyses based on a combined experimental (NMR,
IR and CD spectroscopy) and theoretical approach (DFT
calculations).
Results and Discussion
Scheme 2 depicts three possible hydrogen bonded confor-
mations, D, E and F, with (P)-helical stereochemistry at the
ferrocene as well as an open form of type II conjugates. The
corresponding (M)-helical diastereomeric conformations
can be derived from the mirror images and by changing the
resulting -configuration of the amino acid to . Descriptor
“1-” denotes the amino acid containing the substituent and
descriptor “1Ј-” denotes the CONHMe part of the com-
pounds. Conformations D and E can be described by seven-
membered “van Staveren”-like intramolecular hydrogen
bonds (Scheme 1, B), whereas form F is stabilised by a 10-
membered intramolecular hydrogen bonded ring, which can amide esters (type II).
Scheme 2. Possible intramolecular hydrogen bond patterns in di-
Scheme 3. Possible intramolecular hydrogen bond patterns in triamides (type III).
Eur. J. Inorg. Chem. 2007, 2014–2024
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J. Lapic´, D. Siebler, K. Heinze, V. Rapic´
FULL PAPER
steric demand of the amino acid side chain (R). Conforma- tivation of acid 6 with HOBt/EDC (HOBt = 1-hydroxy-
tion E was recently observed in the solid state and in a benzotriazole, EDC = N-(3-dimethylaminopropyl)-NЈ-eth-
CDCl3 solution of 1Ј-(butylcarbamoyl)-N-morpholinofer- ylcarbodiimide hydrochloride) in CH2Cl2 solution, followed
rocene-1-carboxamide.[18]
by treatment with NH2Me (obtained from NH2Me·HCl
Intramolecular hydrogen bonding patterns possible in and NEt3) gave 45% of methyl 1Ј-(methylcarbamoyl)ferro-
type III conjugates are shown in Scheme 3. Three confor- cene-1-carboxylate (7). Amide ester 7 was hydrolysed with
mations are analogous to forms D, E and F of amide esters NaOH/H2O in MeOH to give 1Ј-(methylcarbamoyl)ferro-
and for clarity, they are denoted as DЈ, EЈ and FЈ. However, cene-1-carboxylic acid (8) (97% yield). Acid 8 was activated
owing to the additional 1-NHMe group, a further hydrogen by HOBt/EDC and coupled with Gly–OMe, -Ala–OMe,
bond between 1-NHMe and 1-CO in DЈ2, EЈ2 and FЈ or -Ala–OMe and -Val–OMe (obtained from AA–
between 1-NHMe and 1Ј-CO in DЈ3 is possible. In theore- OMe·HCl by treatment with NEt3), which resulted in the
tically possible conformation G, a 10-membered hydrogen formation of diamide esters 9 (42%), 10 (60%), 10a (54%)
bonded ring between 1Ј-CO and 1-NHMe occurs together and 11 (46%), respectively. Hydrolysis of diamide esters 9–
with an intrachain hydrogen bond between 1-NHMe and 11 gave MeNHCO–Fn–CO–AA–OH in good yields [12
1-CO. Thus, the conformational space of type III conju- (94%), 13 (81%) and 14 (94%)] which were subsequently
gates is considerably expanded relative to type II conju- transformed into triamides 15 (24%) 16 (56%) and 17
gates.
(20%), respectively, in a manner analogous to that de-
scribed for the preparation of 7. Unexpectedly, compounds
16 and 17 thus obtained had racemized during hydrolysis
as they displayed only a negligible Cotton effect (in contrast
to 10 and 11, Table 6). Therefore, 8 was directly coupled
with AA–NHMe (AA = Gly, -Ala, -Val) to give triamide
15 (45%), as well as optically pure triamides 16 (45%) and
17 (34%).
Type II and type III conjugates (9–11 and 15–17) were
fully characterised by multinuclear and two-dimensional
NMR spectroscopy, IR and CD spectroscopy, as well as by
high-resolution mass spectrometry (Tables 1, 4, 5 and 6).
Synthesis of Type II and Type III Conjugates
The syntheses of diamide esters 9–11 and triamides 15–
17 are depicted in Scheme 4. The starting compound, 1Ј-
(methoxycarbonyl)ferocene-1-carboxylic acid (6), was pre-
pared according to a previously described procedure.[30] Ac-
Spectroscopy of Type II and Type III Conjugates
Intramolecular hydrogen bonds found in the solid state
often undergo cleavage even in weakly coordinating sol-
vents (e.g. chloroform, dichloromethane) with competitive
formation of hydrogen-bond-free states and species with hy-
drogen bonded rings of different sizes. The conformational
equilibria are usually fast on the NMR timescale, which
results in time-averaged and population-weighted chemical
shifts, but in some cases, barriers are high enough to allow
the detection of individual conformers or conformer
groups.[19] On the faster IR timescale, however, absorptions
for NH and CO stretching vibrations are detected for each
conformer present in solution (unfortunately with severe
overlap, which often precludes detailed assignment).[20] In
chiroptical experiments (CD spectroscopy) the measured
signal represents the sum of signals for all species present
in solution.
To elucidate the conformational equilibria of 9–11 and
15–17 in solution and to probe the influence of the amino
acid side chain [R = H, CH3, CH(CH3)2], we used IR and
CD spectroscopy, NMR spectroscopy (solvent-dependent,
temperature-dependent) and DFT calculations (B3LYP,
LanL2DZ[19,21–24]).
IR spectra of 7, 9–11 and 15–17 were measured in
CH2Cl2 solution at different concentrations (Table 1). The
characteristic signals (NH, CO) were unchanged in the con-
centration range 0.5ϫ10–2 to 2.5ϫ10–2 , which confirms
Scheme 4. Synthesis of Fn(COOH)2-derived oligoamides. a) 1.
HOBt/EDC, CH2Cl2, 2. NH2Me·HCl, NEt3, CH2Cl2; b) NaOH/
H2O, MeOH; c) 1. HOBt/EDC, CH2Cl2, 2. -AA–OMe·HCl, NEt3,
CH2Cl2; d) NaOH/H2O, dioxane; e) 1. HOBt/EDC, CH2Cl2, 2. -
AA–NHMe·HCl, NEt3, CH2Cl2.
