Amino-acid-functionalized solvatochromic probes

Article abstract of DOI:10.1002/poc.1306

N-(4-nitrophenyl)-L-proline (2) has been obtained by a nucleophilic aromatic substitution reaction of 4-fluoronitrobenzene with L-proline. The corresponding amide derivatives 3-5 have been synthesized by peptide coupling of 2 with different amino acid derivatives and chiral amines. Solvatochromism of the long-wavelength UV/Vis band in the electronic absorption spectra of the compounds 2-5 has been studied and analyzed using the empirical Kamlet-Taft solvent polarity parameters π* (dipolarity/polarizability), α (hydrogen bond donating ability), and β (hydrogen bond accepting ability). Reasonable Kamlet-Taft solvatochromic correlations (r > 0.95) were established for the three amide derivatives 3-5 in a range of common solvents and three room temperature ionic liquids (RTILs). The UV/Vis absorption of the 4-nitroaniline derivative 2 showed a hypsochromic shift with increasing concentration due to intermolecular hydrogen bonded aggregate formation in protic solvents, which is not observed for compounds 3-5. Copyright 2008 John Wiley & Sons, Ltd.

Full text of DOI:10.1002/poc.1306

Research Article
Received: 10 April 2007,
Revised: 1 November 2007,
Accepted: 2 November 2007,
Published online in Wiley InterScience: 17 January 2008
(www.interscience.wiley.com) DOI 10.1002/poc.1306
Amino-acid-functionalized
solvatochromic probes
a
Katja Schreiter and Stefan Spange
a
*
N-(4-nitrophenyl)-L-proline (2) has been obtained by a nucleophilic aromatic substitution reaction of 4-fluoroni-
trobenzene with L-proline. The corresponding amide derivatives 3–5 have been synthesized by peptide coupling of 2
with different amino acid derivatives and chiral amines. Solvatochromism of the long-wavelength UV/Vis band in the
electronic absorption spectra of the compounds 2–5 has been studied and analyzed using the empirical Kamlet–Taft
*
solvent polarity parameters p (dipolarity/polarizability), a (hydrogen bond donating ability), and b (hydrogen bond
accepting ability). Reasonable Kamlet–Taft solvatochromic correlations (r > 0.95) were established for the three amide
derivatives 3–5 in a range of common solvents and three room temperature ionic liquids (RTILs). The UV/Vis
absorption of the 4-nitroaniline derivative 2 showed a hypsochromic shift with increasing concentration due to
intermolecular hydrogen bonded aggregate formation in protic solvents, which is not observed for compounds 3–5.
Copyright ß 2008 John Wiley & Sons, Ltd.
Keywords: amino acid; chirality; nucleophilic substitution; chromophores; solvatochromism
used as the guest component in a a- and b-cyclodextrine
complex, respectively.[57,58]
INTRODUCTION
The development of specific molecular probes for the recognition
of specific binding sites in peptides and proteins is a challenge
due to the manifold interaction which can possibly occur in those
complex systems.[1–6]
The aim of the present work was the synthesis and structural
characterization of several amino acid and dipeptide functiona-
lized 4-nitroaniline derivatives 2–5 and the investigation of their
solvatochromic properties in detail (Scheme 1).
