N-(p-Ethynylbenzoyl) derivatives of amino acid and dipeptide methyl esters - Synthesis and structural study

Article abstract of DOI:10.1016/j.molstruc.2011.08.034

A series of N-(p-ethynylbenzoyl) derivatives (1-4) of the amino acids glycine and l-alanine as well as the dipeptides glycylglycine and l-alanylglycine has been synthesized via a two-step reaction sequence including the reaction of an appropriate N-(p-bro

Full text of DOI:10.1016/j.molstruc.2011.08.034

Journal of Molecular Structure 1005 (2011) 121–128
Contents lists available at SciVerse ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
N-(p-Ethynylbenzoyl) derivatives of amino acid and dipeptide methyl
esters – Synthesis and structural study
⇑
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:
Received 13 July 2011
Received in revised form 19 August 2011
Accepted 19 August 2011
Available online 27 August 2011
A series of N-(p-ethynylbenzoyl) derivatives (1–4) of the amino acids glycine and L-alanine as well as the
dipeptides glycylglycine and L-alanylglycine has been synthesized via a two-step reaction sequence
including the reaction of an appropriate N-(p-bromobenzoyl) precursor with trimethylsilylacetylene fol-
lowed by deprotection of the trimethylsilyl protecting group, respectively. X-ray crystal structures of the
amino acid and dipeptide methyl esters 1–4 are reported. The amide and peptide bonds within each
molecular structure are planar and adopt the trans-configuration. The packing structures are governed
by NAHꢀ ꢀ ꢀO interactions leading to the formation of characteristic strand motifs. Further stabilization
Keywords:
N-(p-ethynylbenzoyl) amino acid
N-(p-ethynylbenzoyl) peptide
X-ray crystal structure
Hydrogen bonding
results from weaker CAHꢀ ꢀ ꢀO and CAHꢀ ꢀ ꢀp contacts.
Ó 2011 Elsevier B.V. All rights reserved.
Strand packing motif
1. Introduction
[14], here we present a new method of incorporating a reactive ter-
minal C„C triple bond into natural amino acids and peptides with
the ethynyl moiety being part of an N-benzoyl substituent. Using
this method, we synthesized a series of four new N-(p-eth-
ynylbenzoyl) derivatized amino acid and peptide methyl esters
(1–4, Fig. 1) contributing to an expansion of the pool of non-natural
ethynyl-containing amino acids and peptides that offer potential
applications in bioconjugate formation. In this connection, the
knowledge of the solid state structures of the new compounds is
of relevance. Thus, here we describe the synthesis of the respective
compounds (Fig. 1) and report their X-ray crystal structures focus-
ing on molecular geometries and characteristic packing motifs.
Amino acids and peptides can be considered as interesting
molecular building blocks for the construction of bio-inspired
materials or nanotechnological devices [1,2]. The synthesis of those
bioconjugate structures demands the linkage of synthetic mole-
cules and amino acid or peptide fragments via covalent bonds [3].
Hence, amino acid or peptide building blocks containing a func-
tional group that ensures a chemoselective covalent bond forma-
tion are required in order to build up the intended bioconjugates.
Metal-catalyzed coupling or cycloaddition reactions [4] are very
promising methods for this kind of bond formation. Regarding
these types of reactions, ethynyl substituted compounds are impor-
tant building units as they serve as excellent coupling components
in respective CAC coupling reactions, including the methods origi-
nally developed by Sonogashira et al. [5], Cadiot and Chodkiewicz
[6] or Eglinton et al. [7]. Ethynyl derivatives are also important
for 1,3-dipolar Huisgen type cycloadditions [8], nowadays referred
to as ‘‘click’’ reactions [9]. Although in the literature a number of
examples of ethynyl-containing derivatives of the simple amino
acids glycine and alanine as well as other natural amino acids can
2. Experimental
2.1. Materials and methods
The starting materials N-(p-bromobenzoyl)glycine methyl ester,
N-(p-bromobenzoyl)-
zoyl)glycylglycine methyl ester and N-(p-bromobenzoyl)-
L
-alanine methyl ester, N-(p-bromoben-
-alanyl-
L
glycine methyl ester were prepared as described in a previous
paper [14]. All other chemicals were purchased from commercial
sources and used without further purification. Dry solvents (ethyl
acetate, triethylamine and methanol) were obtained using stan-
dard drying procedures.
Thin layer chromatography (TLC) was performed using alumi-
num sheets coated with silica gel 60 F254 (MERCK, Darmstadt, Ger-
many). Silica gel 60, 0.040–0.063 mm (MERCK, Darmstadt,
Germany) was used for flash column chromatography.
be found, research in this field has mainly focused on
a-ethynyl
[10], -propargyl [11], propargylic ester [12] and N-propargyl
a
derivatives [13]. In extension to our recent study relating to N-(p-
bromobenzoyl) amino acids and peptides as promising building
blocks for the construction of bio-inspired hybrid compounds
⇑
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.2011.08.034

122
F. Eißmann, E. Weber / Journal of Molecular Structure 1005 (2011) 121–128
41.29 (CH2); 51.81 (OACH3); 96.70 (C„CASiA(CH3)3); 104.43
(PhAC„C); 125.20, 127.62, 131.69, 133.60 (ArAC); 165.81
ꢀ
(PhACOANH); 170.31 (COAOACH3). IR:
m
¼ 3281; 3088; 2958;
2895; 2157; 1755; 1651; 1606; 1546; 1499; 1442; 1404; 1372;
1328; 1306; 1283; 1255; 1207; 1185; 1021; 1008; 875; 859;
840; 758; 698; 666; 634; 561. MS: m/z calcd for C15H19NO3Si:
289.11, found: 289 [M]+Å. EA: % calcd: C, 62.25, H, 6.62, N, 4.84,
found: C, 61.88, H, 6.67, N, 4.78.