2016
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Conformational Analysis of Heteroannularly Substituted Ferrocene Oligoamides
FULL PAPER
that intermolecular interactions are absent under these con-
ditions. Signals for non-hydrogen-bonded NH groups as
well as hydrogen bonded NH groups are observed. For 7,
the low-energy COester absorption indicates a quite strong
hydrogen bond from 1Ј-NH to the ester carbonyl group,
which corresponds to the only possible hydrogen bonded
conformation E. Thus, 7 exists in solution as conformer E
in equilibrium with the open form.
Table 1. IR data [cm–1] for 7, 9–11 and 15–17 in CH2Cl2 (c =
10–2 ).
Figure 1. CD spectra of 10 and 10a in CH3CN.
νNH (free)
νNH (assoc.) νCO (ester)
νCO (amide I)
7
3462
3446, 3391
3451
3453, 3418
3449
3449
3373
3259
3271
3293
3341
3363, 3327
3342, 3326
1712
1742
1740
1736
–
–
–
1659
1650
1650
1665
1655
1653
1657
9
adjacent to ferrocene carbonyl (1-NH, 1Ј-NH) display NOE
cross peaks to two Cp protons, while 1-NHMe shows an
NOE contact to CHα.
10
11
15
16
17
3451
Chiral amide esters 10 and 11 display Cotton effects at
about 350 (300 nm), –275 (348 nm), –155 (411 nm), and
395°–1 cm–1 (470 nm) in acetonitrile. For chiral triamides
16 and 17, the following Cotton effects were observed: 825
(305 nm), –410 (352 nm), –230 (417 nm) and 470°–1 cm–1
(480 nm) (Experimental Section, Table 6). The spectra are
very similar to those of type I derivatives with “Herrick
conformations” (Scheme 1, A). A positive Cotton effect
around the ferrocene absorption (λmax ≈ 440 nm; Experi-
mental Section, Table 6) was previously interpreted as being
indicative of (P)-enantiomers of the helically ordered ferro-
Figure 2. Part of the NOESY spectrum of 16, which indicates NOE
contacts between NH protons and Cp-H and CHα (* denotes Cp-H).
To address the question as to which NH group preferen-
cenes.[9,17] However, the CD intensities of 10, 11, 16 and 17 tially participates in hydrogen bonds, NH chemical shifts
are one order of magnitude lower than those found for type were measured in different solvents [“variation ratio” (v.r.)
I (P)-helical “Herrick conformations” (Scheme 1, A; Mθ ≈ method][25] and at different temperatures (VT 1H NMR
5000°–1 cm–1) with two intramolecular hydrogen bonds spectroscopy). For interpretation of the observed δNH val-
between the -amino acid side arms. Thus, CD spec- ues, it has proven useful to compare them to those of stan-
troscopy of -amino acid derivatives suggests that (P)-heli- dard (reference) compounds. The standard compounds pos-
cal conformations are present in slight excess over (M)-heli- sess NH groups in a comparable chemical environment but
cal and open conformations, whereas (M)-helical conforma- without any intramolecular hydrogen bonds (non-hydro-
tions are slightly preferred for -Ala derivative 10a (Fig- gen-bonded reference state) in noncoordinating solvents
ure 1, Experimental Section, Table 6). As expected, CD (e.g. CDCl3). The fully hydrogen-bonded reference state is
spectra of amide esters 10 and 10a derived from - and - simulated by measuring the 1H NMR spectrum in the
Ala, respectively, are mirror images of each other (Fig- strongly coordinating solvent [D6]DMSO (Experimental
ure 1). Interestingly, the positive Cotton effects increase for Section, Tables 4 and 5).
amide esters 10 and 11 from 360 to 430°–1 cm–1 (470 nm)
Chemical shift variation from [D6]DMSO to CDCl3
as well as for triamides 16 and 17 from 410 to 530°–1 cm–1 (∆δNH) provides a measure of the extent to which an amide
(480 nm). This slight enhancement could be attributed to proton takes part in an intramolecular hydrogen bond. If
an increased amount of (P)-helical ferrocenes present in the shift variation of a particular NH proton is distinctly
solution, which results from an increase in the size of the smaller than that of the hydrogen-bond-free reference, the
amino acid side chain from R = CH3 to R = CH(CH3)2.
NH proton is considered to be intramolecularly hydrogen
To address the engagement of specific NH protons (1- bonded in CDCl3 solution. The variation ratio v.r. =
1
NH, 1Ј-NH, 1-NHMe) in hydrogen bonding by H NMR ∆δNH(substrate)/∆δNH(reference) describes the involvement
spectroscopy, all the NH proton signals have to be correctly of the considered proton in an intramolecular hydrogen
assigned. NOE spectroscopy allowed all NH proton signals bond. Small v.r. values indicate strong hydrogen bonds
to be distinguished as specific NOE cross peaks are ob- whereas larger v.r. values suggest weak hydrogen bonds.[25]
served to cyclopentadienyl protons and CHα of the amino We, and others, have previously synthesised a number of
acid as shown exemplarily for 16 in Figure 2. NH protons peptides derived from 1Ј-aminoferrocene-1-carboxylic acid
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1
Table 2. H NMR spectroscopic data for 7, 9–11, 15–17 and standard (reference) compounds (c = 5ϫ10–3 to 2ϫ10–4 ).[a]
δNH / ppm (CDCl3)[b]
δNH / ppm ([D6]DMSO)[b]
∆δ / ppm ([D6]DMSO/CDCl3) v.r. (standard)
–∆δ/T[c] / ppbK–1
1
2
3
4
5
7
5.43
6.08
6.02
5.90
5.73
6.10
7.71
8.25
8.23
8.08
7.73
7.75
2.37
2.17
2.21
2.18
2.00
1.65
0.83 (5)
9
10
11
6.72
6.88
7.03
7.39
7.03
6.63
7.73
7.75
7.66
8.40
8.24
7.88
1.01
0.87
0.63
1.01
1.21
1.25
0.51 (5) 0.47 (2)
0.44 (5) 0.55 (3)
0.32 (5) 0.57 (4)
7.0
16.0
8.4
7.0
[d]
15
16
17
6.89
7.08
7.20
7.15
6.77
6.52
6.86
6.71
6.55
7.98
7.97
7.88
8.17
7.88
7.65
7.85
7.91
8.01
1.09
0.89
0.68
1.02
1.11
1.13
0.99
1.20
1.46
0.55 (5) 0.47 (2) 0.42 (1) 6.1
0.45 (5) 0.50 (3) 0.51 (1) 18.9 7.9
0.34 (5) 0.52 (4) 0.62 (1) 11.8 2.6
0.4
8.9
11.5
10.9
[a] All values are given in the sequence 1Ј-NH, 1-NH and 1-NHMe. [b] δNH (CDCl3) and δNH ([D6]DMSO) for compounds 1–5 are taken
from refs.[25,26] [c] 1.0ϫ10–4  in CDCl3. [d] Sample precipitates under these conditions.