The detection of separate di- or tripeptide sequences in rapid
protein scans requires the application of suitable sets of sequence
specific UV/Vis sensors. However, the pioneering works of
Still[7–17] and other scientists[18–30] have shown that specific
peptide sequences can be recognized by artificial receptors,
which are based on cage-compounds and related molecular struc-
tures. The usage of such a complementary di- or tripeptide
sequence, which is suitable to interact specifically with a target
peptide sequence, seems a promising concept, because the same
principle occurs in nature. However, even the distinct differen-
tiation of the 20 common genetically encoded amino acids by a
suitable UV/Vis probe is still not established, because of the chemical
similarity of the amino acids due to their ionic nature.[31,32]
The objective of this study is the synthesis of novel UV/Vis
probes bearing amino acid sequences linked to the chromo-
phoric p-electron system. The direct linking of amino acid
moieties to UV/Vis and fluorescence probes for environment
responsive probing is a new field where scientific activities have
been started since the last 5 years.[33–38] For preliminary and basic
studies we chose 4-nitroaniline derivatives as these have been
widely used in materials science (nonlinear optics)[39–43] and
analysis (solvatochromism).[44–55] There are a large number of
substituted p-nitroaniline derivatives, which are used as
solvent-sensitive indicators for setting up polarity scales,[44–52]
as lipophilic indicators in micelles, bi-layers, and biological
membranes.[53–55] In this context, amino acid (L-proline)
substituted nitroaniline derivatives are chiral organic compounds
suitable as materials for optical second harmonic generation.[56]
4-N-proline substituted nitroaniline derivatives have been also
Compound 2 was first synthesized by Yoshino et al.,[56]
however, no details of the preparation procedure and chemical
analysis were reported. The synthesis of 2 was also reported by Lo
Meo et al.[58] using another synthetic procedure. Major attention
was devoted to the study of the complex formation with a- and
b-cyclodextrine.[58] At the same time, nitroanilines such as 2 are
an interesting object studying the specific solvatochromic effects,
in view of the fact that these compounds can form several types
of hydrogen bonded complexes. However, interpretation of
preliminary solvatochromic investigations of 2 by El-Sayed[59]
showed inadequate conclusions.
In this work we wanted to show particularly whether and how
the peptide moiety of 3, 4, and 5 has an effect on the
chromophoric p-electron system as a result of interactions with
the surroundings of the molecules. It is to clarify, what proportion
of these environment effects are dipole–dipole and/or hydrogen
bond or acid–base interactions. To separate the individual solva-
tion effects we used the simplified Kamlet–Taft equation[49,50]
[Eqn (1)] from which the coefficients of the individual interaction
*
Department of Polymer Chemistry, Institute of Chemistry, Chemnitz University
of Technology, Strasse der Nationen 62, 09111 Chemnitz, Germany.
E-mail: stefan.spange@chemie.tu-chemnitz.de
a
K. Schreiter, S. Spange
Department of Polymer Chemistry, Institute of Chemistry, Chemnitz University
of Technology, Strasse der Nationen 62, 09111 Chemnitz, Germany
J. Phys. Org. Chem. 2008, 21 242–250
Copyright ß 2008 John Wiley & Sons, Ltd.

SOLVATOCHROMIC PROBES
Scheme 1. Compounds 2–5 studied in this work
Scheme 3. Reaction scheme for peptide coupling reactions
contributions can be determined using multiple correlation
analysis.[44,45]
The method of choice was the synthetic strategy I in presence
of N,N0-dicyclohexylcarbodiimide (DCC)/Et3N/N,N-dimethylamino
pyridine (DMAP)[75,76] to afford the corresponding amides 3–5
(Scheme 3).
nmax ¼ nmax;0 þ aa þ bb þ spÃ
where nmax is the longest wavelength UV/Vis absorption maxi-
(1)
~
~
~
For the peptide coupling reaction, the hydrochlorides of
glycine methyl ester and L-alanine methyl ester have been
selected. For this study we also considered a sterically demanding
bicyclic amine linked via a peptide bond to the proline carboxylic
group to show the influence of twisting of the L-proline ring upon
solvation. In regard to the configuration of the amide derivatives
it proved to be more difficult than expected. The absolute con-
figurations of the chiral crystals of 2, 3, and 4 were determined by
X-ray crystal structure analysis using the Flack[77–79] parameter
method. X-ray crystal structure analyses reveal that partial
racemization was only obtained for compound 4. In a subsequent
paper we will report on the solid state structures.[80]
~
mum of the compound measured in a particular solvent, nmax;0 is
[46]
that of a nonpolar reference solvent, a
hydrogen bond donor (HBD) ability, b
reflects solvent
reflects solvent
[47]
hydrogen bond acceptor (HBA) ability, and p*[48,49] describes the
dipolarity/polarizability of the solvent. a, b, and s are the solvent-
independent correlation coefficients, which allow the effects of a
particular parameter on the solvatochromic properties of the
compound to be determined.