2.2.2. N-[p-(Trimethylsilylethynyl)benzoyl]-
L-alanine methyl ester (6)
N-(p-Bromobenzoyl)- -alanine methyl ester (4.29 g, 15 mmol)
L
and ethyl acetate (40 ml) were used (reaction time: 4.5 h). Purifica-
tion by flash column chromatography (n-hexane/ethyl acetate 2:1
v/v) afforded 6 as a colorless solid (3.91 g, 86%), mp 126–128 °C.
Fig. 1. Compound formulas of N-(p-ethynylbenzoyl) substituted amino acid and
dipeptide methyl ester derivatives 1–4 studied in this paper.
½
a 2D0
: +13.3 (0.05 M, methanol). Rf: 0.49 (n-hexane/ethyl acetate
ꢁ
2:1 v/v). 1H NMR: dH = 0.26 (9H, s, SiA(CH3)3); 1.41 (3H, d,
3JHH = 7.30, CHACH3); 3.65 (3H, s, OACH3); 4.49 (1H, qui,
Melting points (mp) were determined with a BÜCHI Melting
Point B-450 device (BÜCHI Labortechnik AG, Flawil, Switzerland)
and are uncorrected. Optical rotation measurements were per-
formed on a Perkin–Elmer 241 polarimeter at 20 °C and with
3
3JHH = 7.20, CH); 7.57 (2H, d, JHH = 8.50, ArAH); 7.90 (2H, d,
3
3JHH = 8.55, ArAH); 8.90 (1H, d, JHH = 6.90, NH). 13C NMR:
dC = ꢂ0.16 (SiA(CH3)3); 16.73 (CHACH3); 48.36 (CH); 51.94
(OACH3); 96.62 (C„CASiA(CH3)3); 104.45 (PhAC„C); 125.12,
127.79, 131.56, 133.65 (ArAC); 165.40 (PhACOANH); 173.31
ꢀ
k = 589.3 nm (NaD line). The ½a D20
ꢁ
values are given in 10ꢂ1°cm2 gꢂ1
(including the molar concentration and solvent used for the appro-
priate measurement). 1H and 13C NMR spectra were recorded on a
Bruker Avance III 500 NMR spectrometer at 500.13 MHz and
125.76 MHz, respectively, at 25 °C and with DMSO-d6 as solvent.
Chemical shifts (d) are given in ppm (referring to tetramethylsilane
as internal standard) and coupling constants (3JHH, 2JHH) in Hz. The
multiplicity is given as s (singlet), d (doublet), dd (doublet of dou-
blets), t (triplet), q (quintuplet), m (multiplet) or br s (broad sin-
glet). IR spectra were recorded in the range of
(COAOACH3). IR:
m
¼ 3294; 3066; 2993; 2955; 2895; 2157;
1755; 1739; 1632; 1606; 1543; 1499; 1448; 1435; 1337; 1274;
1252; 1211; 1185; 1166; 1119; 865; 843; 767; 672; 631. MS: m/
z calcd for C16H21NO3Si: 303.13; found: 303 [M]+Å. EA: % calcd: C,
63.33, H, 6.97, N, 4.62, found: C, 63.50, H, 7.23, N, 4.64.
2.2.3. N-[p-(Trimethylsilylethynyl)benzoyl]glycylglycine methyl ester
(7)
ꢂ1
ꢀ
m
N-(p-Bromobenzoyl)glycylglycine
methyl
ester
(4.95 g,
¼ 4000—400 cm using a Nicolet 510-FT-IR spectrometer (KBr
15 mmol) and ethyl acetate (120 ml) were used (reaction time:
5 h). Purification by flash column chromatography (n-hexane/ethyl
acetate 1:3 v/v) yielded 7 as a colorless solid (4.74 g, 91%), mp 135–
137 °C. Rf: 0.31 (n-hexane/ethyl acetate 1:3 v/v). 1H NMR: dH = 0.25
pellets). MS spectra were obtained using a GC/MS system Hew-
lett–Packard 5890 Series II/MS 5989A (electron ionization). The
ESI-MS spectrum was measured on a Varian 320-MS LC/MS system
in negative (ꢂ) scan mode. Elemental analyses (EA) were per-
formed on an Elementar Vario Micro Cube elemental analysator.
3
(9H, s, SiA(CH3)3); 3.63 (3H, s, OACH3); 3.86 (2H, d, JHH = 5.85,
CH2); 3.91 (2H, d, 3JHH = 5.90, CH2); 7.56 (2H, d, 3JHH = 8.25, ArAH);
3
3
7.89 (2H, d, JHH = 8.30, ArAH); 8.36 (1H, t, JHH = 5.80, NH); 8.89
2.2. General procedure for the preparation of the N-[p-
(trimethylsilylethynyl)benzoyl] amino acid and dipeptide methyl
esters 5–8
(1H, t, JHH = 5.90, NH). 13C NMR: dC = ꢂ0.14 (SiA(CH3)3); 40.63,
3
42.48 (CH2); 51.73 (OACH3); 96.56 (C„CASiA(CH3)3); 104.50
(PhAC„C); 124.99, 127.75, 131.57, 134.04 (ArAC); 165.71
(PhACOANH); 169.49, 170.30 (CH2ACOANH, COAOACH3). IR:
ꢀ
The corresponding N-(p-bromobenzoyl) amino acid or dipep-
tide methyl ester (15 mmol) and trimethylsilylacetylene (6.3 ml,
45 mmol) were added to a mixture of dry ethyl acetate and dry
triethylamine (37.5 ml). The resulting mixture was degassed by
sonication for 10 min under argon. Bis(triphenylphosphane)pal-
ladium(II) chloride (105.3 mg, 0.15 mmol), triphenylphosphane
(78.7 mg, 0.3 mmol) and copper(I) iodide (57.1 mg, 0.3 mmol)
were added and the reaction mixture was stirred at 60 °C under ar-
gon. After completion of the reaction (monitored by TLC) and cool-
ing to room temperature, the mixture was washed twice with
saturated NH4Cl solution and once with saturated NaCl solution.