(Fca)[21,27] and natural amino acids.[19,24,26,28,29] In this con-
text, we have successfully employed the v.r. method in the
estimation of intramolecular hydrogen bond strengths and
conformer populations in Fca–AA conjugates.[24,26]
Suitable reference compounds for amide esters 9–11 are
Ac–AA–OEt (AA = Gly, Ala, Val; 2–4) for the amino acid
containing substituent in position 1- and N-methylferro-
cenecarboxamide Fc–CONHMe (5) for the 1Ј-NHMe part.
For the 1-NHMe moiety of triamides 15–17, N-methylacet-
amide (MeCONHMe, 1) is used as a reference compound.
As mentioned above, the reference compounds are unable
to engage in intramolecular hydrogen bonds and exhibit
chemical shifts of the amide protons at positions well below
δ = 7 ppm in CDCl3. In [D6]DMSO solution, the signals
Figure 3. Part of the 1H NMR spectra of 9 in CDCl3 (top) and
[D6]DMSO (bottom) (* denotes Cp-H).
are shifted to lower field (δ ≈ 8 ppm), which indicates inter-
molecular hydrogen bonds to the solvent (∆δNH Ն2.0 ppm,
Table 2).
To exemplify this approach, v.r. calculations for ester
amide 9 will be described. In CDCl3 solution, compound 9
In the sequence 9, 10, 11, a monotonous lowering of v.r.
exhibits amide resonances at δ = 6.72 ppm for 1Ј-NH and values of the 1Ј-NH protons occurred (0.51 Ͼ 0.44 Ͼ 0.32),
δ = 7.39 ppm for 1-NH groups (unambiguously assigned by which indicates an enrichment of conformations E and/or F
NOESY experiments and coupling patterns). In [D6]- displaying 1Ј-NH···O bonds. Concomitantly, conformations
DMSO, the corresponding resonances appear at δ = with 1-NH···O bonds (D) are less populated (v.r. values:
7.73 ppm and δ = 8.40 ppm (Figure 3). The difference in 0.47 Ͻ 0.55 Ͻ 0.57). Similar to amide esters 9–11, in the
the chemical shifts of the two amide protons in the two order 15, 16, 17, v.r. values for 1Ј-NH protons decrease
solvents is ∆δ = 1.01 ppm for both protons. A suitable stan- (0.55 Ͼ 0.45 Ͼ 0.34) and increase for 1-NH protons (0.47
dard (reference) for 1Ј-NH is FcCONHMe (5) with ∆δ = Ͻ 0.50 Ͻ 0.52). 1-NHMe protons show increasing v.r. val-
2.00 ppm, and for 1-NH Ac–Gly–OEt (2) with ∆δ = ues (0.34 Ͻ 0.52 Ͻ 0.62). Once again, these findings indi-
2.17 ppm was chosen. Thus, v.r. (1Ј-NH) = 0.51 and v.r. (1- cate enrichment of EЈ and/or FЈ forms at the expense of
NH) = 0.47 can be calculated for 9, and these values indi- conformers DЈ and G (Scheme 3).
cate medium–strong hydrogen bonds for both protons. This
Additionally, variable temperature NMR experiments
finding can only be explained by the presence of several were undertaken in CDCl3 solution (Figure 4). However,
conformations which are in equilibrium in solution. As only valine derivative 11 visibly precipitates upon cooling (pre-
conformer D possesses a hydrogen bonded 1-NH group, sumably by association through intermolecular hydrogen
this species is surely present in solution, whereas the v.r. bonds). For 9 and 16, the large temperature shifts ∆δ/T of
data do not discriminate between conformations E and F NH protons are indicative of beginning intermolecular hy-
as both possess 1Ј-NH involved in hydrogen bonds drogen bonding upon cooling (Table 2). Thus, temperature
(Scheme 2).
shifts ∆δ/T of 9, 16 and 17 are clearly not interpretable in
2018
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Conformational Analysis of Heteroannularly Substituted Ferrocene Oligoamides
FULL PAPER
terms of intramolecular hydrogen bonding. Thus, for 10 (B3LYP, LanL2DZ) in different conformations, that is, with
and 15, it should also be considered that intermolecular respect to hydrogen bonding patterns (D, E, F, open, DЈ,
interactions (especially through 1Ј-NH and 1-NHMe) are EЈ, FЈ, GЈ and openЈ) and ferrocene helicity (P, M) (Table 3,
highly probable at lower temperatures.
Figures 5 and 6). In all cases, the open form is calculated
to be higher in energy by 13–19 kJmol–1 relative to the cal-
culated minimum geometry. Type II compounds 9–11 with
two hydrogen-donors and three hydrogen-acceptors will be
discussed before type III conjugates 15–17 with three do-
nors and three acceptors are addressed.
Figure 5. DFT-calculated (P)-helical minimum structures of 10.
For glycine derivative 9, all conformations D, E and F
are local minima with marginal energy differences, which
confirms that no conformation is especially preferred over
the others and also substantiates conclusion (2) above. In
sterically more demanding conjugates 10 and 11, conforma-
tions D(M) and F(M) are destabilised by the larger substit-
uent R (Figure 7). Thus, less (M)-helical ferrocenes equal-
ling more (P)-helical conformers are present in the ensem-
ble in accordance with conclusion (1) above. According to
the calculations, the ensemble is enriched in E conformers
as D(M) and F(M) are energetically unfavourable for 10
and 11. Conformers E exhibit 1Ј-NH···O hydrogen bonds,
which accounts for conclusion (3). Additionally, F(P) be-
comes the most stable conformation for 11, which also
shows 1Ј-NH···O hydrogen bonds and furthermore explains
the lower C=Oester stretching vibration frequency of 11 rela-
tive to that of 9 (Table 1).