RESULTS AND DISCUSSION
An associated problem derives from the unknown influence of
the push–pull p-electron system on the electronic properties of
the amino acid or dipeptide linkage. This point plays a role in the
interpretation of the results.
Synthesis
As extension of our studies on solvatochromic compounds[60–71]
and to establish the influence of intermolecular hydrogen bonds
between crystals in combination with a chiral center on the
photophysical properties of these compounds, we prepared
N-(4-nitrophenyl)-L-proline (2) by nucleophilic aromatic substi-
tution in a mixture of EtOH/H2O (3:1) (Scheme 2). Due to the high
reactivity of 1-fluoro-4-nitrobenzene[72] and the cyclic amine[73]
L-proline a high yield was obtained with aqueous ethanol[74] as
solvent.
Compound 2 can be coupled with other amino acids,
dipeptides or oligopeptides via the remaining C-terminus, which
allows the extension of the recognition sequence.
Principally, two synthetic strategies can be applied to the
synthesis of oligopeptide functionalized UV/Vis probes.
Solvent effects on the UV/Vis absorption spectra
For the solvatochromic investigations we used the four nitroani-
line derivatives 2–5 (Scheme 1). All four chromophores
investigated have a push–pull-substituted aromatic p-electron
system, which is responsible for the solvatochromic properties.
Due to the high polarity and HBD/HBA capability of the
amino-acid-functionalized chromophores, it is likely that associ-
ation will occur in different solvents and this can have an
influence on the UV/Vis absorption maximum. UV/Vis measure-
ments of compound 2 show a significant indication of probe
aggregation.[81] It is well-known that carboxylic acids form
intermolecular hydrogen bonded aggregates such as I–III
(Scheme 4).[82–86] The existence of monomeric, dimeric (I, II)
and polymer (III) species depends on acid concentration,
temperature and solvent polarity.
I. The amino-acid-functionalized chromophoric system is syn-
thesized in a first step and then the peptide moiety is coupled
using established synthetic procedures to extend peptide
sequences (Scheme 3).
II. The whole peptide moiety is linked directly by a chemical
reaction to the chemically activated chromophore in one step.
At the high concentration range from c ¼ 0.5 Â 10À4 to
4.0 Â 10À4 M, the long-wavelength UV/Vis absorption maximum
Scheme 2. Reaction scheme for the nucleophilic aromatic substitution
of fluoro compound 1 with L-proline
Scheme 4. Intermolecular hydrogen bonded aggregates of carboxylic
acids: I cyclic dimer, II linear dimer, III polymer
J. Phys. Org. Chem. 2008, 21 242–250
Copyright ß 2008 John Wiley & Sons, Ltd.
www.interscience.wiley.com/journal/poc

K. SCHREITER AND S. SPANGE
Figure 1. UV/Vis absorption spectra of 2 in ethanol (a) and methanol (b)
of 2 was hypsochromically shifted from lmax ¼ 403 to 388 nm in
ethanol and from lmax ¼ 400 to 386 nm in methanol, respectively
(Fig. 1). Thus, dye aggregation in solution is observed in the
concentration interval studied for the solvatochromic measure-
ments.
long-wavelength symmetric UV/Vis absorption band. Compound
2, which has been quantified only in 25 solvents due to the
observed probe aggregation in protic solvents, shows also a
bathochromic shift with increasing the solvent polarity. These
bathochromic shifts are in agreement with an increased
delocalization of electron density due to the conjugation of
the lone-pair of electrons on the nitrogen atom of substituted
proline derivative donors with the aromatic p-electron system
and the nitro-group acceptor.
Furthermore, UV/Vis absorption spectra of compound 2 in
ethanol were recorded in a temperature range from 223 to 323 K
in 10 K intervals. The UV/Vis absorption maximum is shifted to
longer wavelength from 393 to 399 nm with increasing
temperature. An isosbestic point was observed at around
419 nm by the temperature changes. Thus, the resulting changes
of the UV/Vis spectra observed by the temperature-sensitive
measurements in protic solvents are enthalpically controlled.