The organic phase was dried over Na2SO4, the solvent removed in
vacuo and the resulting residue subjected to a flash column chro-
matography. Specific details for each compound are given below.
m
¼ 3297; 3079; 2958; 2930; 2895; 2854; 2160; 1739; 1676;
1641; 1606; 1546; 1496; 1442; 1410; 1382; 1306; 1280; 1252;
1217; 1182; 1119; 1033; 1017; 998; 865; 843; 764; 701; 666;
618; 549. MS: m/z calcd for C17H22N2O4Si: 346.13, found: 346
[M]+Å. EA: % calcd: C, 58.93, H, 6.40, N, 8.09, found: C, 59.18, H,
6.55, N, 7.92.
2.2.4. N-[p-(Trimethylsilylethynyl)benzoyl-L-alanylglycine methyl
ester (8)
N-(p-Bromobenzoyl)-L-alanylglycine methyl ester (5.16 g,
15 mmol) and ethyl acetate (150 ml) were used (reaction time:
3.5 h). Purification by flash column chromatography (n-hexane/
ethyl acetate 1:2 v/v) afforded 8 as a colorless solid (3.75 g, 69%),
mp 128–130 °C. ½a D20
ꢁ
: +30.7 (0.02 M, acetone). Rf: 0.35 (n-hexane/
ethyl acetate 1:2 v/v). 1H NMR: dH = 0.24 (9H, s, SiA(CH3)3); 1.35
3
2.2.1. N-[p-(Trimethylsilylethynyl)benzoyl]glycine methyl ester (5)
N-(p-Bromobenzoyl)glycine methyl ester (4.08 g, 15 mmol) and
ethyl acetate (60 ml) were used (reaction time: 5 h). Purification by
flash column chromatography (n-hexane/ethyl acetate 1:1 v/v)
yielded 5 as a colorless solid (3.84 g, 88%), mp 108–110 °C. Rf:
0.52 (n-hexane/ethyl acetate 1:1 v/v). 1H NMR: dH = 0.25 (9H, s,
(3H, d, JHH = 7.25, CHACH3); 3.62 (3H, s, OACH3); 3.82 (1H, dd,
2JHH = 17.35, 3JHH = 5.85, CH2); 3.88 (1H, dd, 2JHH = 17.35,
3JHH = 6.00, CH2); 4.52 (1H, qui, JHH = 7.25, CH); 7.55 (2H, d,
3
3JHH = 8.45, ArAH); 7.91 (2H, d, JHH = 8.45, ArAH); 8.34 (1H, t,
3
3JHH = 5.90, CH2ANH); 8.66 (1H, d, JHH = 7.50, CHANH). 13C NMR:
3
dC = ꢂ0.14 (SiA(CH3)3); 17.83 (CHACH3); 40.69 (CH2); 48.88 (CH);
51.74 (OACH3); 96.51 (C„CASiA(CH3)3); 104.56 (PhAC„C);
124.96, 127.97, 131.49, 134.10 (ArAC); 165.31 (PhACOANH);
ꢀ
3
SiA(CH3)3); 3.66 (3H, s, OACH3); 4.02 (2H, d, JHH = 5.85, CH2);
3
3
7.57 (2H, d, JHH = 8.35, ArAH); 7.87 (2H, d, JHH = 8.40, ArAH);
3
9.05 (1H, t, JHH = 5.85, NH). 13C NMR: dC = ꢂ0.15 (SiA(CH3)3);
170.33, 172.95 (CHACOANH, COAOACH3). IR:
m
¼ 3351; 3291;

F. Eißmann, E. Weber / Journal of Molecular Structure 1005 (2011) 121–128
123
3
3088; 2955; 2895; 2164; 1755; 1673; 1647; 1609; 1537; 1496;
1451; 1410; 1375; 1252; 1217; 1182; 1014; 869; 843; 761; 701;
669. MS: m/z calcd for C18H24N2O4Si: 360.15, found: 360 [M]+Å.
EA: % calcd: C, 59.97, H, 6.71, N, 7.77, found: C, 59.59, H, 7.10, N,
7.82.
3JHH = 5.95, CH2); 4.38 (1H, s, C„CAH); 7.59 (2H, d, JHH = 8.30,
3
3
ArAH); 7.90 (2H, d, JHH = 8.30, ArAH); 8.37 (1H, t, JHH = 5.80,
NH); 8.90 (1H, t, JHH = 5.95, NH). 13C NMR: dC = 40.66, 42.49
3
(CH2); 51.76 (CH3); 82.96 (C„C); 124.64, 127.76, 131.69, 134.11
(ArAC); 165.76 (PhACOANH); 169.53, 170.33 (CH2ACOANH,
ꢀ
COAOACH3). IR:
m
¼ 3332; 3291; 3231; 3079; 2996; 2980; 2952;
2.3. General procedure for the preparation of the N-(p-ethynylbenzoyl)
amino acid and dipeptide methyl esters 1–4
2917; 2854; 2103; 1733; 1670; 1641; 1609; 1559; 1505; 1461;
1442; 1423; 1407; 1394; 1372; 1356; 1328; 1309; 1280; 1258;
1236; 1195; 1059; 1040; 1017; 995; 859; 767; 726; 691; 628;
552. MS: m/z calcd for C14H14N2O4: 274.10, found: 274 [M]+Å.
EA: % calcd: C, 61.31, H, 5.14, N, 10.21, found: C, 61.13, H, 5.22,
N, 10.21.