Type III conjugates show a more complicated behaviour
as the number of possible conformations with hydrogen
bonds has doubled relative to type II compounds. No stable
minimum structure could be obtained for the G conforma-
tion shown in Scheme 3 as the 1-NHMe···1Ј-CO hydrogen
bond is disrupted, which leaves only the intrachain hydro-
gen bond between 1-NHMe and 1-CO. This conformation
is almost as high in energy as the open form and rules out
a significant contribution (Table 3). Glycine conjugate 15
1
Figure 4. Partial VT H NMR spectra of 17 in CDCl3 (top) and δ
versus T plot of the amide protons.
The combined experimental data can be summarised as
follows: (1) chiral -amino acid conjugates form predomi-
nantly (P)-helical conformations in solution for both type
II and III conjugates, (2) all NH protons are involved in
intramolecular hydrogen bonding in the ensemble, (3) ac-
cording to NH v.r. values for types II and III, increasing
the steric bulk of the amino acid side chain (R) results in a
larger fraction of conformers with 1Ј-NH···O hydrogen
bonds and a smaller fraction of conformers with 1-NH···O
hydrogen bonds, (4) for type III conjugates, an increase in
the steric bulk of the amino acid side chain (R) leads to a
depletion of conformers with 1-NHMe···O hydrogen bonds
in the ensemble.
DFT Calculations
To gain deeper insight into the possible conformations, shows no conformational preference as does its type II
the geometries of compounds 9–11 and 15–17 were op- counterpart 9, that is, all conformations DЈ1, DЈ2, DЈ3, EЈ1,
timised by DFT calculations without symmetry constraints EЈ2 and FЈ with (P) and (M) helical ferrocenes are present
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J. Lapic´, D. Siebler, K. Heinze, V. Rapic´
Table 3. DFT calculated relative energies and (N)H···O distances of hydrogen bonds of conformers for 9–11 and 15–17.
FULL PAPER
Erel / kJmol–1
(N)H···O / Å (interchain)
(N)H···O / Å (intrachain)
9D
9E
0.6
0.0
1.87
1.93
–
–
9F
9-open
3.9
13.4
2.00
–
–
–
10D(P;M)
10E(P;M)
10F(P;M)
10-open
11D(P;M)
11E(P;M)
11F(P;M)
11-open
0.0; 12.0
0.4; 0.7
3.7; 17.2
13.6
7.8; 25.6
1.7; 2.4
0.0; 25.5
15.0
1.89; 1.87
1.93; 1.93
1.99; 1.97
–
1.96; 1.87
1.93; 1.93
2.00; 2.16
–
–; –
–; –
–; –
–
–
–; –
–; –
–
15DЈ1
15DЈ2
7.3
0.0
1.86
1.85
–
1.93
15DЈ3
15EЈ1
9.1
1.9
2.17, 1.90
1.91
–
–
15EЈ2
15FЈ
5.5
7.0
1.97
1.99
2.03
(2.45)
15G
15openЈ
16.2
17.1
–
–
1.97
–
16DЈ1(P;M)
16DЈ2(P;M)
16DЈ3(P;M)
16EЈ1(P;M)
16EЈ2(P;M)
16FЈ(P;M)
16G(P;M)
16openЈ
17DЈ1(P;M)
17DЈ2(P;M)
17DЈ3(P;M)
17EЈ1(P;M)
17EЈ2(P;M)
17FЈ(P;M)
17G(P;M)
17openЈ
–; –
–; –
–; – (both converged to 16DЈ2)
1.94; 1.84
–
–
2.03; 1.90
(2.60); (3.06)
2.01; 1.92
0.0; 8.7
10.6; 13.1
6.6; 6.4
1.7; 18.5
5.9; 18.9
14.4; 30.9
16.7
13.5; –
0.0; 5.0
12.7; 15.7
7.6; 6.3
3.4; 12.4
2.9; 14.7
17.0; 44.6
19.4
1.87; 1.85
2.16, 1.92; 1.96, 1.94
1.92; 1.92
1.94; 1.96
1.98; 1.93
–; –
–
–
1.99; –
–; – (the latter converged to 17DЈ2(M)
1.86; 1.85
2.13, 1.92; 1.97, 1.93
1.93; 1.92
1.95; 1.96
1.97; 2.05
–; –
2.00; 1.84
–
–; –
2.10; 1.91
(2.48); 2.06
1.89; 1.89
–
–
Figure 6. DFT-calculated (P)-helical minimum structures of 15.
in the ensemble (Figure 7). An increase in the size of R in ensemble, conformers DЈ2(P), DЈ2(M), EЈ1(P), EЈ1(M),
the -amino acid destabilises conformations DЈ1(P), EЈ2(P) and FЈ(P) are still present, which results in an excess
DЈ1(M), DЈ3(P), DЈ3(M), EЈ2(M) and FЈ(M). Thus, in the of (P)-helical ferrocenes for 16 and 17 and corroborates
2020
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Eur. J. Inorg. Chem. 2007, 2014–2024

Conformational Analysis of Heteroannularly Substituted Ferrocene Oligoamides
FULL PAPER
in the CD spectra. Furthermore, large amino acid side
chains favour conformations with 1Ј-NH···O hydrogen
bonds (conformations E/EЈ and F/FЈ) as shown by NMR
spectroscopic techniques (v.r. method) and DFT calcula-
tions.
A single hydrogen bond spanning the 1- and 1Ј-substitu-
ents already provides an explanation for the preference of
(P)-helical ferrocenes in asymmetrical type II and III conju-
gates with one -amino acid attached. This effect is even
more pronounced in symmetrically substituted type I conju-
gates with two -amino acids and two hydrogen bonds be-
tween the ferrocene substituents. For Fn(CO–Ala–OMe)2,
the energy difference between (P)- and (M)-“Herrick” con-
formers was calculated as 17.3 kJmol–1 by DFT meth-
ods.[22] However, in these systems, an increase in the number
of -amino acids has no further stabilising effect.
On the basis of the results obtained in this study, it is
expected that an increase in the size of the amino acid side
chains adjacent to the ferrocene carbonyl might be a means
to further stabilise chiral secondary structures, for example,
turn motifs.
Experimental Section
Figure 7. Relative energies of conformations of type II conjugates
9–11 (top) and of conformations of type III conjugates 15–17 (bot-
tom) [for 16DЈ1(P), 16DЈ1(M) and 17DЈ1(M), the relative energy
must be arbitrarily set to 20 kJmol–1; the dotted lines at 10 kJmol–1
are a guide for the eye].