UV/Vis spectroscopic measurements reveal a concentration
dependence of 2 only for protic solvents. It is possible that
different types of aggregation of 2 occur in protic and also aprotic
solvents. But in the concentration interval studied for UV/Vis
measurements a displacement of the UV/Vis absorption band of
compound 2 is observed only in protic solvents. However, at this
time we are not able to determine which species of 2 is present in
aprotic solvents as well as in the investigated concentration
range of protic solvents.
Probe 2 was also measured in solvents, in which no change of
the UV/Vis absorption was observed with changing the
concentration of the probe. UV/Vis absorption spectra of 2 in
these selected solvents and additionally in ethanol and methanol
(Table 1) have been considered for the solvatochromic linear
solvation energy (LSE) correlation analysis. Furthermore, UV/Vis
measurements of compounds 3–5 show no significant contri-
bution of probe aggregation in protic and nonprotic solvents.
Thus, the solvatochromism of 3–5 could be investigated in protic
solvents, too. Hence, UV/Vis measurements were carried out on
compound 2 in 25 and compounds 3–5 in 38 and 39, respectively,
common solvents of different polarity and hydrogen bond ability
at 293 K as shown in Table 1 to determine the coefficients a, b,
and s from Eqn (1).
The UV/Vis shifts range from l ¼ 361 nm in tetrachloro-
methane to l ¼ 403 nm in hexamethylphosphoramide (2), from
l ¼ 354 nm in tetrachloromethane to l ¼ 402 nm in water (3),
from l ¼ 355 nm in tetrachloromethane to l ¼ 406 nm in water
(4), and from l ¼ 349 nm in cyclohexane to l ¼ 405 nm in forma-
mide (5). The extent of the solvatochromic shift of N-(4-nitrophenyl)-
L-proline (2) (Dn ¼ 2890 cmÀ1) as function of the solvent polarity
~
is lower than that of the amide derivative 3 (D~n ¼ 3370 cmÀ1), 4
À1
(Dn ¼ 3540 cm ), and 5 (Dn ¼ 3960 cmÀ1).
~
~
Furthermore, solvatochromic investigations were performed in
room temperature ionic liquids (RTILs). RTILs are salts whose
melting point (mp) is <100 8C and therefore represent a class of
solvents with ionic character. These solvents show strong solva-
ting power which is utilized to investigate specific HBA effects
caused by the anion of RTILs. Of topical interest is also the
investigation of the true polarity of ionic liquids, because this
point is controversially discussed in literature.[89,90] Measure-
ments were taken on compounds 2–5 in 1-hexyl-3-methyli-
midazolium [C6-mim] salts at 293 K as shown in Table 2.
There is a significant influence of the anion of RTIL observed on
the shift of the solvatochromic UV/Vis absorption band. As
expected, the UV/Vis absorption spectra of these compounds
show a bathochromic shift from [C6-mim][PF6] to [C6-mim][Cl] of
the solvatochromic long-wavelength symmetric UV/Vis band
with increasing ability of the anion of ionic liquids to interact as
H-bond acceptor or electron-pair donor (EPD), respectively
(Table 2).
UV/Vis spectra of compound 5 in eight solvents of different
polarity are shown in Fig. 2.
Overall, as the solvent polarity increases from cyclohexane to
water (compounds 3, 4) and formamide (compound 5),
respectively, the UV/Vis absorption spectra of the compounds
3–5 show a significant bathochromic shift of the solvatochromic
LSE correlation analyses
In order to determine the respective contributions of solvent
~
properties on nmax, the simplified form of the Kamlet–Taft linear
solvation energy relationship (LSER) was used [Eqn (1)] The
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Copyright ß 2008 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2008, 21 242–250

SOLVATOCHROMIC PROBES
Table 1. UV/Vis absorption maxima of 2 measured in 25 and of 3–5 in 38 and 39, respectively, solventsa of different polarity and
hydrogen bond ability.