The corresponding N-[p-(trimethylsilylethynyl)benzoyl] amino
acid or dipeptide methyl ester (8 mmol) was dissolved in dry
methanol. Finely powdered K2CO3 (0.11 g, 0.8 mmol) was added
and the mixture was stirred at room temperature. After completion
of the reaction (monitored by TLC), the mixture was diluted with
65 ml of ethyl acetate, washed with diluted NaHCO3 solution
(2 ꢃ 30 ml) and 25 ml of water. After drying over Na2SO4, the sol-
vent was removed in vacuo and the resulting residue purified by
flash column chromatography or recrystallization. Specific details
for each compound are given below.
2.3.4. N-(p-Ethynylbenzoyl)- -alanylglycine methyl ester (4)
L
Compound 8 (2.89 g, 8 mmol) and methanol (25 ml) were used
(reaction time: 3.5 h). Recrystallization from methanol/diethyl
ether afforded 4 as an off-white solid (1.61 g, 70%), mp 166–
167 °C. ½a 2D0
ꢁ
: +6.7 (0.05 M, methanol). 1H NMR: dH = 1.36 (3H, d,
3JHH = 7.25, CHACH3); 3.63 (3H, s, OACH3); 3.83 (1H, dd,
2JHH = 17.35, 3JHH = 5.85, CH2); 3.89 (1H, dd, 2JHH = 17.30,
3JHH = 6.00, CH2); 4.37 (1H, s, C„CAH); 4.53 (1H, qui, JHH = 7.30,
3
2.3.1. N-(p-Ethynylbenzoyl)glycine methyl ester (1)
CH); 7.58 (2H, d, 3JHH = 8.25, ArAH); 7.93 (2H, d, 3JHH = 8.30, ArAH);
8.36 (1H, t, 3JHH = 5.85, CH2ANH); 8.67 (1H, d, 3JHH = 7.50, CHANH).
13C NMR: dC = 17.76 (CHACH3); 40.61 (CH2); 48.79 (CH); 51.66
(OACH3); 82.80, 82.91 (C„C); 124.50, 127.88, 131.49, 134.10
(ArAC); 165.30 (PhACOANH); 170.26, 172.87 (CHACOANH,
ꢀ
Compound 5 (2.32 g, 8 mmol) and methanol (25 ml) were used
(reaction time: 3 h). Purification by flash column chromatography
(n-hexane/ethyl acetate 1:1 v/v) yielded 1 as a colorless solid
(1.42 g, 82%), mp 116–118 °C. Rf: 0.39 (n-hexane/ethyl acetate
3
1:1 v/v). 1H NMR: dH = 3.66 (3H, s, CH3); 4.03 (2H, d, JHH = 5.85,
3
CH2); 4.39 (1H, s, C„CAH); 7.61 (2H, d, JHH = 8.35, ArAH); 7.89
COAOACH3). IR:
m
¼ 3297; 3265; 3082; 2984; 2958; 2933; 2107;
3
3
(2H, d, JHH = 8.40, ArAH); 9.06 (1H, t, JHH = 5.80, NH). 13C NMR:
dC = 41.32 (CH2); 51.84 (CH3); 82.89, 83.06 (C„C); 124.85,
127.63, 131.84, 133.70 (ArAC); 165.90 (PhACOANH); 170.35
ꢀ
1746; 1663; 1625; 1559; 1537; 1499; 1448; 1385; 1366; 1340;
1293; 1277; 1220; 1182; 1166; 1021; 976; 897; 856; 767; 713;
666; 634. ESI(-)-MS: m/z calcd for C15H16N2O4: 288.11, found:
287.1 [MꢂH]ꢂ, 322.9 [M+Cl]ꢂ. EA: % calcd: C, 62.49, H, 5.59, N,
9.72, found: C, 62.49, H, 5.84, N, 9.57.
(COAOACH3). IR:
m
¼ 3265; 3085; 3072; 3028; 2955; 2857;
2110; 1749; 1625; 1546; 1499; 1432; 1416; 1369; 1328; 1309;
1283; 1217; 1182; 1112; 1071; 1024; 998; 976; 862; 777; 720;
650; 637; 542. MS: m/z calcd for C12H11NO3: 217.07, found: 217
[M]+Å. EA: % calcd: C, 66.35, H, 5.10, N, 6.45, found: C, 66.00, H,
5.27, N, 6.23.
2.4. X-ray structure determination
Crystals suitable for X-ray crystal structure determination were
obtained by slow evaporation of solutions of the respective com-
pounds in ethyl acetate (1–3) and methanol (4).
The X-ray crystal structure analyses were performed using a
Bruker Kappa diffractometer equipped with an APEX II CCD area
2.3.2. N-(p-Ethynylbenzoyl)- -alanine methyl ester (2)
L
Compound 6 (2.42 g, 8 mmol) and methanol (25 ml) were used
(reaction time: 4 h). Purification by flash column chromatography
(n-hexane/ethyl acetate 2:1 v/v) afforded 2 as a colorless solid
detector and graphite-monochromatized Mo
Ka radiation
(1.58 g, 85%), mp 113–115 °C. ½a D20
ꢁ
: +4.8 (0.05 M, methanol). Rf:
(k = 0.71073 Å) employing and scan modes. The data were cor-
u
x
0.33 (n-hexane/ethyl acetate 2:1 v/v). 1H NMR: dH = 1.41 (3H, d,
3JHH = 7.30, CHACH3); 3.65 (3H, s, OACH3); 4.39 (1H, s, C„CAH);
rected for Lorentz and polarization effects. Semiempirical absorp-
tion corrections were applied using the SADABS program and the
SAINT program was utilized for the integration of the diffraction
profiles [15]. 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 [16]. All non-hydrogen atoms
were refined anisotropically; hydrogen atoms were generated at
ideal geometrical positions and refined with the appropriate riding
model. Geometrical calculations were performed using PLATON
[17] and molecular graphics were generated using SHELXTL [16].