General: The syntheses were carried out under an atmosphere of
argon. CH2Cl2 that was used for syntheses and FTIR spectroscopy
was dried (P2O5), distilled from CaH2 and stored over molecular
sieves (4 Å). EDC, HOBt (Aldrich) and amino acid esters and
amides (Merck) were used as received. NMR spectroscopic data
for compounds 1–5 were taken from refs.[25,26]. Products were puri-
fied by preparative thin layer chromatography on silica gel (Merck,
Kieselgel 60 HF254) by using CH2Cl2/EtOAc or CH2Cl2/MeOH.
Melting points were determined with a Buechi apparatus. IR spec-
tra were recorded as CH2Cl2 solutions with a Bomem MB 100 mid
FTIR spectrophotometer. 1H- and 13C{1H}-NMR spectra were re-
corded with a Varian EM 360 or Varian Gemini 300 spectrometer
in CDCl3 and [D6]DMSO solutions with Me4Si as the internal
standard or with a Varian Unity Plus 400 spectrometer. ESI mass
spectra were recorded with a Finnigan TSQ 700 spectrometer. High
resolution FAB mass spectra were recorded with a JEOL JMS-700.
CD spectra were recorded as CH3CN solutions with CD spectro-
photometer Jasco-810. 1Ј-(Methoxycarbonyl)ferrocene-1-carbox-
ylic acid (6) was prepared according to a literature procedure.[30]
conclusion (1) above. Analogously to type II conjugates, the
ensembles of 16 and 17 contain more E conformers relative
to the ensemble of glycine derivative 15. This confirms con-
clusion (3), which states that a larger fraction of conformers
with 1Ј-NH···O hydrogen bonds exists for derivatives with
larger R substituents. As for type II derivatives, FЈ(P) con-
formations (with 1Ј-NH···O hydrogen bonds) are increas-
ingly stabilised by larger R side chains.
Interchain 1-NHMe hydrogen bonds are only present in
conformations DЈ3 and G (Scheme 3), which are quite high
in energy. Thus, 1-NHMe hydrogen bonds are mainly intra-
chain in nature and occur in conformations DЈ2, EЈ2 and
17FЈ(M) (Table 3). As EЈ2(M) and FЈ(M) are destabilised
for 16 and 17, the number of conformations with 1-NHMe
hydrogen bonds is reduced relative to the ensemble of 15.
This accounts for the observed weakening of 1-NHMe hy-
drogen bonds [conclusion (4) above].
Computational Method: Density functional calculations were car-
ried out with the Gaussian03/DFT[31] series of programs. The
B3LYP formulation of density functional theory was used by em-
ploying the LanL2DZ basis set.[31] All points were characterised as
minima (Nimag = 0) by frequency analysis.
Methyl 1Ј-(methylcarbamoyl)ferrocene-1-carboxylate (7): EDC
(1.7 g, 9.1 mmol) and HOBt (1.2 g, 9.1 mmol) were added to a sus-
pension of 1Ј-(methoxycarbonyl)ferrocene-1-carboxylic acid (6; 2 g,
7 mmol) in dry dichloromethane (20 mL), and the solution was
stirred for 1 h at room temp. MeNH2·HCl (682.5 mg, 10.5 mmol)
was suspended in dichloromethane (5 mL) at 0 °C and dissolved by
the addition of dry NEt3 until ca. pH 8. This solution was added
to the solution of activated 6. After stirring for 1 h at room temp.,
the reaction mixture was washed with saturated aqueous NaHCO3
and water. The organic layer was dried with Na2SO4 and evapo-
rated in vacuo. TLC purification of the crude product with CH2Cl2/
Conclusions
It was shown that ferrocene-1,1Ј-dicarboxylic acid conju-
gates of types II and III form an ensemble of conformations
in weakly coordinating solvents without a preference for
one specific conformer. However, an increase in the steric
demand of the -amino acid side chain reduces the number
of conformations [especially with respect to (M)-helical fer-
rocenes] in solution, which provides an explanation for the
observed positive Cotton effect at the ferrocene absorption EtOAc (10:1) gave 900 mg (45%) of orange crystals. M.p. 135–
Eur. J. Inorg. Chem. 2007, 2014–2024
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjic.org
2021

J. Lapic´, D. Siebler, K. Heinze, V. Rapic´
FULL PAPER
137 °C. 1H NMR (300 MHz, CDCl3): δ = 6.16 (br. s, 1 H, NH),
40.85 (s, CH2Gly), 26.07 (s, NHCH ) ppm. IR (CH Cl ): ν = 3446
˜
3 2 2
4.77 (pt, 2 H, H2,5), 4.59 (pt, 2 H, H2Ј,5Ј), 4.46 (pt, 2 H, H3,4), 4.37 (m, NH, free), 3259 (w, NH, assoc.), 1742 (s, COester) 1650 (s, amide
3
(pt, 2 H, H3Ј,4Ј), 3.85 (s, 3 H, COOCH3), 2.98 (d, JHH = 4.9 Hz, 3
I), 1609 (m), 1535 (s, amide II) cm–1. IR (KBr): ν = 3401 (s, NH,
˜
H,
NHCH3)
ppm.
1H
NMR
(300 MHz,
[D6]- free), 3273 (s, NH, assoc.), 1737 (s, COester), 1634 (s, amide I), 1540
DMSO): δ = 7.75 (br. q, 1 H, NH), 4.80 (s, 2 H, H2,5), 4.71 (s, 2
(s, amide II) cm–1. MS (ESI+, CH3CN): m/z (%) = 359.3 (100) [M
H, H2Ј,5Ј), 4.44 (s, 2 H, H3,4), 4.36 (s, 2 H, H3Ј,4Ј), 3.71 (s, 3 H, + H]+, 381.3 (7) [M + Na]+, 397.2 (5) [M + K]+, 717.3 (14) [2M +
COOCH3), 2.32 (d, 3JHH = 4.5 Hz, 3 H, NHCH3) ppm. 13C NMR,
APT (75 MHz, CDCl3): δ = 172.0 (s, COOCH3), 169.72 (s, C=O),
H]+, 739.3 (4) [2M + Na]+, 755.3 (2) [2M + K]+. HRMS (FAB):
calcd. for C16H18FeN2O4 358.0616; found 358.0619. 10 (AA = -
78.66 (s, C1Ј), 71.99 (s, C1), 72.64 (s, C2,5), 71.84 (s, C2Ј,5Ј), 71.31 (s, Ala): Yield: 157 mg (61%), orange resin. 13C NMR, APT (75 MHz,
C3,4), 70.06 (s, C3Ј,4Ј), 51.96 (s, OCH3), 26.55 (s, NHCH3) ppm. IR
CDCl3): δ = 174.25 (s, COOCH3), 170.82 (s, CONHCH3), 170.39
(CH Cl ): ν = 3462 (s, NH, free), 3373 (vw, NH, assoc.), 1712 (s, (s, C=O), 78.54 (s, C1Ј), 76.75 (s, C1), 71.37 (s, C2), 71.32 (s, C5),
˜
2
2
COester), 1659 (s, amide I) 1606 (m), 1530 (s, amide II) cm–1.
