Synthesis and structural characterization of amino acid and peptide derivatives featuring N-(p-bromobenzoyl) substituents as promising connection unit for bio-inspired hybrid compounds

Article abstract of DOI:10.1016/j.molstruc.2011.03.058

Using a sequence of activation, blocking and peptide coupling procedures, a series of ten amino acid and peptide derivatives 1-6 (a, b, respectively) featuring a p-bromobenzoyl substituent attached to the amino group of the parent compound has been synthe

Full text of DOI:10.1016/j.molstruc.2011.03.058

Journal of Molecular Structure 994 (2011) 392–402
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Synthesis and structural characterization of amino acid and peptide derivatives
featuring N-(p-bromobenzoyl) substituents as promising connection unit
for bio-inspired hybrid compounds
⇑
Frank Eißmann, Edwin Weber
Institut für Organische Chemie, Technische Universität Bergakademie Freiberg, Leipziger Str. 29, D-09596 Freiberg/Sachsen, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Using a sequence of activation, blocking and peptide coupling procedures, a series of ten amino acid and
peptide derivatives 1–6 (a, b, respectively) featuring a p-bromobenzoyl substituent attached to the amino
group of the parent compound has been synthesized. X-ray crystal structures of two corresponding
amino acid (1a, 1b), two amino acid ester (3a, 3b) and three peptide ester derivatives (4a, 4b, 5b) are
reported, with the amide and peptide bonds of the molecules all being planar and trans configurated.
Intramolecular interactions dominating the packing motifs and thus giving rise to the formation of
strands (1a, 3a, 3b, 4a, 4b), molecular pairs (1b) or sheets (5b) derive from N–Hꢀ ꢀ ꢀO contacts, being fur-
ther assisted by O–Hꢀ ꢀ ꢀO and weaker C–Hꢀ ꢀ ꢀO interactions, while bromo involved contacts are of minor
importance.
Received 23 February 2011
Received in revised form 23 March 2011
Accepted 24 March 2011
Available online 30 March 2011
Keywords:
N-(p-bromobenzoyl) amino acid
N-(p-bromobenzoyl) peptide
X-ray crystal structure
Hydrogen bonding
Ó 2011 Elsevier B.V. All rights reserved.
Strand packing motif
Peptide sheet structure
1. Introduction
of modern Pd0 catalyzed C–C coupling reactions, comprising the
methods originally developed by Sonogashira and Hagihara, Suzu-
Being an interesting category of biomolecules, amino acids and
peptides are extensively studied with regard to applications in the
assembly of bio-inspired hybrid materials and nanotechnological
devices [1,2]. Thus, functionalized, non-natural amino acids and
peptides are of unbroken interest as they are essential building
blocks for the construction of bioconjugates being comprised of
synthetic molecules and amino acid or peptide fragments cova-
lently linked to each other [3]. For a specific construction of bio-
conjugate materials, potential building blocks require functional
groups allowing a chemoselective covalent bond formation be-
tween the components of the desired conjugate structure. Very
attractive methods for this kind of bond formation are, among oth-
ers, Pd0 catalyzed cross-couplings or cycloaddition reactions [4].
For these types of reactions, halogenated compounds with the hal-
ogen substituent linked to a sp2 carbon atom play a decisive role as
corresponding building units or respective precursors. In the case
ki, Stille or Negishi [5], aryl halides can serve as one of the coupling
components or can be further converted to terminal aryl acety-
lenes, aryl boronic acid derivatives, aryl stannanes and organozinc
halides, being the second necessary building block for the coupling
reactions mentioned above, respectively. Aryl halide derivatives
are also important precursors for 1,3-dipolar Huisgen type cycload-
ditions, recently undergoing a revival referred to as ‘‘click’’ reac-
tions [6], as they can easily be converted to the corresponding
terminal aryl acetylene compounds [7] or to aryl azides [8]. In
the literature, a few examples of halogen containing amino acids
with a sp2 C–Br bond can be found, mostly being derivatives of
the natural aromatic amino acids phenylalanine [9], tryptophane
[10], histidine [11] and tyrosine [12,13]. Another way to incorpo-
rate a reactive sp2 C–Br bond into amino acids or peptides is the
derivatization of the amino or carboxy group. Following this strat-
egy, we synthesized a series of ten new bromo containing amino
acid and peptide derivatives with the bromo substituent being part
of a benzoyl moiety linked to the amino group (1–6; a, b, respec-
tively; Fig. 1) in order to expand the pool of non-natural halogen
containing amino acids and peptides as potential building blocks
for bioconjugate formation. In view of this potential application,
there is also interest in the knowledge of the solid state structures
of the new compounds. Here we describe the preparation of the
respective compounds (Fig. 1) and report the X-ray crystal struc-
Abbreviations: DMF, N,N-dimethylformamide; Et3N, triethylamine; EtOAc, ethyl
acetate; Et2O, diethyl ether; MeOH, methanol; HOBt, 1-hydroxybenzotriazole; DCC,
N,N0-dicyclohexylcarbodiimide; TMSCl, trimethylsilyl chloride; H–Gly–OMe,
glycine methyl ester; H–Gly–Gly–OMe, glycylglycine methyl ester; DMSO, dimethyl
sulfoxide.
⇑
Corresponding author. Tel.: +49 3731 39 2386; fax: +49 3731 39 3170.
E-mail address: edwin.weber@chemie.tu-freiberg.de (E. Weber).
0022-2860/$ - see front matter Ó 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.molstruc.2011.03.058

F. Eißmann, E. Weber / Journal of Molecular Structure 994 (2011) 392–402
393
2.2.1. N-(p-bromobenzoyl)glycine (1a)
NaOH (4.00 g, 100.0 mmol) in water (200 ml), glycine (3.75 g,
50.0 mmol) and p-bromobenzoyl chloride (10.97 g, 50.0 mmol)
were used (reaction time: 3 h). The crude product was stirred in
100 ml of Et2O, reseparated and dried to afford 1a (10.39 g, 81 %),
mp 163–164 °C [lit. [16]: 162 °C, lit. [17]: 163–164 °C (EtOH)]. 1H
3
3
NMR: dH = 3.93 (2H, d, JHH = 5.85, CH2); 7.71 (2H, d, JHH = 8.60,
3
3
Ar–H); 7.82 (2H, d, JHH = 8.60, Ar–H); 8.95 (1H, d, JHH = 5.85,
NH); 12.64 (1H, br s, CO–OH). 13C NMR: dC = 41.33 (CH2); 125.29,
129.46, 131.51, 133.03 (Ar–C); 165.67 (CO–NH); 171.28 (CO–OH).
ESI(ꢂ)-MS: m/z calcd for C9H8BrNO3: 256.97, found: 255.6
[M–H]ꢂ, 514.9 [2M–H]ꢂ. EA: calcd: C, 41.89; H, 3.12; N, 5.43,
found: C, 41.88; H, 3.26; N, 5.61.