The crystallographic data and refinement details of all compounds
studied are summarized in Table SUP-1.
3
3
4.49 (1H, qui, JHH = 7.20, CH); 7.59 (2H, d, JHH = 8.40, ArAH);
3
3
7.90 (2H, d, JHH = 8.55, ArAH); 8.89 (1H, d, JHH = 6.90, NH). 13C
NMR: dC = 16.76 (CHACH3); 48.39 (CH); 51.97 (OACH3); 82.91,
83.01 (C„C); 124.76, 127.80, 131.71, 133.76 (ArAC); 165.50
ꢀ
(PhACOANH); 173.12 (COAOACH3). IR:
m
¼ 3332; 3246; 3006;
2952; 2923; 2851; 2107; 1739; 1641; 1609; 1530; 1496; 1461;
1363; 1318; 1271; 1220; 1169; 856; 774; 701; 653; 628. MS: m/z
calcd for C13H13NO3: 231.09, found: 231 [M]+Å. EA: % calcd: C, 67.52,
H, 5.67, N, 6.06, found: C, 67.32, H, 5.76, N, 6.04.
2.3.3. N-(p-Ethynylbenzoyl)glycylglycine methyl ester (3)
Compound 7 (2.77 g, 8 mmol) and methanol (50 ml) were used
(reaction time: 2 h). In contrast to the general procedure described
above, the precipitated solid was separated and washed with
methanol (2 ꢃ 20 ml) to yield a first product fraction. The remain-
ing solution was diluted with 150 ml of ethyl acetate, washed with
diluted NaHCO3 solution (2 ꢃ 50 ml) and 50 ml of water. After dry-
ing over Na2SO4, the solvent was removed in vacuo. The resulting
second product fraction was purified by recrystallization from
methanol. Both product fractions were combined to yield 3 as an
off-white solid (1.74 g, 79%), mp 178–180 °C. 1H NMR: dH = 3.63
3. Results and discussion
3.1. Synthesis of N-(p-ethynylbenzoyl) amino acid and dipeptide
methyl esters
Starting from corresponding N-(p-bromobenzoyl) amino acid
and dipeptide methyl esters [14], a series of four N-(p-eth-
ynylbenzoyl) amino acid and dipeptide methyl ester derivatives
(1–4)was synthesizedvia a reactionsequenceas shownin Scheme1,
respectively. In a first step, the N-(p-bromobenzoyl) derivatives
3
(3H, s, CH3); 3.86 (2H, d, JHH = 5.85, CH2); 3.92 (2H, d,

124
F. Eißmann, E. Weber / Journal of Molecular Structure 1005 (2011) 121–128
were reacted with trimethylsilylacetylene (TMSA) in a Pd-catalyzed
Sonogashira-Hagihara-type CAC coupling procedure [5,18] to yield
the ethynyl-protected N-[(p-trimethylsilylethynyl)benzoyl] amino
acid and dipeptide methyl esters (intermediates 5–8). In the second
step, the deprotection of the ethynyl group of 5–8 using potassium
carbonate in methanol was carried out to afford the target com-
pounds 1–4 used for the crystallographic study.
3.2. Crystal structures of the amino acid derivatives 1 and 2
The molecular structures of compounds 1 and 2 (Fig. 2) are
characterized by nearly planar and trans-configurated amide bonds
being be derived from the torsion angles O1AC7AN1AC8 [1: 4.2
(2)°, 2: 1.5(2)°] and xꢂ1⁄ [1: ꢂ173.8(1)°, 2: ꢂ176.9(2)°], respec-
tively (Table 1). Differences occur in the torsion angle
C3AC4AC7AO1 referring to the torsion of the phenyl ring with re-
gard to the amide fragment and to a minor extent in the character-
istic torsion angles u1 as well as w1⁄ defining the conformation of
the amino acid (Table 1). Hence, except for the different torsion of
the phenyl ring with reference to the amide bond which could be
caused by packing effects, the additional methyl group in the L-ala-
Fig. 2. Molecular structures of compounds
1 (a) and 2 (b) including atom
nine derivative 2 does not significantly influence the molecular
structure of the amino acid which is illustrated by a structural
overlay plot in Fig. 3.
numbering schemes. Thermal displacement ellipsoids are drawn at the 50%
probability level.
The packing structures of the glycine and L-alanine derivatives 1
and 2 are stabilized by numerous hydrogen bonding interactions
including stronger NAHꢀ ꢀ ꢀO [19] and weaker CAHꢀ ꢀ ꢀO contacts
[20] (Table 2). In both crystal packings molecular strands are
formed due to the N1AH1ꢀ ꢀ ꢀO1 interaction involving the amide
N atom as donor and the amide O atom as acceptor site (Fig. 4).