71.28 (s, C2Ј), 71.26 (s, C5Ј), 70.89 (s, C3), 70.83 (s, C4), 70.77 (s,
C3Ј), 70.09 (s, C4Ј), 52.57 (s, OCH3), 48.39 (s, CHAla), 26.58 (s,
1Ј-(Methylcarbamoyl)ferrocene-1-carboxylic acid (8): A solution of
NaOH (140 mg, 3.5 mmol) in water (5 mL) was added to a solution
of amide ester 7 (900 mg, 3 mmol) in methanol (20 mL). After heat-
ing to 80 °C for 50 min, the reaction mixture was extracted with
CH2Cl2. The alkaline aqueous layer was treated with conc. HCl
(pH = 1–2), extracted with EtOAc and washed with water. The
organic layer was dried with Na2SO4 and evaporated in vacuo to
afford 840 mg (97%) of orange crystals. M.p. 146–149 °C. IR
NHCH3), 17.71 (s, CH3Ala) ppm. IR (CH Cl ): ν = 3451 (m, NH,
˜
2
2
free), 3271 (w, NH, assoc.), 1740 (s, COester), 1650 (s, amide I), 1534
(s, amide II) cm–1. MS (ESI+, CH3CN): m/z (%) = 373.3 (100) [M
+ H]+, 395.3 (18) [M + Na]+, 411.3 (21) [M + K]+, 745.3 (8) [2M
+ H]+, 767.3 (14) [2M + Na]+, 783.2 (6) [2M + K]+. HRMS (FAB):
calcd. for C17H20FeN2O4 372.0773; found 372.0766. 10a (AA =
-Ala): Yield: 54%, orange resin. NMR and IR spectra of 10a were
similar to those of 10. 11 (AA = -Val): Yield: 130 mg (46%),
orange resin. 13C NMR, APT (75 MHz, CDCl3): δ = 173.28 (s,
COOCH3), 170.72 (s, CONHCH3), 170.57 (s, C=O), 78.69 (s, C1Ј),
76.81 (s, C1), 71.51 (s, C2), 71.38 (s, C2Ј,5), 71.12 (s, C3,5Ј), 70.83 (s,
C4), 70.25 (s, C3Ј), 70.07 (s, C4Ј), 57.53 (s, CHαVal), 52.34 (s, OCH3),
30.73 (s, CHβVal), 26.55 (s, NHCH3), 19.20 (s, CH3Val), 18.19 (s,
(KBr): ν = 3334 (s, NH), 3089 (s, OH), 1676 (s, COacid), 1637 (s,
˜
amide I), 1550 (s, amide II) cm–1.
MeNHCO–Fn–CO–AA–OMe (9–11): Compound
8 (200 mg,
0.7 mmol) was activated by using EDC/HOBt (as described for the
preparation of 7). The solution was cooled to 0 °C and AA–OMe
(obtained from AA–OMe·HCl by treatment with NEt3 in CH2Cl2,
pH ca. 8) was added. The reaction mixture was stirred for 1 h at
room temp., washed thrice with a saturated aqueous solution of
NaHCO3, 10% aqueous solution of citric acid, and H2O. After
drying over Na2SO4 and evaporating in vacuo, the crude products
were TLC-purified with EtOAc as eluent. 9 (AA = Gly): Yield:
110 mg (42%), orange crystals. M.p. 149–152 °C. 13C NMR, APT
(75 MHz, CDCl3): δ = 170.49 (s, CONHCH3), 170.48 (s, CO-
OCH3), 170.44 (s, C=O), 78.07 (s, C1Ј), 76.62 (s, C1), 70.69 (s, C2,5),
70.59 (s, C2Ј,5Ј), 70.40 (s, C3,4), 70.29 (s, C3Ј,4Ј), 51.85 (s, OCH3),
CH3Val) ppm. IR (CH Cl ): ν = 3453, 3418 (m, NH, free), 3293 (w,
˜
2
2
NH, assoc.), 1736 (s, COester), 1665 (s, amide I), 1520 (s, amide II)
cm–1. MS (ESI+, CH3CN): m/z (%) = 401.3 (100) [M + H]+, 423.3
(28) [M + Na]+, 439.3 (18) [M + K]+, 801.4 (5) [2M + H]+, 823.3
(17) [2M + Na]+, 839.2 (7) [2M + K]+. HRMS (FAB): calcd. for
C19H24FeN2O4 400.1085; found 400.1073.
MeNHCO–Fn–CO–AA–OH (12–14): MeNHCO–Fn–CO–AA–
OMe (9–11, 0.3 mmol) was dissolved in a mixture of dioxane
(10 mL) and water (10 mL). After cooling to 10 °C and the ad-
1
Table 4. H NMR chemical shifts for 9–11 and 15–17 in CDCl3.