2.2.2. N-(p-bromobenzoyl)-
L
-alanine (1b)
NaOH (4.00 g, 100.0 mmol) in water (200 ml),
L-alanine (4.45 g,
50.0 mmol) and p-bromobenzoyl chloride (10.97 g, 50.0 mmol)
were used (reaction time: 7 h). The crude product was stirred in
125 ml of Et2O, reseparated and dried. A second product fraction
was obtained from the Et2O solution by concentrating it in vacuo
and repetition of the purification process described before with
50 ml of Et2O. A total yield of 11.07 g (81%) of 1b, mp 155–
Fig. 1. Compound formulas of the N-(p-bromobenzoyl) substituted amino acid and
peptide derivatives studied in this paper.
tures of the amino acid (1a, 1b), the amino acid ester (3a, 3b) and
the peptide ester derivatives (4a, 4b, 5b).
158 °C, was afforded. ½a D20
ꢁ
= + 9.3 (0.05 M, methanol). 1H NMR:
3
3
2. Experimental
dH = 1.41 (3H, d, JHH = 7.35, CH3); 4.43 (1H, q, JHH = 7.25, CH);
3
3
7.70 (2H, d, JHH = 8.50, Ar–H); 7.86 (2H, d, JHH = 8.55, Ar–H);
3
8.79 (1H, d, JHH = 7.20, NH); 12.60 (1H, br s, CO–OH). 13C NMR:
2.1. Materials and methods
dC = 16.95 (CH3); 48.36 (CH); 125.26, 129.69, 131.41, 133.12
(Ar–C); 165.35 (CO–NH); 174.23 (CO–OH). ESI(ꢂ)-MS: m/z calcd
for C10H10BrNO3: 270.98, found: 269.8 [M–H]ꢂ, 542.9 [2M–H]ꢂ.
EA: calcd: C, 44.14, H, 3.70, N, 5.15, found: C, 44.08, H, 3.74, N, 4.88.
Commercial chemicals (glycine,
L-alanine, glycylglycine,
p-bromobenzoic acid, TMSCl, 2,2-dimethoxypropane, HOBtꢀH2O
and DCC) and solvents were used without further purification. Prep-
aration of p-bromobenzoyl chloride, H–Gly–OMeꢀHCl and H–Gly–
Gly–OMeꢀHCl was afforded using literature procedures [14,15].
Melting points (mp) were determined with a hot stage micro-
scope and are uncorrected. Optical rotation measurements were
performed on a Perkin–Elmer 241 polarimeter at 20 °C and with
2.2.3. N-(p-bromobenzoyl)glycylglycine (2)
NaOH (1.60 g, 40.0 mmol) in water (80 ml), glycylglycine
(2.64 g, 20.0 mmol) and p-bromobenzoyl chloride (4.39 g,
20.0 mmol) were used (reaction time: 6.0 h). Further purification
was afforded by recrystallization from ethanol to yield 2 (5.30 g,
84 %), mp 228–229 °C. 1H NMR: dH = 3.78, 3.91 (each 2H, each d,
k = 589.3 nm (NaD line). ½a D20
ꢁ
values are given in 10ꢂ1 cm2 gꢂ1
(including the molar concentration and solvent used for the appro-
priate measurement). NMR spectra were recorded on a Bruker
Avance III 500 NMR spectrometer at 500.13 MHz [1H] and
125.76 MHz [13C], respectively, at 25 °C and with DMSO-d6 as sol-
vent (unless otherwise stated). Chemical shifts (d) are given in ppm
(referring to tetramethylsilane as internal standard) and coupling
3
each JHH = 5.95, CH2–CO–NH, CH2–CO–OH); 7.70 (2H, d,
3
3JHH = 8.55, Ar–H); 7.83 (2H, d, JHH = 8.50, Ar–H); 8.24, 8.89 (each
3
1H, each t, each JHH = 5.95, NH); 12.58 (1H, br s, CO–OH). 13C
NMR: dC = 40.69, 42.48 (CH2–CO–NH, CH2–CO–OH); 125.12,
129.56, 131.33, 133.22 (Ar–C); 165.62 (Ph–CO–NH); 169.24
(CH2–CO–NH); 171.16 (CO–OH). ESI(+)-MS: m/z calcd for
constants (3JHH 2JHH) in Hz. The multiplicity is given as s (singlet),
,
11H11BrN2O4: 313.99, found: 336.9 [M+Na]+, 653.0 [2M+Na]+,
d (doublet), dd (doublet of doublets), t (triplet), q (quintuplet), m
(multiplet) or br s (broad singlet). IR spectra were measured on a
Nicolet 510-FT-IR spectrometer (KBr pellets). Wave numbers (
C
984.8 [3M+K]+. EA: calcd: C, 41.93, H, 3.52, N, 8.89, found: C,
42.00, H, 3.67, N, 8.97.
ꢀ
m
)
are given in cmꢂ1. IR spectroscopic data of all compounds are in-
cluded in the Electronic supplementary material. MS spectra were
obtained using a GC/MS system Hewlett–Packard 5890 Series II/MS
5989A (electron ionization). ESI-MS spectra were measured on a
Varian 320-MS LC/MS system in positive (+) or negative (ꢂ) scan
mode. Elemental analyses (EA) were performed on an Elementar
Vario Micro Cube elemental analysator.
2.3. General procedure for the preparation of the N-(p-bromobenzoyl)
substituted amino acid ester derivatives 3a and 3b
TMSCl (6.4 ml, 50.0 mmol) was added slowly to 25.0 mmol of
the solid N-(p-bromobenzoyl) amino acid under an atmosphere
of argon. 25 ml of dry MeOH were added to the resulting suspen-
sion in three portions and the mixture was stirred for 18 h at room
temperature (argon atmosphere). The reaction mixture was con-
centrated in vacuo and the oily residue was dissolved in 50 ml of
MeOH. Concentration of the MeOH solution under reduced pres-
sure afforded a solid residue which was recrystallized from
MeOH/Et2O. Further details for each compound are specified
below.
2.2. General procedure for the preparation of the substituted amino
acid derivatives 1a, 1b and of the corresponding dipeptide derivative 2
The amino acid or the peptide was dissolved in an aqueous solu-
tion of sodium hydroxide and finely powdered p-bromobenzoyl
chloride was added portionwise under stirring. The reaction mix-
ture was stirred for the appropriate reaction time and after separa-
tion of possibly remaining undissolved solid, the mixture was
acidified dropwise with semi-concentrated hydrochloric acid un-
der cooling in an ice bath. The resulting solid was separated,
washed thoroughly with water and dried. Further details for each
compound are specified below.