In the packing of compound 1, the strand motif is further stabilized
by an additional (aryl)CAHꢀ ꢀ ꢀO type contact (C5AH5ꢀ ꢀ ꢀO1) result-
ing in the formation of a bifurcated-acceptor type hydrogen bond
[21] which is also the case for the corresponding N-(p-bromoben-
zoyl) derivative described in a previous study [14]. The character-
istic strands formed by the molecules of compound 1 run along the
crystallographic c axis and exhibit an alternating arrangement of
molecules. In contrast to 1, the strand formation in the packing
of compound 2 is assisted by a CAHꢀ ꢀ ꢀO interaction involving the
Table 1
Selected torsion angles (°) for the compounds 1 and 2.
Torsion angle
1
2
C3AC4AC7AO1
C4AC7AN1AC8 (xꢂ1⁄
C7AN1AC8AC9 (u1
C7AN1AC8AC11
C8AC9AO3AC10 (x1⁄
N1AC8AC9AO3 (w1⁄
O1AC7AN1AC8
14.5(2)
ꢂ173.8(1)
ꢂ67.8(2)
–
177.0(2)
158.2(1)
4.2(2)
30.5(2)
)
ꢂ176.9(2)
ꢂ74.9(2)
163.3(2)
ꢂ178.1(2)
146.5(2)
1.5(2)
)
)
)
L
-alanine C methyl group (C11) as donor and the ester O atom
a
(O3) as acceptor being in agreement with the previously published
structure of the corresponding N-(p-bromobenzoyl)- -alanine
L
methyl ester [14]. In the packing of compound 2, the strands are
arranged parallel to the crystallographic a axis and show a regular,
non-alternating molecular arrangement pattern.
The interactions between different strands within the crystal
structures of 1 and 2 comprising (methyl)CAHꢀ ꢀ ꢀO and (ethy-
nyl)CAHꢀ ꢀ ꢀO contacts [20] are of a weaker nature. In the packing
of 1, different strands are linked via (ethynyl)C12AH12ꢀ ꢀ ꢀO2 inter-
actions on one edge and (methyl)C10AH10Cꢀ ꢀ ꢀO1 contacts on the
Fig. 3. Structural overlay of 1 (orange) and 2 (cyan). The overlay was calculated
with RMS = 0.168 using pairs of atoms C7AC10, O1AO3 and N1, respectively. (For
interpretation of the references to colour in this figure legend, the reader is referred
to the web version of this article.)
Scheme 1. Two-step synthesis of compounds 1–4 via the respective intermediates 5–8 starting from the appropriate N-(p-bromobenzoyl) amino acid or peptide methyl
ester.

F. Eißmann, E. Weber / Journal of Molecular Structure 1005 (2011) 121–128
125
Table 2
Interactions in the crystal structures of compounds 1 and 2.
Atoms involved
Symmetry
Distance (Å)
Angle (°)
r(DAH)
d(Hꢀ ꢀ ꢀA)
D(Dꢀ ꢀ ꢀA)
h(DAHꢀ ꢀ ꢀA)
1
N1AH1ꢀ ꢀ ꢀO1
C5AH5ꢀ ꢀ ꢀO1
C10AH10Cꢀ ꢀ ꢀO1
C12AH12ꢀ ꢀ ꢀO2
x, ꢂy + 1/2, zꢂ1/2
x, ꢂy + 1/2, z ꢂ 1/2
ꢂx + 2, ꢂy + 1, ꢂz + 1
ꢂx + 1, ꢂy + 1, ꢂz
0.88
0.95
0.98
0.95
2.00
2.38
2.54
2.35
2.848(2)
3.275(2)
3.120(2)
3.191(2)
162.5
156.5
117.8
147.0
2
N1AH1ꢀ ꢀ ꢀO1
C11AH11Bꢀ ꢀ ꢀO2
C11AH11Cꢀ ꢀ ꢀO3
C13AH13ꢀ ꢀ ꢀO2
x + 1, y, z
x, y, z + 1
x + 1, y, z
ꢂx + 1, y ꢂ 1/2, ꢂz + 1
0.88
0.98
0.98
0.95
2.20
2.43
2.41
2.31
3.052(2)
3.293(2)
3.345(2)
3.258(3)
164.1
146.7
158.7
174.4
Fig. 4. Characteristic strand motifs within the packing structures of 1 (a) and 2 (b). Hydrogen bonding interactions are represented as dashed lines.
other one while for 2 the connection of different strands is realized
via (ethynyl) C13AH13ꢀ ꢀ ꢀO2 and (methyl)C11AH11Bꢀ ꢀ ꢀO2 interac-
tions both contributing to bifurcated-acceptor type hydrogen
bonds [21]. Packing diagrams of the crystal structures of the amino
acid derivatives 1 and 2 are included in the electronic supplemen-
tary material (Figs. 1sup and 2sup).