9
10
11
15
16
17
1-NH
7.39 (1 H, br. t)
7.03 (d, 1 H, J =
7.0 Hz)
6.63 (d, 1 H, J =
8.4 Hz)
7.15 (1 H, br. t)
6.77 (d, 1 H, J =
6.8 Hz)
6.52 (1 H, br. d, J =
7.9 Hz)
1Ј-NH
1-NHCH3
CHα
6.72 (1 H, br. q)
–
4.13 (d, 2 H, J =
5.8 Hz)
6.88 (1 H, br. q)
–
4.62 (m, 1 H)
7.03 (1 H, br. q)
–
4.61 (m, 1 H)
6.89 (1 H, br. q)
6.86 (1 H, br. q)
4.03 (d, 2 H, J =
5.8 Hz)
7.08 (1 H, br. q)
6.71 (1 H, br. q)
4.55 (m, 1 H)
7.20 (1 H, br. q)
6.55 (1 H, br. q)
4.32 (m, 1 H)
Cp-H
4.69 (2 H, pt)
4.53 (2 H, pt)
4.38 (4 H, pt)
4.73 (1 H, pt)
4.63 (1 H, pt)
4.58 (1 H, pt)
4.44 (1 H, pt)
4.39 (m, 2 H)
4.36 (1 H, pt)
4.33 (1 H, pt)
4.62 (1 H, pt)
4.60 (m, 2 H)
4.43 (1 H, pt)
4.41 (1 H, pt)
4.38 (1 H, pt)
4.36 (1 H, pt)
4.32 (1 H, pt)
4.64 (2 H, pt)
4.59 (2 H, pt)
4.40 (2 H, pt)
4.37 (2 H, pt)
4.68 (1 H, pt)
4.65 (1 H, pt)
4.57 (1 H, pt)
4.44 (1 H, pt)
4.42 (1 H, pt)
4.39 (1 H, pt)
4.36 (1 H, pt)
4.32 (1 H, pt)
2.95 (d, 3 H, J =
4.7 Hz)
4.69 (m, 2 H)
4.51 (1 H, pt)
4.48 (1 H, pt)
4.41 (1 H, pt)
4.36 (1 H, pt)
4.35 (1 H, pt)
4.31 (1 H, pt)
1Ј-NHCH3 2.91 (d, 3 H, J =
2.91 (d, 3 H, J =
4.8 Hz)
2.95 (d, 3 H, J =
4.7 Hz)
2.90 (d, 3 H, J =
4.7 Hz)
2.94 (d, 3 H, J =
4.7 Hz)
4.8 Hz)
OCH3/
3.78 (s, 3 H)
3.78 (s, 3 H)
3.82 (s, 3 H)
2.86 (d, 3 H, J =
4.7 Hz)
2.87 (d, 3 H, J =
4.7 Hz)
2.87 (d, 3 H, J =
4.7 Hz)
1-NHCH3
R
–
1.51 (d, 3 H, J =
2.11 (m, 1 H)
–
1.47 (d, 3 H, J =
2.16 (m, 1 H)
7.3 Hz)
6.8 Hz)
1.04 (d, 3 H, J =
6.7 Hz)
1.01 (d, 3 H, J =
6.7 Hz)
1.02 (d, 3 H, J =
6.7 Hz)
1.00 (d, 3 H, J =
6.7 Hz)
2022
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Eur. J. Inorg. Chem. 2007, 2014–2024

Conformational Analysis of Heteroannularly Substituted Ferrocene Oligoamides
FULL PAPER
1
Table 5. H NMR chemical shifts for 9–11 and 15–17 in [D6]DMSO.
9
10
11
15
16
17
1-NH
8.40 (1 H, br. t, J = 8.24 (d, 1 H, J =
7.88 (d, 1 H, J =
7.9 Hz)
8.17 (t, 1 H, J =
5.9 Hz)
7.88 (1 H, br. d, J = 7.65 (1 H, br. d, J =
5.2 Hz)
6.9 Hz)
7.4 Hz)
8.6 Hz)
1Ј-NH
1-NHCH3
CHα
7.73 (1 H, br. q)
–
3.92 (d, 2 H, J =
5.7 Hz)
7.75 (1 H, br. q)
–
4.35 (m, 1 H)
7.66 (1 H, br. q)
–
4.26 (1 H, pt, J =
7.6 Hz)
7.98 (1 H, br. q)
7.85 (1 H, br. q)
3.74 (d, 2 H, J =
5.9 Hz)
7.97 (1 H, br. q)
7.91 (1 H, br. q)
4.32 (m, 1 H)
7.88 (1 H, br. q)
8.01 (1 H, br. q)
4.11 (pt, 1 H, J =
8.0 Hz)
Cp-H
4.76 (s, 2 H)
4.73 (s, 2 H)
4.38 (s, 2 H)
4.31 (s, 2 H)
4.78 (s, 1 H)
4.76 (s, 1 H)
4.71 (s, 2 H)
4.38–4.31 (m, 4 H)
4.77 (m, 3 H)
4.71 (s, 1 H)
4.34 (m, 2 H)
4.30 (m, 2 H)
4.73 (s, 2 H)
4.70 (s, 2 H)
4.38 (s, 2 H)
4.34 (s, 2 H)
4.78 (s, 1 H)
4.72 (m, 3 H)
4.36 (s, 2 H)
4.32 (s, 2 H)
4.81 (s, 1 H)
4.79 (s, 1 H)
4.70 (s, 1 H)
4.68 (s, 1 H)
4.33 (s, 1 H)
4.31 (s, 1 H)
4.28 (s, 2 H)
2.70 (d, 3 H, J =
4.1 Hz)
1Ј-NHCH3 2.69 (d, 3 H, J =
2.70 (d, 3 H, J =
4.5 Hz)
2.72 (d, 3 H, J =
4.6 Hz)
2.69 (d, 3 H, J =
4.5 Hz)
2.71 (d, 3 H, J =
4.5 Hz)
4.2 Hz)
OCH3/
3.67 (s, 3 H)
3.66 (s, 3 H)
3.67 (s, 3 H)
2.64 (d, 3 H, J =
4.5 Hz)
2.63 (d, 3 H,J =
4.5 Hz)
2.61 (d, 3 H, J =
4.2 Hz)
1-NHCH3
R
–
1.39 (d, 3 H, J =
2.18 (m, 1 H)
–
1.30 (d, 3 H, J =
2.07 (m, 1 H)
7.3 Hz)
7.2 Hz)
1.01 (d, 3 H, J =
6.8 Hz)
0.94 (d, 3 H, J =
6.6 Hz)
0.96 (d, 3 H, J =
6.8 Hz)
0.89 (d, 3 H, J =
6.7 Hz)
dition of NaOH (23 mg, 0.6 mmol), the reaction mixture was
stirred at room temp. for 10 min. The solution was treated with
conc. HCl to pH = 2–3, extracted with EtOAc, washed with satu-
rated aqueous NaHCO3 and water. The organic layer was dried
with Na2SO4 and evaporated in vacuo. Compounds 12–14 were
used without purification for further transformation. 12 (AA =
Gly): Yield: 100 mg (94%), orange crystals. M.p. 115–117 °C. IR
70.62 (s, C4), 70.58 (s, C3Ј), 70.19 (s, C4Ј), 49.47 (s, CHAla), 26.62
(s, NHCH3), 26.48 (s, NHCH3), 18.18 (s, CH3Ala) ppm. IR
(CH Cl ): ν = 3449 (m, NH, free), 3363, 3327 (m, NH, assoc.),
˜
2
2
1653 (s, amide I), 1536 (s, amide II) cm–1. MS (ESI+, CH3CN):