~nmax  10À3 cmÀ1
Kamlet–Taft parameters
*
p
Solvent
(2)
(3)
(4)
(5)
a
b
b
b
b
b
b
b
Cyclohexane
n-Hexane
Triethylamine
Tetrachloromethane
p-Xylene
o-Xylenea
Toluene
Benzene
Diethyl ether
1,4-Dioxane
Anisole
Tetrahydrofurane
Ethyl acetate
1,2-Dimethoxyethane
Chloroform
1,1,2,2-Tetrachloroethane
Pyridine
28.65
28.33
27.78
28.17
27.40
27.17
27.25
27.17
27.40
26.74
26.53
26.32
26.60
26.18
26.88
26.11
25.45
26.53
25.06
25.25
26.32
25.58
25.77
25.25
25.13
25.25
24.75
25.71
25.64
26.60
26.11
26.11
25.91
26.18
26.11
25.32
24.69
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.20
0.00
0.00
0.13
0.00
0.00
0.00
0.00
0.08
0.00
0.00
0.00
0.00
0.19
0.22
0.70
0.84
0.76
0.84
0.86
0.98
0.90
0.71
1.51
1.17
1.96
0.00
0.00
0.71
0.10
0.12
0.12
0.11
0.10
0.47
0.37
0.32
0.55
0.45
0.41
0.10
0.00
0.64
0.10
1.05
0.80
0.10
0.37
0.43
0.76
0.69
0.49
0.76
0.40
0.06
0.82
0.84
0.84
0.90
0.75
0.66
0.52
0.48
0.00
0.47
0.00
0.00
À0.04
0.14
0.28
0.43
0.51
0.54
0.59
0.27
0.55
0.73
0.58
0.55
0.53
0.58
0.95
0.87
0.82
0.87
0.83
0.81
0.90
0.71
0.88
0.88
0.87
1.00
0.75
0.85
0.45
0.47
0.48
0.52
0.54
0.60
0.92
0.97
0.73
1.09
0.65
26.60
27.70
27.03
27.03
26.81
26.81
27.10
26.53
25.97
26.04
26.32
26.11
26.18
25.71
25.13
26.11
24.81
25.45
25.97
25.45
27.55
28.25
27.40
27.17
27.25
27.17
27.47
26.81
26.60
26.46
26.67
26.39
26.95
26.32
25.51
26.63
25.19
25.25
26.63
25.71
25.84
25.32
25.25
25.38
24.94
25.91
25.77
26.81
26.39
26.25
26.25
26.39
26.18
25.38
25.00
25.84
24.88
25.64
3370
27.47
28.17
27.32
27.25
27.17
27.17
27.32
26.81
26.53
26.32
26.46
26.25
26.95
26.18
25.45
26.60
25.06
25.19
26.46
25.64
25.84
25.25
25.25
25.32
24.81
25.84
25.71
26.67
26.18
26.11
26.18
26.11
26.04
25.32
24.88
25.84
24.63
25.58
3540
Dichloromethane
Hexamethylphosphoramide
Tetramethylurea
1,2-Dichloroethane
Benzonitrile
Acetone
25.77
c
N,N-dimethylacetamide
N,N-dimethylformamide
4-Butyrolactone
Dimethyl sulfoxide
Acetonitrile
Nitromethane
1-Decanol
1-Butanol
2-Propanol
1-Propanol
Ethanol
Methanol
c
c
c
25.77
25.71
c
c
c
c
24.81
25.00
c
Ethane-1,2-diol
Formamide
2,2,2-Trifluoroethanol
Water
c
c
c
c
25.84
b
1,1,1,3,3,3-Hexafluoro-2-propanol
25.71
3960
D~nmaxðcmÀ1
Þ
*
2890
a
a, b, and p values for all solvents were taken from Refs [87,88].
b Probe is insoluble in this solvent.
c Probe shows significant contribution of probe aggregation in this solvent.
*
solvatochromic parameters a, b, and p for the multiple–linear
indicates a high validity of the multiparameter equations and
allows significant conclusions to be drawn.