In agreement with the amino acid derivatives 1 and 2, the
packing structures of the N-substituted dipeptide methyl esters
3 and 4 are characterized by the formation of strands being sta-
bilized by NAHꢀ ꢀ ꢀO hydrogen bonding interactions [19] compris-
ing the peptide group as donor and acceptor site (N2AH2Nꢀ ꢀ ꢀO2
for 3, N2AH2Nꢀ ꢀ ꢀO6 and N4AH4Nꢀ ꢀ ꢀO2 for 4, Table 4). As shown
in Fig. 7a, the strands in the packing of 3 are orientated in direc-
tion of the crystallographic a axis while the strands in the crystal
structure of 4 are aligned parallel to the [ac] face diagonal and
consist of the independent molecules 40and 400 arranged in an
alternating manner (Fig. 7b). Besides the NAHꢀ ꢀ ꢀO contacts,
weaker (alkyl)CAHꢀ ꢀ ꢀO interactions [20] assist the formation of
the characteristic strand motifs. For 3, an additional (methy-
lene)CAHꢀ ꢀ ꢀO interaction (C10AH10ꢀ ꢀ ꢀO3) is observed, while in
the strand of 4, the NAHꢀ ꢀ ꢀO contact is assisted by CAHꢀ ꢀ ꢀO
interactions comprising methyl, methine and methylene C atoms
3.3. Crystal structures of the dipeptide derivatives 3 and 4
The asymmetric units of the dipeptide derivatives consist of one
molecule in the case of compound 3 and two molecules (40 and 400)
in the case of compound 4 (Fig. 5). The examination of appropriate
torsion angles shows that both the amide and the peptide bond
within the respective molecular structures are nearly planar and
trans-configurated. The planarity of these bonds can be deduced
from the torsion angles O1AC7AN1AC8 (3 and 40) and
O5AC22AN3AC23 (400) for the amide bonds as well as
O2AC9AN2AC10 (3 and 40) and O6AC24AN4AC25 for the peptide
bonds, respectively, being approximately 0° (Table 3). The trans-
configuration is proven by the torsion angles xꢂ1⁄ and x1 for the
amide and peptide bonds, respectively, adopting values of approx-
imately 180° (Table 3). A maximum deviation for these ideal val-
ues is found for the peptide bond in 40 with torsion angles of
as
donor
sites
(C12AH12Bꢀ ꢀ ꢀO7,
C23AH23ꢀ ꢀ ꢀO2
and
C25AH25Aꢀ ꢀ ꢀO3).
In the crystal structures of 3 and 4, the molecular strands are
connected by different interactions with the remaining amide
group and the ethynyl substituent being of major importance. In
both of the crystal structures, the strands are linked to each other
via NAHꢀ ꢀ ꢀO interactions (N1AH1Nꢀ ꢀ ꢀO1 for 3, N1AH1Nꢀ ꢀ ꢀO5 and
N3AH3Nꢀ ꢀ ꢀO1 for 4) which are slightly weaker than those mediat-
ing the linkage within the strands (Table 4). The ethynyl substitu-
ent in each crystal structure acts both as hydrogen bonding donor
and acceptor. Acting as a donor, CAHꢀ ꢀ ꢀO contacts are formed (3:
C14AH14ꢀ ꢀ ꢀO3, 4: C15AH15ꢀ ꢀ ꢀO3). In the function of an acceptor,
the midpoint of the triple bond takes part in different CAHꢀ ꢀ ꢀCg
interactions (Table 4). The resulting rather complex packing dia-
grams caused by the numerous intermolecular interactions are in-
cluded in the electronic supplementary material (Figs. 3sup and
4sup).
10.3(2)° (O2AC9AN2AC10) and ꢂ170.4(2)° (
x1). As already un-
veiled in Fig. 5b, the torsion angle w2⁄ (N2AC10AC11AO4 for 40
and N4AC25AC26AO8 for 400, respectively) is the major conforma-
tive difference between the two independent molecules within the
asymmetric unit of 4. A structural overlay plot, making this differ-
ence more obvious, is given in Fig. 6. For 3, 40 and 400, differences
occur in the torsion of the phenyl ring with reference to the amide
bond being represented by values of ꢂ10.4(2)°, 23.2(2)° and
34.0(2)° for the appropriate torsion angle C3AC4AC7AO1 or
C18AC19AC22AO5, respectively.

126
F. Eißmann, E. Weber / Journal of Molecular Structure 1005 (2011) 121–128
Fig. 5. Asymmetric units of the dipeptide derivatives 3 (a) and 4 (b) including atom numbering schemes. The two independent molecules in the asymmetric unit of 4 are 40 on
the top and 400 at the bottom of (b). Thermal displacement ellipsoids are drawn at the 50% probability level.
Table 3
Selected torsion angles (°) for compounds 3 and 4.
Torsion angle
3
4
40
400
C3AC4AC7AO1/C18AC19AC22AO5a
C4AC7AN1AC8/C19AC22AN3AC23a
C7AN1AC8AC9/C22AN3AC23AC24a
ꢂ10.4(2)
179.3(2)
ꢂ77.0(2)
–
ꢂ174.7(2)
ꢂ58.9(2)
179.2(2)
175.6(2)
ꢂ34.9(2)
ꢂ0.2(2)
5.0(2)
23.2(2)
34.0(2)
(
xꢂ1⁄
u1
)
ꢂ177.3(2)
ꢂ67.2(2)
170.5(2)
ꢂ170.4(2)
ꢂ65.4(2)
ꢂ175.8(2)
162.2(2)
ꢂ40.4(2)
0.9(2)
ꢂ176.4(2)
ꢂ71.4(2)
167.6(2)
179.4(2)
ꢂ73.3(2)
178.0(2)
157.8(2)
146.3(2)
2.0(2)
(
)
C7AN1AC8AC13/C22AN3AC23AC28a
C8AC9AN2AC10/C23AC24AN4AC25a
(
x1
u2
x2⁄
)
C9AN2AC10AC11/C24AN4AC25AC26a
(
)
C10AC11AO4AC12/C25AC26AO8AC27a
(
)
N1AC8AC9AN2/N3AC23AC24AN4a
(w1
)
N2AC10AC11AO4/N4AC25AC26AO8a
O1AC7AN1AC8/O5AC22AN3AC23a
O2AC9AN2AC10/O6AC24AN4AC25a
(w2⁄)
10.3(2)
1.4(2)
a
The first torsion angle refers to 3 and 40, the second one to 400, respectively.