2.3.1. N-(p-bromobenzoyl)glycine methyl ester (3a)
6.45 g (25.0 mmol) of 1a were used to afford 3a (6.37 g, 94%),
mp 109–111 °C. 1H NMR (CDCl3): dH = 3.80 (3H, s, CH3); 4.22 (2H,
3
3
d, JHH = 4.95, CH2); 6.92 (1H, br s, NH); 7.56 (2H, d, JHH = 8.55,
Ar–H); 7.68 (2H, d, JHH = 8.50, Ar–H). 13C NMR (CDCl3):
3

394
F. Eißmann, E. Weber / Journal of Molecular Structure 994 (2011) 392–402
dC = 41.70 (CH2); 52.52 (CH3); 126.56, 128.67, 131.82, 132.38
(Ar–C); 166.53 (CO–NH); 170.43 (CO–O–CH3). MS: m/z calcd for
C
was continued for another 10 min followed by the addition of
HOBtꢀH2O. After cooling to ꢂ10 °C, a solution of DCC in dry CH2Cl2
was added in small portions and the mixture was stirred for 2 h at
ꢂ10 °C. After warming to room temperature, the suspension was
stirred for 6 h and then left without stirring overnight. Further de-
tails for each compound are specified below.
10H10BrNO3: 270.98, found 271 [M]+Å. EA: calcd: C, 44.14, H,
3.70, N, 5.15, found: C, 44.10, H, 3.71, N, 5.20.
2.3.2. N-(p-bromobenzoyl)- -alanine methyl ester (3b)
L
6.80 g (25.0 mmol) of 1b were used to yield 3b (5.98 g, 84%), mp
96–98 °C. ½a 2D0
ꢁ
= + 24.3 (0.05 M, acetone). 1H NMR: dH = 1.40 (3H, d,
2.5.1. N-(p-bromobenzoyl)- -alanylglycine methyl ester (4b)
L
3
3JHH = 7.35, CH–CH3); 3.65 (3H, s, O–CH3); 4.48 (1H, q, JHH = 7.25,
H–Gly–OMeꢀHCl (1.26 g, 10.0 mmol) in DMF (50 ml), Et3N
(1.39 ml, 10.0 mmol), 1b (2.72 g, 10.0 mmol), HOBtꢀH2O (1.68 g,
11.0 mmol) and DCC (2.27 g, 11.0 mmol) in CH2Cl2 (25 ml) were
used. After separation of the solid, the filtrate was concentrated in
vacuo and the resulting solid residue was added to 250 ml of EtOAc.
Afterseparation of insoluble material, the organicphase was washed
twice with saturated NaHCO3 solution (50 ml each), once with satu-
rated NaCl solution (50 ml), dried over Na2SO4 and put into the
refrigerator overnight. The solid which had crystallized (N,N0-dicy-
clohexyl urea) was separated and the solution concentrated to dry-
ness in vacuo. The residue was recrystallized from MeOH/Et2O to
3
3
CH); 7.71 (2H, d, JHH = 8.60, Ar–H); 7.84 (2H, d, JHH = 8.55, Ar–
H); 8.91 (1H, d, JHH = 6.85, NH). 13C NMR: dC = 16.77 (CH–CH3);
3
48.42 (CH); 52.01 (O–CH3); 125.36, 129.67, 131.43, 132.81
(Ar–C); 165.40 (CO–NH); 173.13 (CO–O–CH3). MS: m/z calcd for
C
11H12BrNO3: 285.00, found: 285 [M]+Å. EA: calcd: C, 46.18, H,
4.23, N, 4.90, found: C, 45.99, H, 4.29, N, 4.96.
2.4. Synthesis of N-(p-bromobenzoyl)glycylglycine methyl ester (4a)
To a suspension of 2 (4.73 g, 15.0 mmol) in 300 ml of 2,2-dime-
thoxypropane were added 15 ml of concentrated hydrochloric acid.
The resulting mixture was stirred for 2 h at room temperature.
After having left without stirring overnight, the mixture was con-
centrated cautiously in vacuo (max. bath temperature of 40 °C).
The resulting solid was separated and washed with Et2O. Further
concentration of the reaction mixture and the combined Et2O solu-
tions resulted in a second product fraction. Pure 4a (3.15 g, 64%),
mp 171–172 °C, was obtained by recrystallization from MeOH/
afford 4b (2.43 g, 71%), mp 135–137 °C. ½a D20
ꢁ
= +24.6 (0.05 M, ace-
3
tone). 1H NMR: dH = 1.35 (3H, d, JHH = 7.20, CH–CH3); 3.63 (3H, s,
2
3
O–CH3); 3.82 (1H, dd, JHH = 17.35, JHH = 5.85, CH2); 3.88 (1H, dd,
2JHH = 17.30, JHH = 5.95, CH2); 4.52 (1H, q, JHH = 7.30, CH); 7.69
3
3
(2H, d, JHH = 8.45, Ar–H); 7.86 (2H, d, 3JHH = 8.45, Ar–H); 8.35 (1H,
3
t, 3JHH = 5.85, CH2–NH); 8.66 (1H, d, 3JHH = 7.50, CH–NH). 13C NMR:
dC = 17.84 (CH–CH3); 40.68 (CH2); 48.85 (CH); 51.74 (O–CH3);
125.11, 129.80, 131.24, 133.24 (Ar–C); 165.23 (Ph–CO–NH);
170.33, 172.91 (CH–CO–NH, CO–O–CH3). ESI(+)-MS: m/z calcd for
Et2O. 1H NMR: dH = 3.63 (3H, s, CH3); 3.87 (2H, d, JHH = 5.90,
CH2); 3.92 (2H, d, JHH = 5.95, CH2); 7.70 (2H, d, JHH = 8.55, Ar–
3
C
13H15BrN2O4: 342.02, found: 364.9 [M+Na]+, 380.9 [M+K]+, 708.8
3
3
[2M+Na]+. EA: calcd: C, 45.50, H, 4.41, N, 8.16, found: C, 45.59, H,
4.42, N, 8.35.
3
3
H); 7.84 (2H, d, JHH = 8.55, Ar–H); 8.36 (1H, t, JHH = 5.85, NH);
3
8.89 (1H, t, JHH = 5.95, NH). 13C NMR: dC = 40.64, 42.46 (CH2);
51.75 (CH3); 125.17, 129.59, 131.35, 133.18 (Ar–C); 165.65 (Ph–
CO–NH); 169.48, 170.31 (CH2–CO–NH, CO–O–CH3). ESI(+)-MS: m/
z calcd for C12H13BrN2O4: 328.01, found: 328.9 [M+H]+, 350.8
[M+Na]+, 680.9 [2M+Na]+. EA: calcd: C, 43.79, H, 3.98, N, 8.51,
found: C, 43.59, H, 4.07, N, 8.66.