m/z (%) = 372.3 (100) [M + H]+, 394.3 (2) [M + Na]+, 410.4 (4)
[M + K]+, 743.3 (21) [2M + H]+, 765.2 (5) [2M + Na]+, 781.2 (3)
[2M + K]+. HRMS (FAB): calcd for C17H21FeN3O3 371.0932;
found 371.0965. 17 (AA = -Val): orange resin. 13C NMR, APT
(KBr): ν = 3458 (m, NH, free), 3092 (s, OH), 1630 (s, amide I),
˜
1534 (s, amide II) cm–1. 13 (AA = -Ala): Yield: 94 mg (81%),
(75 MHz, CDCl3): δ = 172.68 (s, CONHCH3), 170.65 (s,
orange resin. IR (CH Cl ): ν = 3450 (m, NH, free), 3100 (s, OH),
CONHCH3), 170.60 (s, C=O), 78.13 (s, C1Ј), 76.8 (s, C1), 71.67 (s,
C2) 71.39 (s, C5), 71.31 (s, C2Ј,5Ј), 71.15 (s, C3) 70.91 (s, C4), 69.87
(s, C3Ј) 69.74 (s, C4Ј), 59.34 (s, CHVal), 30.74 (s, CHVal), 26.64 (s,
˜
2
2
1655 (s, amide I), 1534 (s, amide II) cm–1. 14 (AA = -Val): Yield:
96 mg (94%), orange resin. IR (CH Cl ): ν = 3453 (m, NH, free),
˜
2
2
3110 (s, OH), 1650 (s, amide I), 1534 (s, amide II) cm–1.
NHCH3), 26.40 (s, NHCH3), 19.51 (s, CH3Val), 18.53 (s, CH3Val
)
(Tables 4, 5 and 6) ppm. IR (CH Cl ): ν = 3451 (m, NH, free),
˜
2
2
MeNHCO–Fn–CO–AA–NHMe (15–17). Procedure A: MeNHCO–
Fn–CO–AA–OH (12–14; 0.25 mmol) was activated (as described
for 7) and reacted with MeNH2·HCl (cf. preparation of 9–11). The
crude products were purified by TLC using EtOAc as the eluent to
give orange resins 15 (24%), 16 (56%) and 17 (20%), respectively.
Procedure B: Acid amide 8 (150 mg, 0.526 mmol) was activated by
using EDC/HOBt as described for 7 and reacted with AA–NHMe
(obtained from AA–NHMe·HCl similarly as in preparation of 9–
11). The products were purified by TLC using EtOAc as the eluent
to give orange resins 15 (45%), 16 (45%), 17 (34%). The com-
pounds prepared by these alternative procedures display identical
NMR and IR spectra. 15 (AA = Gly): orange resin. 13C NMR,
APT (75 MHz, CDCl3): δ = 170.31 (s, CONHCH3), 170.22 (s,
CONHCH3), 169.72 (s, C=O), 77.75 (s, C1Ј), 76.25 (s, C1), 70.93 (s,
C2,5), 70.75 (s, C2Ј,5Ј), 70.12 (s, C3,4), 69.92 (s, C3Ј,4Ј), 43.01 (s,
CH2Gly), 26.08 (s, NHCH3), 25.85 (s, NHCH3) ppm. IR (CH2Cl2):
3342, 3326 (m, NH, assoc.), 1657 (s, amide I), 1605 (m), 1532 (s,
amide II) cm–1. MS (ESI+, CH3CN): m/z (%) = 400.4 (100) [M +
H]+, 422.4 (24) [M + Na]+, 438.3 (4) [M + K]+, 799.4 (9) [2M +
H]+, 821.3 (4) [2M + Na]+, 837.3 (2) [2M + K]+. HRMS (FAB):
calcd for C19H25FeN3O3 399.1245; found 399.1227.
Table 6. UV/Vis and CD data for 10, 11, 16 and 17 in CH3CN.
λmax / nm
λmax / nm (Mθ / °–1 cm–1)
10
452
10a 442
299 (340), 349 (–220), 411 (–120), 471 (360)
300 (–260), 350 (170), 413 (90), 475 (–250)
301 (360), 347 (–330), 411 (–190), 470 (430)
305 (810), 352 (–340), 419 (–190), 483 (410)
305 (860), 352 (–480), 415 (–270), 479 (530)
11
16
17
439
452
444
Supporting Information (see footnote on the first page of this arti-
cle): DFT calculated cartesian coordinates for all conformers of 9,
10, 11, 15, 16 and 17.
ν = 3449 (m, NH, free), 3341 (w, NH, assoc.), 1655 (s, amide I),
˜
1607 (s), 1534 (s, amide II) cm–1. MS (ESI+, CH3CN): m/z (%) =
358.4 (100) [M + H]+, 380.4 (5) [M + Na]+, 715.3 (4) [2M +
H]+, 737.5 (3) [2M + Na]+. HRMS (EI): calcd. for C16H19FeN3O3
357.0776; found 357.0754. 16 (AA = -Ala): orange resin. 13C Acknowledgments
NMR, APT (75 MHz, CDCl3): δ = 173.80 (s, CONHCH3), 170.69
(s, CONHCH3), 170.32 (s, C=O), 78.16 (s, C1Ј), 76.40 (s, C1), 71.59 The authors are grateful to Ph. D. Dinko Ziher, GlaxoSmithKline
(s, C2), 71.38 (s, C5), 71.34 (s, C2Ј) 71.01 (s, C5Ј), 70.65 (s, C3), Research Centre Zagreb, Ltd., for the CD measurements. We thank
ˇ
Eur. J. Inorg. Chem. 2007, 2014–2024
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjic.org
2023

J. Lapic´, D. Siebler, K. Heinze, V. Rapic´
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Received: December 22, 2006
Published Online: March 23, 2007
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