The best regression fit for 2 is obtained from a two-parameter
regression analysis were taken from Refs [87,88]. The results of the
multiple–linear regression analyses are summarized in Table 3.
The correlations statistically provide a solid base to understand
the manifold solvent effects on the solvatochromic long-
wavelength UV/Vis absorption band of these molecules. The
correlation coefficient r is greater than 0.95 for LSERs, which
*
equation with b and p . However, including the results in
methanol and ethanol at low concentration of 2 (c ꢀ 4.0 Â
10À4 mol/L) also a significant regression fit with a three-
parameter equation is obtained.
J. Phys. Org. Chem. 2008, 21 242–250
Copyright ß 2008 John Wiley & Sons, Ltd.
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K. SCHREITER AND S. SPANGE
polarizability. On the strength of the higher dipole moment the
energy of the electronically excited state decreases more than
the ground state. This is well in agreement with bathochromic
shifted UV/Vis absorption maxima with increasing polarity of the
solvents.
The influence of the b-term of the solvent on the shift of lmax
for compound 2 in comparison to compounds 3–5 is similar (refer
to Table 3). The results of the regression analyses indicate that the
influence of the HBA property arises from the formation of
hydrogen bonds donated from the carboxyl group and amide
group (Scheme 5), respectively, of the probe to the lone-pair of
the solvent molecule. This effect is new and noteworthy. We
found a related effect of the b-parameter on the solvatochro-
mism of N-(2-hydroxyethyl)-substituted Michler’s ketone and
N-methyl-N-[1-(2,3-dihydroxypropyl)]-4-nitroaniline
deriva-
Figure 2. UV/Vis absorption spectra of 5 in different solvents
tives.[68–71] The sign of the correlation coefficient b is negative,
indicating that hydrogen bonding with a protophilic solvent
leads to displacement of lmax to lower frequencies.
All investigated compounds 2–5 show a positive solvatochro-
mism with increasing acidity, basicity, and dipolarity/polarizability
of the solvents.
The results of the regression analyses show that the extent of
the solvatochromic shift of the amide bond containing
chromophores 3–5 show a significantly stronger dependence
The comparison of the value of coefficients a shows that
specific interactions between HBD solvents and the solute are
larger for compound 2 than for the compounds 3–5. Then, the
stronger bathochromic shift of the nitroaniline derivative 2
observed in protic solvents is caused by the HBD strength of the
solvent. This effect is of importance for the construction of
peptide bond containing UV/Vis probes. Obviously the carboxyl
group disturbs the HBA solvation of the proline-N-atom at the
push–pull aromatic p-electron system. Thus, the HBD solvation of
the nitro group has a stronger effect on the bathochromic shift of
the UV/Vis absorption band of 2.
*
on the p term of the solvent compared to compound 2 as
indicated by the s coefficient < À3. The negative sign of the s
correlation coefficient indicates that the electronically excited
state of these molecules becomes stronger solvated and
consequently stabilized with increasing the solvents dipolarity/
Table 2. UV/Vis absorption maxima of 2–5 measured in 3 RTIL[89,90]
nmax  10À3 cmÀ1
Kamlet–Taft parameters
~
*
p
Ionic liquid
(2)
(3)
(4)
(5)
a
b
[C6-mim][PF6]
[C6-mim][BF4]
[C6-mim][Cl]
25.13
25.19
24.94
25.38
25.25
24.75
25.32
25.19
24.63
25.25
25.13
24.51
0.57[89]
0.68[89]
0.23[89]
0.50[90]
0.61[90]
0.97[90]
0.91[90]
0.90[90]
0.91[90]
*
Table 3. Solvent-independent correlation coefficients a, b, and s of the Kamlet–Taft parameters a, b, and p , respectively, solute
property of the reference system ~nmax;0, correlation coefficient (r), significance ( f), standard deviation (sd), and number of solvents (n)
calculated for the solvatochromism of compounds 2–5
~
nmax,0
Compound
a
b
s
n
r
f
sd
(2)a
(2)b
(3)c
(4)c
(5)d
28.234 ꢁ 0.150
28.240 ꢁ 0.135
28.912 ꢁ 0.145
28.872 ꢁ 0.142
28.765 ꢁ 0.119
—
À1.213 ꢁ 0.167
À1.302 ꢁ 0.145
À1.005 ꢁ 0.135
À1.115 ꢁ 0.133
À1.031 ꢁ 0.137
À2.578 ꢁ 0.209
À2.476 ꢁ 0.187
À3.138 ꢁ 0.184
À3.116 ꢁ 0.180
À3.081 ꢁ 0.167
23
25
38
38
39
0.956
0.971
0.958
0.961
0.967
<0.0001
<0.0001
<0.0001
<0.0001
<0.0001
0.215
0.193
0.248
0.243
0.261
À1.101 ꢁ 0.160
À0.379 ꢁ 0.082
À0.416 ꢁ 0.080
À0.402 ꢁ 0.088
a Only in solvents in which no probe aggregation of 2 is observed.