2.5.2. N-(p-bromobenzoyl)glycylglycylglycine methyl ester (5a)
H–Gly–OMeꢀHCl (1.26 g, 10.0 mmol) in DMF (50 ml), Et3N
(1.39 ml, 10.0 mmol), 2 (3.15 g, 10.0 mmol), HOBtꢀH2O (1.68 g,
11.0 mmol) and DCC (2.27 g, 11.0 mmol) in CH2Cl2 (25 ml) were
used. The solid was separated, stirred in 500 ml of boiling EtOAc,
reseparated and dried on air. The purification step was repeated
with 150 ml of boiling water to yield 5a (2.96 g, 77%), mp 248–
2.5. General procedure for the preparation of the peptide ester
derivatives 4b, 5a, 5b and 6
3
250 °C. 1H NMR: dH = 3.63 (3H, s, CH3); 3.77 (2H, d, JHH = 5.75,
3
3
A mixture of H–Gly–OMeꢀHCl or H–Gly–Gly–OMeꢀHCl and dry
DMF was neutralized with Et3N. After stirring for 10 min, the N-
(p-bromobenzoyl) amino acid or peptide was added and stirring
CH2); 3.87 (2H, d, JHH = 5.85, CH2); 3.93 (2H, d, JHH = 5.70, CH2);
3
3
7.71 (2H, d, JHH = 8.45, Ar–H); 7.84 (2H, d, JHH = 8.45, Ar–H);
3
8.27–8.30 (2H, m, 2ꢃNH); 8.90 (1H, t, JHH = 5.70, NH). 13C NMR:
Scheme 1. Synthesis of compounds 1a, 1b and 2 starting from p-bromobenzoic acid.

F. Eißmann, E. Weber / Journal of Molecular Structure 994 (2011) 392–402
395
3
dC = 40.53, 41.75, 42.74 (CH2); 51.70 (CH3); 125.13, 129.51, 131.30,
133.07 (Ar–C); 165.72 (Ph–CO–NH); 169.20, 169.38, 170.17 (CH2–
CO–NH, CO–O–CH3). ESI(ꢂ)-MS: m/z calcd for C14H16BrN3O5:
385.03, found: 383.7 [M–H]ꢂ. EA: calcd: C, 43.54, H, 4.18, N,
10.88, found: C, 43.53, H, 4.16, N, 10.86.
3JHH = 7.15, CH–CH3); 3.63 (3H, s, O–CH3); 3.75 (2H, d, JHH = 5.90,
3
3
CH2); 3.88 (2H, d, JHH = 6.05, CH2); 4.47 (1H, q, JHH = 7.10, CH);
7.69 (2H, d, JHH = 8.55, Ar–H); 7.86 (2H, d, JHH = 8.55, Ar–H);
3
3
3
3
8.23 (1H, t, JHH = 5.85, CH2–NH); 8.28 (1H, t, JHH = 5.85, CH2–
NH); 8.71 (1H, d, JHH = 7.00, CH–NH). 13C NMR: dC = 17.64 (CH–
3
CH3); 40.63, 41.92 (CH2); 49.35 (CH); 51.79 (O–CH3); 125.20,
129.82, 131.27, 133.13 (Ar–C); 165.53 (Ph–CO–NH); 169.45,
170.25, 172.66 (CH–CO–NH, CH2–CO–NH, CO–O–CH3). ESI(+)-MS:
m/z calcd for C15H18BrN3O5: 399.04, found: 399.9 [M+H]+, 423.8
[M+Na]+, 822.9 [2M+Na]+. EA: calcd: C, 45.01, H, 4.53, N, 10.50,
found: C, 45.11, H, 4.62, N, 10.48.
2.5.3. N-(p-bromobenzoyl)- -alanylglycylglycine methyl ester (5b)
L
H–Gly–Gly–OMeꢀHCl (3.65 g, 10.0 mmol) in DMF (100 ml), Et3N
(2.78 ml, 20.0 mmol), 1b (5.44 g, 20.0 mmol), HOBtꢀH2O (3.37 g,
22.0 mmol) and DCC (4.54 g, 22.0 mmol) in CH2Cl2 (50 ml) were
used. The reaction mixture was concentrated in vacuo, the residue
stirred in 200 ml of boiling EtOAc, reseparated, stirred in 200 ml of
boiling water, reseparated and dried on air. Pure 5b (4.69 g, 59%),
mp 194–196 °C, was afforded by recrystallization from MeOH/
2.5.4. N-(p-bromobenzoyl)glycylglycylglycylglycine methyl ester (6)
H–Gly–Gly–OMeꢀHCl (0.37 g, 2.0 mmol) in DMF (10.0 ml), Et3N
Et2O. ½a 2D0
ꢁ
= + 22.5 (0.05 M, methanol). 1H NMR: dH = 1.35 (3H, d,
(0.28 ml, 2.0 mmol),
2
(0.63 g, 2.0 mmol), HOBtꢀH2O (0.34 g,
Scheme 2. Synthesis of N-(p-bromobenzoyl) substituted amino acid and peptide ester derivatives 3a, 3b, 4a, 4b, 5a, 5b and 6.

396
F. Eißmann, E. Weber / Journal of Molecular Structure 994 (2011) 392–402
Fig. 2. Molecular structures of compounds 1a (a), 1b (b), 3a (c) and 3b (d) including atom numbering schemes.
3
3
CH2); 7.70 (2H, d, JHH = 8.35, Ar–H); 7.83 (2H, d, JHH = 8.40, Ar–
3
Table 1
H); 8.19 (1H, t, JHH = 5.70, NH); 8.23–8.28 (2H, m, 2ꢃNH); 8.91
(1H, t, JHH = 5.55, NH). 13C NMR: dC = 40.62, 41.81, 42.20, 42.86
3
Selected torsion angles (°) for compounds 1a, 1b, 3a and 3b.
(CH2); 51.81 (CH3); 125.26, 129.63, 131.42, 133.17 (Ar–C); 165.87
(Ph–CO–NH); 169.28, 169.43, 169.44, 170.28 (CH2–CO–NH, CO–
O–CH3). ESI(ꢂ)-MS: m/z calcd for C16H19BrN4O6: 442.05, found:
479.0 [M+Cl]ꢂ. EA: calcd: C, 43.36, H, 4.32, N, 12.64, found: C,
43.09, H, 4.22, N, 12.60.
Torsion angle
1a
1b
3a
3b
C3–C4–C7–O1
C4–C7–N1–C8(xꢂ1⁄
C7–N1–C8–C9 (u1
C7–N1–C8–C10/C11a
C8–C9–O3–C10 (x1⁄
ꢂ28.9(5)
178.7(3)
ꢂ67.3(4)
–
ꢂ18.8(3)
ꢂ175.23(15)
ꢂ88.7(2)
147.81(17)
–
21.3(4)
ꢂ179.2(2)
ꢂ76.9(3)
–
173.4(2)
174.6(2)
ꢂ1.1(4)
29.6(2)
)
178.51(12)
ꢂ78.89(16)
160.14(13)
176.52(13)
143.25(12)
ꢂ1.5(2)
)
)
–
N1–C8–C9–O3 (w1⁄
O1–C7–N1–C8
)
170.4(3)
ꢂ0.1(5)
160.24(15)
3.5(3)
2.6. X-ray crystal structure analyses
a
The relevant atoms are C10 for 1b and C11 for 3b, respectively.