4. Conclusions
Four new amino acid and dipeptide derivatives featuring N-(p-
ethynylbenzoyl) substituents have been prepared and character-
ized by standard analytical methods. The presented compounds
are promising building blocks for the generation of new bioconju-
gate structures. The synthetic procedure is based on N-(p-bromo-
benzoyl) amino acid and dipeptide methyl esters which can be
prepared by a previously described protocol [14] and comprises a
CAC coupling step of the Sonogashira-Hagihara-type using
Fig. 6. Structural overlay of 40 (green) and 400 (yellow). The overlay was calculated
with RMS = 0.181 using all pairs of non-hydrogen atoms except those labeled in the
figure. (For interpretation of the references to colour in this figure legend, the reader
is referred to the web version of this article.)

F. Eißmann, E. Weber / Journal of Molecular Structure 1005 (2011) 121–128
127
Table 4
Interactions in the crystal structures of compounds 3 and 4.
Atoms involved
Symmetry
Distance (Å)
Angle (°)
r(DAH)
d(Hꢀ ꢀ ꢀA)
D(Dꢀ ꢀ ꢀA)
h(DAHꢀ ꢀ ꢀA)
3
N1AH1Nꢀ ꢀ ꢀO1
N2AH2Nꢀ ꢀ ꢀO2
C10AH10Aꢀ ꢀ ꢀO3
C10AH10Bꢀ ꢀ ꢀCg*
C12AH12Cꢀ ꢀ ꢀCg*
C14AH14ꢀ ꢀ ꢀO3
x, ꢂy + 1/2, zꢂ1/2
x + 1, y, z
x + 1, y, z
x + 1, ꢂy + 1/2, z + 1/2
x + 1, ꢂy + 1/2, zꢂ1/2
ꢂx, yꢂ1/2, ꢂz + 3/2
0.88
0.88
0.99
0.99
0.98
0.95
2.05
1.94
2.48
2.82
2.74
2.33
2.865(2)
2.809(2)
3.337(2)
3.795(2)
3.718(2)
3.282(2)
154.1
168.5
144.2
170.4
176.9
174.6
4
N1AH1Nꢀ ꢀ ꢀO5
N2AH2Nꢀ ꢀ ꢀO6
N3AH3Nꢀ ꢀ ꢀO1
N4AH4Nꢀ ꢀ ꢀO2
C10AH10Aꢀ ꢀ ꢀO7
C12AH12Bꢀ ꢀ ꢀO7
C12AH12Cꢀ ꢀ ꢀCg1*
C15AH15ꢀ ꢀ ꢀO3
C23AH23ꢀ ꢀ ꢀO2
C25AH25Aꢀ ꢀ ꢀO3
C27AH27Aꢀ ꢀ ꢀO3
C27AH27Bꢀ ꢀ ꢀCg2*
C27AH27Cꢀ ꢀ ꢀCg2*
x, y, z
0.88
0.88
0.88
0.88
0.99
0.98
0.98
0.95
1.00
0.99
0.98
0.98
0.98
2.28
2.04
2.26
2.05
2.56
2.50
2.94
2.23
2.54
2.51
2.58
2.98
2.91
3.134(2)
2.880(2)
3.116(2)
2.905(2)
3.150(2)
3.473(3)
3.769(5)
3.181(2)
3.188(2)
3.286(2)
3.555(2)
3.633(5)
3.708(4)
165.0
159.8
164.7
162.3
118.5
175.8
142.9
178.1
122.2
135.4
173.6
125.0
139.3
x, y, zꢂ1
xꢂ1, y, z + 1
xꢂ1, y, z
x + 1, y, z ꢂ 1
x + 1, y, z
ꢂx + 1, y + 1/2, ꢂz + 1
ꢂx + 2, y ꢂ 1/2, ꢂz + 1
xꢂ1, y, z
xꢂ1, y, z
xꢂ1, y, z + 1
ꢂx, y + 1/2, ꢂz + 2
ꢂx + 1, y + 1/2, ꢂz + 2
*
Cg, Cg1 and Cg2 are the midpoints of the triple bonds C13„C14, C14„C15 and C29„C30.
Fig. 7. Molecular strands within the crystal structures of 3 (a) and 4 (b). Hydrogen bonds are represented as dashed lines. For (b), only hydrogen atoms involved in hydrogen
bonding interactions have been included, others have been omitted for clarity.
trimethylsilylacetylene (TMSA) as a protected acetylene com-
pound, followed by a deprotection step to remove the trimethyl-
silyl group and to generate the free ethynyl substituent.
Appendix A. Supplementary data
Table SUP-1 (containing crystallographic data and refinement
details for the compounds studied), Fig. 1sup, Fig. 2sup, Fig. 3sup
and Fig. 4sup (containing packing diagrams of compounds 1, 2, 3
and 4, respectively). 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 833948 (1), 833949 (2), 833950 (3)
and 833951 (4). Supplementary data associated with this article
can be found, in the online version, at doi:10.1016/
j.molstruc.2011.08.034.
X-ray crystal structures of compounds 1–4 show that the amide
and peptide bonds within the molecules are all planar and adopt
the usually favored trans-configuration. In the molecular structures
of 1–4, the p-ethynylbenzoyl fragment is distorted towards the
neighboring amide bond, with the respective torsion angle varying
from ꢂ10.4(2)° to 34.0(2)°. The deviation from the ideal coplanar
arrangement may be due to sterical hindrance between the amide
hydrogen and the aryl hydrogen in o-position or caused by packing
effects as the amide hydrogen is involved in an NAHꢀ ꢀ ꢀO hydrogen
bond, respectively. The packing structures of compounds 1–4 are
dominated by NAHꢀ ꢀ ꢀO interactions leading to the formation of
molecular strands as characteristic structural motifs. Further sta-
bilization of the packing structures results from weaker CAHꢀ ꢀ ꢀO
or CAHꢀ ꢀ ꢀ
p contacts where – among others – interactions involv-
ing the ethynyl substituent either as donor or acceptor site are of
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