The X-ray crystal structure analyses were performed using a
Bruker Kappa diffractometer equipped with an Apex II CCD area
2.2 mmol) and DCC (0.45 g, 2.2 mmol) in CH2Cl2 (5.0 ml) were
used. The solid was separated, stirred in 100 ml of boiling EtOAc,
reseparated and dried on air to yield 6 (0.60 g, 68%), mp 268–
270 °C. 1H NMR: dH = 3.62 (3H, s, CH3); 3.76–3.78 (4H, m,
detector and graphite-monochromatized Mo K
a
radiation
(k = 0.71073 Å) employing and scan modes. The data were cor-
u
x
rected for Lorentz and polarization effects. Semi-empirical absorp-
tion corrections were applied using the SADABS program and the
SAINT program was utilized for integration of the diffraction
3
3
2ꢃCH2); 3.84 (2H, d, JHH = 5.80, CH2); 3.93 (2H, d, JHH = 5.65,
Fig. 3. Structure overlays for (a) 1a (orange)/3a (blue) [RMS = 0.00874], (b) 1b (red)/3b (green) [RMS = 0.0198], (c) 1a (orange)/1b (red) [RMS = 0.0289] and (d) 3a (blue)/3b
(green) [RMS = 0.0130], calculated from the atoms O1, C7, N1 and C8, respectively. H atoms are omitted for clarity. (For interpretation of the references to color in this figure
legend, the reader is referred to the web version of this article.)

F. Eißmann, E. Weber / Journal of Molecular Structure 994 (2011) 392–402
397
Table 2
Hydrogen bonds in the crystal structures of compounds 1a, 1b, 3a and 3b.
Atoms involved
Symmetry
Distance (Å)
Angle (°)
D(Dꢀ ꢀ ꢀA)
d(Hꢀ ꢀ ꢀA)
h(D–Hꢀ ꢀ ꢀA)
1a
N1–H1ꢀ ꢀ ꢀO1
O3–H3Aꢀ ꢀ ꢀO2
C6–H6ꢀ ꢀ ꢀO1
x + 1, y, z
2.854(4)
2.673(4)
3.304(5)
2.11
1.84
2.51
142.2
175.0
141.8
ꢂx, ꢂy + 1, ꢂz + 2
x + 1, y + 1, z
1b
N1–H1ꢀ ꢀ ꢀO2
O3–H3Aꢀ ꢀ ꢀO1
C5–H5ꢀ ꢀ ꢀO2
ꢂx + 2, ꢂx + y + 1, ꢂz + 5/3
x ꢂ y + 1, ꢂy + 2, ꢂz + 4/3
ꢂx + 2, ꢂx + y + 1, ꢂz + 5/3
2.9452(19)
2.6210(19)
3.338(2)
2.08
1.88(2)
2.49
166.8
165(2)
148.6
3a
N1–H1ꢀ ꢀ ꢀO1
C5–H5ꢀ ꢀ ꢀO1
C5–H5ꢀ ꢀ ꢀO2
C8–H8Aꢀ ꢀ ꢀCga
C8–H8Bꢀ ꢀ ꢀO2
x ꢂ 1/2, y, ꢂz + 3/2
x ꢂ 1/2, y, ꢂz + 3/2
ꢂx, y + 1/2, ꢂz + 3/2
ꢂx, y + 1/2, ꢂz + 3/2
ꢂx + 1/2, y + 1/2, z
2.811(3)
3.240(3)
3.206(4)
3.586(3)
3.555(4)
1.97
2.54
2.49
2.62
2.59
159.8
130.5
132.3
164.0
165.1
3b
N1–H1ꢀ ꢀ ꢀO1
C10–H10Bꢀ ꢀ ꢀO2
C11–H11Cꢀ ꢀ ꢀO3
x + 1, y, z
2.9810(16)
3.455(2)
3.4942(19)
2.13
2.55
2.60
162.7
153.1
151.2
ꢂx + 1, y + 1/2, ꢂz + 3/2
x + 1, y, z
a
Cg is the centroid of the aromatic ring.
profiles [18]. The crystal structures were solved by direct methods
using SHELXS-97 and refined by full-matrix least-squares refine-
ment against F2 using SHELXL-97 [19]. All non-hydrogen atoms
were refined anisotropically; hydrogen atoms were generated at
ideal geometrical positions and refined with the appropriate riding
model or positioned by Difference Fourier synthesis. Geometrical
calculations were performed using PLATON [20] and molecular
graphics were generated using SHELXTL [19].
acids glycine and L-alanine and into the peptide glycylglycine
(Scheme 1). For this purpose, p-bromobenzoic acid was converted
to the corresponding p-bromobenzoyl chloride [14], which was
then reacted with glycine, L-alanine and glycylglycine under Schot-
ten–Baumann conditions, respectively, to afford the N-(p-bro-
mobenzoylated) derivatives 1a, 1b and 2.
Starting from compound 1a (Scheme 2a), the corresponding
glycine methyl ester 3a was obtained by esterification with
TMSCl/MeOH using the protocol described by Li and Sha [15]. Anal-
ogously, compound 1b (Scheme 2b) was converted to the appropri-
ate ester derivative 3b.
3. Results and discussion
3.1. Synthesis
Peptide coupling of the
OMeꢀHCl using HOBt/DCC [21] (according to literature procedures
[22,23]) afforded the N-(p-bromobenzoyl)- -alanylglycine deriva-
tive 4b. The corresponding -alanine derived tripeptide 5b could
L-alanine derivative 1b with H–Gly–
The first step in the preparation of the discussed compounds
was the introduction of the p-bromobenzoyl group into the amino
L
L
Fig. 4. Strand formation within the crystal structures of 1a (a), 3a (b) and 3b (c). Hydrogen bonding interactions are represented as dashed lines.

398
F. Eißmann, E. Weber / Journal of Molecular Structure 994 (2011) 392–402
pounds in solvents as specified in the following: 1a (DMSO), 1b
(MeOH), 3a (Et2O), 3b (MeOH/Et2O), 4a (MeOH/Et2O), 4b (MeOH),
5b (MeOH). The crystallographic data and refinement details of all
compounds studied are summarized in Table SUP-1.
3.3. Crystal structures of the amino acid derivatives 1a, 1b, 3a and 3b
At a first glance, the molecular structures of the amino acid
derivatives 1a, 1b, 3a and 3b (Fig. 2) do not seem to differ signifi-
cantly from each other. However, a detailed view of selected tor-
sions angles (Table 1) reveals some obvious differences. As
expected, in all molecules the amide bond is nearly planar and
trans configurated, which can be derived from the torsion angles
O1–C7–N1–C8 [values ranging from ꢂ1.5(2) to 3.5(3)°] and xꢂ1⁄
[absolute values ranging from 175.23(15) to 179.2(2)°], respec-
tively. Differences occur in the torsion of the phenyl ring with ref-
erence to the amide bond, where torsion angles C3–C4–C7–O1
from ꢂ28.9(5) to 29.6(2)° are found. The torsion of the carboxylic
C atom C9 in relation to the planar amide fragment is also different
for the discussed amino acid derivatives [ꢂ67.3(4) to ꢂ88.7(2)° for
Fig. 5. Formation of molecule pairs in the crystal structure of compound 1b.
Hydrogen bonding interactions are represented as dashed lines. The first level graph
set notations [25] for the N1–H1ꢀ ꢀ ꢀO2 and the C5–H5ꢀ ꢀ ꢀO2 interactions stabilizing
the structural motif are R22ð10Þ and R22ð16Þ, respectively.
u
1]. Moreover, the difference in the torsion angle
u
1 consequently
-ala-
be obtained accordingly using H–Gly–Gly–OMeꢀHCl for the peptide
coupling step (Scheme 2b).
leads to a different torsion angle of the methyl group in the
L
nine derivatives 1b and 3b [147.81(17) and 160.14(13)° for C7–
N1–C8–C10/C11, respectively]. Structural overlay plots (based on
the atoms O1, C7, N1 and C8 of the rigid amide bond), making these
structural differences more obvious, are given in Fig. 3.
The packing structures of 1a, 1b, 3a and 3b are characterized by
numerous hydrogen bonding interactions. In particular, the amide
N–H group plays an important part as hydrogen bonding donor
site. Thus, in all structures, N–Hꢀ ꢀ ꢀO contacts contribute to the for-
mation of structural motifs. In the packing arrangements of 1a, 3a
and 3b, N1–H1ꢀ ꢀ ꢀO1 contacts (Table 2) of C11ð4Þ unitary level graph
set [25] lead to the formation of strands running along the crystal-
lographic a axis (Fig. 4). Regarding these strands, an alternating se-
quence of molecular orientations is found for compound 3a, while
The dipeptide methyl ester 4a resulted from esterification of
compound 2 (Scheme 2c) with 2,2-dimethoxypropane/conc. HCl(aq)
following a literature protocol [24]. Compound 2 could also be con-
verted to the N-(p-bromobenzoyl)glycylglycylglycine derivative 5a
and the corresponding tetrapeptide derivative 6 by HOBt/DCC
mediated peptide coupling with H–Gly–OMeꢀHCl and H–Gly–
Gly–OMeꢀHCl, respectively.
3.2. Crystallization
Crystals suitable for X-ray crystal structure determination were
obtained by slow evaporation of solutions of the respective com-
Fig. 6. Asymmetric units of the crystal structures of compounds 4a (a) and 4b (b) including atom numbering schemes.

F. Eißmann, E. Weber / Journal of Molecular Structure 994 (2011) 392–402
399
Table 3
Table 4
Selected torsion angles (°) for compounds 4a and 4b.
Hydrogen bonds in the crystal structures of compounds 4a and 4b.
Torsion angle
4a
4b
Atoms involved
Symmetry
Distance (Å)
Angle (°)
d(Hꢀ ꢀ ꢀA) h(D–Hꢀ ꢀ ꢀA)
4a0
4a00
D(Dꢀ ꢀ ꢀA)
C3–C4–C7–O1/C15–C16–C19–O5a
C4–C7–N1–C8/C16–C19–N3–C20a
7.9(4)
ꢂ179.8(3) 176.7(3)
ꢂ8.9(5)
24.6(2)
ꢂ178.32(13)
4a
N1–H1Nꢀ ꢀ ꢀO1
N2–H2Nꢀ ꢀ ꢀO2
N3–H3Nꢀ ꢀ ꢀO5
N4–H4Nꢀ ꢀ ꢀO6
C5–H5ꢀ ꢀ ꢀO1
C8–H8Aꢀ ꢀ ꢀO2
C10–H10Bꢀ ꢀ ꢀO3
x, ꢂy + 1, z + 1/2
x + 1, y, z
2.846(3)
2.851(4)
2.841(3)
2.854(3)
3.477(4)
3.163(4)
3.201(4)
2.02
2.00
2.02
2.01
2.57
2.48
2.39
2.84
2.44
2.55
2.38
155.8
161.7
154.6
160.1
159.6
125.6
138.9
166.5
117.4
162.5
141.1
(
xꢂ1⁄)
C7–N1–C8–C9/C19–N3–C20–C21a
68.5(4)
74.1(4)
ꢂ67.79(18)
x, ꢂy + 2, z + 1/2
(u1)
x ꢂ 1, y, z
C7–N1–C8–C13
–
–
170.48(14)
ꢂ173.69(13)
x, ꢂy + 1, z + 1/2
x + 1, y, z
C8–C9–N2–C10/C20–C21–N4–C22a
ꢂ178.4(3) 175.7(3)
(x1
)
x + 1, y, z
C9–N2–C10–C11/C21–N4–C22–
C23a
C10–C11–O4–C12/C22–C23–O8–
C24a(x2⁄
N1–C8–C9–N2/N3–C20–C21–N4a
59.6(4)
61.5(4)
ꢂ66.2(2)
C12–H12Bꢀ ꢀ ꢀBr1 x + 1, ꢂy + 1, z + 1/2 3.802(4)
(u2
)
C12–H12Bꢀ ꢀ ꢀO7
C17–H17ꢀ ꢀ ꢀO5
C22–H22Bꢀ ꢀ ꢀO7
x, y, z
3.022(4)
3.470(4)
3.208(4)
178.5(3)
177.4(3)
ꢂ174.82(18)
x, ꢂy + 2, z + 1/2
)
x ꢂ 1, y, z
ꢂ159.7(3) ꢂ176.5(3) 158.65(13)
4b
(w1)
N1–H1Nꢀ ꢀ ꢀO1
N2–H2Nꢀ ꢀ ꢀO2
C8–H8ꢀ ꢀ ꢀO2
C10–H10Aꢀ ꢀ ꢀO3
x, y, z + 1
x + 1, y, z
x + 1, y, z
x + 1, y, z
3.2490(17) 2.39
2.8370(16) 1.99
3.1889(18) 2.54
3.310(2)
3.520(2)
165.1
161.6
122.6
141.3
161.2
N2–C10–C11–O4/N4–C22–C23–O8a 34.6(4)
33.5(4)
ꢂ38.1(2)
(w2⁄)
O1–C7–N1–C8/O5–C19–N3–C20a
O2–C9–N2–C10/O6–C21–N4–C22a
0.4(5)
ꢂ1.0(5)
ꢂ1.3(4)
ꢂ4.9(5)
0.7(2)
7.3(2)
2.48
2.58
C13–H13Aꢀ ꢀ ꢀO1 x + 1, y, z + 1
a
The first torsion angle refers to 4a0 and 4b, the second to 4a00, respectively.
in 1a and 3b a regular, non-alternating arrangement is formed. Un-
like in 1a, the strands of 3a are additionally stabilized by a weak
(aryl)C5–H5ꢀ ꢀ ꢀO1 interaction [26] of C11ð5Þ synthon mode [25],
leading to the formation of a bifurcated-acceptor type hydrogen
bond [27] (Fig. 4b), while in the strands of 3b a C–Hꢀ ꢀ ꢀO contact
(C11–H11Cꢀ ꢀ ꢀO3, C11ð5Þ motif [25]) contributes to a further stabil-
ization (Fig. 4c). Within the packing of 1b, the N–Hꢀ ꢀ ꢀO interaction
does not lead to a strand motif but to the formation of molecular
pairs (Fig. 5), assisted by a weak (aryl)C–Hꢀ ꢀ ꢀO contact (C5–
H5ꢀ ꢀ ꢀO2). Besides the discussed N–Hꢀ ꢀ ꢀO interactions, O–Hꢀ ꢀ ꢀO
contacts comprising the carboxylic acid function participate in
the formation of the crystal structures of compounds 1a and 1b.
In 1a a classical carboxylic acid dimer [28] of R22ð8Þ synthon mode
[29] is found, while in 1b the carbonyl O2 atom is, among others,
the acceptor for the N–Hꢀ ꢀ ꢀO contact and the hydroxy O–H func-
tion acts as a donor for an O3–H3Aꢀ ꢀ ꢀO1 interaction connecting
the molecule pairs in c direction.
The interactions between different strands or molecular pairs
within the packing structures are mainly of a weaker nature. In
1a, the strands are side-connected via the carboxylic acid dimer-
ization interaction mentioned above on one edge and a Brꢀ ꢀ ꢀBr
interaction of the so-called ‘side on’ mode [30,31]
(D(Br1ꢀ ꢀ ꢀBr1i) = 3.5952(5) Å, h(C1–Br1ꢀ ꢀ ꢀBr1i) = 98.08(11)°, h(C1i–
Br1iꢀ ꢀ ꢀBr1) = 171.24(11)°, symmetry code i = ꢂx + 3/2, y ꢂ 1/2,
ꢂz + 3/2) on the other edge. In the structures of 1a, 3a and 3b, addi-
tional weaker C–Hꢀ ꢀ ꢀO contacts comprising aromatic, methylene
and methyl C atoms as hydrogen bonding donors can be found
(Table 2).
unit of compound 4a consists of two independent dipeptide mole-
cules (4a0 on the left and 4a00 on the right side of Fig. 6a). However,
a comparison of the relevant torsion angles of 4a0 and 4a00 (Table 3)
does not show any significant differences between one and another
which is also obvious from the molecular overlay plot in Fig. 7a. In
contrast to the molecular structure of 4a, in 4b the aromatic ring is
distorted to a greater extent towards the neighboring amide bond
[torsion angles C3–C4–C7–O1 = 7.9(4)° for 4a0 and C15–C16–C19–
O5 = ꢂ8.9(5)° for 4a00 as well as C3–C4–C7–O1 = 24.6(2)° for 4b].
These particular differences in the distortion of the aromatic ring
are visualized in Fig. 7b and Fig. 7c. Similar to the amino acid deriv-
atives (1a, 1b, 3a, 3b), the amide bonds of the dipeptide derivatives
are also approximately planar and trans configurated (cf. respective
torsion angles in Table 3). Fig. 7b and Fig. 7c also clearly show that
4a and 4b differ in the conformation of the peptide chain. Thus, dif-
ferent values for the torsion angle u1 are found [68.5(4)°/74.1(4)°
for 4a0/4a00 and ꢂ67.79(18)° for 4b, respectively]. Further differ-
ences in the peptide chains of the two dipeptide derivatives 4a
and 4b are found for the torsion angles w1, u2 as well as w2⁄
(Table 3).
Just as discussed for the amino acid derivatives (1a, 1b, 3a, 3b),
the packing structures of compounds 4a and 4b are predominantly
characterized by C11ð4Þ type [25] N–Hꢀ ꢀ ꢀO contacts between the
amide N–H groups as donors and carbonyl O atoms as acceptors
(excluding the C terminal amide carbonyl group in the case of
the dipeptide derivatives 4a and 4b; Table 4). In the crystal struc-
tures both the N1–H1Nꢀ ꢀ ꢀO1 (for 4a00 N3–H3Nꢀ ꢀ ꢀO5) and the N2–
H2Nꢀ ꢀ ꢀO2 (for 4a00 N4–H4Nꢀ ꢀ ꢀO6) interactions lead to the forma-
tion of strand structures with the strands running parallel along
the c and a axis, respectively. On closer examination of the strands
parallel to the c axis, these strands in the packing arrangement of
3.4. Crystal structures of the dipeptide derivatives 4a and 4b
The asymmetric units of the dipeptide crystal structures 4a and
4b are represented in Fig. 6. It is remarkable that the asymmetric
Fig. 7. (a) Structure overlay of the components of the asymmetric unit of compound 4a [4a0 (purple)/4a00 (violet) with RMS = 0.2636] calculated from all non H atoms as well
as structure overlays for (b) 4a0 (purple)/4b (light blue) [RMS = 0.0151] and (c) 4a00 (violet)/4b (light blue) [RMS = 0.0146], calculated from the atoms O1, C7, N1 and C8,
respectively. H atoms are omitted for clarity. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

400
F. Eißmann, E. Weber / Journal of Molecular Structure 994 (2011) 392–402
Fig. 8. Strand formation within the crystal structures of compounds 4a and 4b with strands running parallel to the c axis [4a (a), 4b (b)] and a axis [4a (c), 4b (d)],
respectively. Hydrogen bonding interactions are represented as dashed lines.
Fig. 9. Molecular structure of compound 5b including the atom numbering scheme.
compound 4a consist of alternately arranged dipeptide molecules
where the strand formation is assisted by an (aryl)C–Hꢀ ꢀ ꢀO contact
(C5–H5ꢀ ꢀ ꢀO1 and C17–H17ꢀ ꢀ ꢀO5, respectively, C11ð5Þ synthon mode
[25]) leading to a bifurcated-acceptor type hydrogen bonding motif
(cf. compound 3a; Fig. 8a). In the case of compound 4b, the
3.2490(17) Å, d(Hꢀ ꢀ ꢀA) = 2.39 Å] compared to the other N–Hꢀ ꢀ ꢀO
contacts discussed so far. Nevertheless, this contact contributes
to the formation of strands parallel to the c axis with a non-alter-
nating molecule orientation (Fig. 8b). In both crystal structures, the
molecules within the strands running parallel to the a axis are pre-
dominantly linked via N2–H2Nꢀ ꢀ ꢀO2 (for 4a00 N4–H4Nꢀ ꢀ ꢀO6)
N1–H1Nꢀ ꢀ ꢀO1 interaction is of
a
weaker nature [D(Dꢀ ꢀ ꢀA) =

F. Eißmann, E. Weber / Journal of Molecular Structure 994 (2011) 392–402
401
Table 5
antiparallel molecule orientation within the sheets. Besides the
three N–Hꢀ ꢀ ꢀO type interactions, weaker C–Hꢀ ꢀ ꢀO contacts [26]
(C5–H5ꢀ ꢀ ꢀO3, C10–H10Bꢀ ꢀ ꢀO1) participate in the formation of the
sheets elongated parallel to the b axis. In the crystal structure of
5b, different sheets are linked via additional C–Hꢀ ꢀ ꢀO interactions
(C3–H3ꢀ ꢀ ꢀO4, C12–H12Bꢀ ꢀ ꢀO4, C14–H14Bꢀ ꢀ ꢀO2).
Hydrogen bonding interactions in the crystal structure of compound 5b.
Atoms involved Symmetry
Distance (Å)
Angle (°)
D(Dꢀ ꢀ ꢀA) d(Hꢀ ꢀ ꢀA) h(D–Hꢀ ꢀ ꢀA)
N1–H1Nꢀ ꢀ ꢀO3
N2–H2Nꢀ ꢀ ꢀO2
N3–H3Nꢀ ꢀ ꢀO1
C3–H3ꢀ ꢀ ꢀO4
C5–H5ꢀ ꢀ ꢀO3
ꢂx + 1, y ꢂ 1/2, ꢂz + 3/2 3.020(4) 2.22
150.1
ꢂx + 1, y + 1/2, ꢂz + 3/2 2.880(4) 2.04
158.7
156.2
143.8
127.3
133.7
138.3
129.3
ꢂx + 1, y ꢂ 1/2, ꢂz + 3/2 2.901(4) 2.07
ꢂx + 3/2, ꢂy + 2, z + 1/2 3.280(5) 2.46
ꢂx + 1, y ꢂ 1/2, ꢂz + 3/2 3.155(4) 2.49
4. Conclusions
C10–H10Bꢀ ꢀ ꢀO1 ꢂx + 1, y ꢂ 1/2, ꢂz + 3/2 3.144(4) 2.38
A series of new non-natural amino acid and peptide derivatives
featuring N-(p-bromobenzoyl) substituents has been synthesized
and characterized successfully. The discussed compounds seem
promising as useful building blocks for the construction of differ-
ent bioconjugates. The synthetic strategy is based on rather simple
starting materials being commercially available, such as p-bromo-
C12–H12Bꢀ ꢀ ꢀO4 xꢂ1/2, ꢂy + 3/2, ꢂz + 1
3.271(5) 2.46
C14–H14Bꢀ ꢀ ꢀO2 x ꢂ 1/2, ꢂy + 3/2, ꢂz + 1 3.313(5) 2.60
benzoic acid, glycine, L-alanine or glycylglycine. Standard coupling
methods and characteristic protecting and activating techniques
were used for the formation of amide or peptide bonds. Thus, a
way for the synthesis of similar amino acid or peptide derivatives
using analogous starting materials for the coupling steps has been
made accessible.
X-ray crystal structures obtained from compounds 1a, 1b, 3a
and 3b, being amino acid or amino acid ester derivatives, as well
as from the peptide ester derivatives 4a, 4b and 5b, all show
molecular structures with amide or peptide bonds being planar
and trans configurated. The p-bromobenzoyl moiety is found
slightly distorted with reference to the neighboring amide bond.
In the crystals, N–Hꢀ ꢀ ꢀO contacts can be considered as dominating
intramolecular interactions contributing to the formation of char-
acteristic structural motifs of the packing arrangements, namely
strands (1a, 3a, 3b, 4a, 4b), molecular pairs (1b) or sheets (5b).
Moreover, O–Hꢀ ꢀ ꢀO and weaker C–Hꢀ ꢀ ꢀO contacts also contribute
moderately to the structure formation, while bromo involved
interactions are very minor, although the bromine atom of the
respective molecules is in a favorable peripheral position for an
intermolecular contact. Nevertheless, it is obvious from the results
of this study that sheets, similar to b-sheets known as an important
peptide secondary structure, are formed neither in the case of the
present amino acid nor dipeptide derivatives. Only the tripeptide
derivative 5b shows a corresponding structural motif in the solid
state. Hence, if b-sheet formation is intended to be used in the de-
sign and construction of solid bioconjugates [34] and other bio-in-
spired hybrid materials including hydrogen bonded organic
framework structures [2], a lower limit of at least two peptide
bonds seems necessary.
Fig. 10. Sheet formation within the crystal structure of compound 5b. Hydrogen
bonding interactions are represented as dashed lines.
hydrogen bonding interactions (Fig. 8c and d). Additional contribu-
tions to the strand formation emanate from numerous weak
C–Hꢀ ꢀ ꢀO interactions (4a0: C8–H8Aꢀ ꢀ ꢀO2, C10–H10Bꢀ ꢀ ꢀO3; 4a00:
C22–H22Bꢀ ꢀ ꢀO7, 4b: C8–H8ꢀ ꢀ ꢀO2, C10–H10Aꢀ ꢀ ꢀO3; C11ð4Þ first level
graph set [25], respectively; Table 4). Besides the hydrogen bond-
ing interactions mentioned so far, additional intermolecular con-
tacts stabilizing the packing structures are listed in Table 4. As
these interactions are of the (alkyl)C–Hꢀ ꢀ ꢀO [26] and (alkyl)C–
Hꢀ ꢀ ꢀBr contact mode [32], they can be considered as interactions
of rather weak nature.
Appendix A. Supplementary data
Supplementary material available Table SUP-1: Summary of
crystallographic data and refinement details for the compounds
studied. Table SUP-2: Selected torsion angles (°) for compound
5b. IR spectroscopic data. The crystal structure data for this paper
have been deposited to the Cambridge Structural Database (CSD)
and can be obtained free of charge at www.ccdc.cam.ac.uk/
data_request/cif [or from the Cambridge Crystallographic Data
Centre (CCDC), 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44
(0)1223 336033; e-mail: deposit@ccdc.cam.ac.uk], quoting the
CCDC deposition numbers 799300 (1a), 799301 (1b), 799302
(3a), 799303 (3b), 799304 (4a), 799305 (4b) and 799306 (5b).
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.molstruc.2011.03.058.
3.5. Crystal structure of the tripeptide derivative 5b
The molecular structure of the tripeptide 5b is illustrated in
Fig. 9. Relevant torsion angles are given in Table SUP-2. As men-
tioned for the compounds above, the three amide bonds of 5b
are again nearly planar and trans configurated (cf. appropriate tor-
sion angles in Table SUP-2).
In the packing of compound 5b, the most dominant interactions
are N–Hꢀ ꢀ ꢀO contacts (N1–H1Nꢀ ꢀ ꢀO3, N2–H2Nꢀ ꢀ ꢀO2, N3–H3Nꢀ ꢀ ꢀO1,
Table 5) leading to the formation of sheet structures with an alter-
nating molecule orientation (Fig. 10), similar to the antiparallel
b-sheet motif known as a typical peptide secondary structure
[33]. Considering unitary level graph sets [25], the N1–H1Nꢀ ꢀ ꢀO3,
N2–H2Nꢀ ꢀ ꢀO2 and N3–H3Nꢀ ꢀ ꢀO1 contacts can be described using
the notations C11ð8Þ, C11ð4Þ and C11ð10Þ, respectively, reflecting the
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