b In methanol and ethanol (low concentration of 2) and in solvents in which no probe aggregation of 2 is observed.
c Insoluble in n-hexane and cyclohexane.
d Insoluble in water.
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J. Phys. Org. Chem. 2008, 21 242–250

SOLVATOCHROMIC PROBES
Steric effects of the substituent at the amide bond seem to be
of minor importance due to the observation that the solvato-
chromic properties of 3–5 do not differ significantly from each
other.
The possible intermolecular solute–solvent interactions with
1,3-dialkylimidazolium-based ionic liquids as solvent are mani-
fold, because the imidazolium cation interacts as a weak HBD/EPA
and the effect of the anion is that of a HBA/EPD (Scheme 5). The
Scheme 5. (a) HBA/EPD solvents such as the chloride ion of [C6-mim][Cl]
lower the (ÀI)-effect of the CONH-substituent, which causes a bath-
ochromic band shift compared to nitroaniline derivative. (b) HBD/EPA
solvents such as 1,1,1,3,3,3-hexafluoro-2-propanol enhance the (ÀM)- and
(ÀI)-effect of the NO2-substituent, which causes a bathochromic band
shift compared to nitroaniline derivative
*
behavior of the probes 3–5, which are sensitive mainly to p and
in the second instance to b, also can confirm former studies that
have characterized the polarity of ionic liquids, in this case of ionic
liquids with 1-hexyl-3-imidazolium cations with various anions
À
[90]
*
[X ]. A previous analysis determined p -parameter to be 1.08
for [C6-mim][PF6], 1.07[90] for [C6-mim][BF4], and 1.27[90] for
[C6-mim][Cl] corresponding to the values in the order of
magnitude of dimethyl sulfoxide or water.
The negative sign of correlation coefficient a indicates
formation of hydrogen bonds between protic solvents which
have HBD and electron-pair acceptor (EPA) ability, and the oxygen
atoms of the nitro-group (Scheme 5).
Altogether, the absolute s value is significantly larger than the a
and b coefficient for the calculated LSERs for the compounds 2–5.
This result demonstrates that the ability of the used solvents to
donate or accept hydrogen bonds is much weaker than
solute–solvent dipole–dipole interactions.
The improved UV/Vis spectroscopic method for determining b
[90]
*
and p for RTILs (Table 2)
provides much better agreement
with the observed UV/Vis absorption maxima than the data from
the Ref. [89]. Hence, the use of the novel nitroaniline solvato-
chromic probes confirms these new aspects of the HBA strength
and dipolarity/polarizability on the overall polarity of ionic liquids.
The position of the UV/Vis absorption band of compound 2 in
the investigated ionic liquids is independent from the concen-
tration. The quantitatively best regression fit obtained for the key
compound 2 is shown in Fig. 3.
The results of the multiple–linear regression analyses are
summarized in Table 4.
Solvatochromic measurements in RTILs which interact as
hydrogen bond acceptor confirm the b sensitivity of the probes.
CONCLUSION
Amino acid functionalities as substituents of push–pull p-electron
systems such as N-(4-nitrophenyl)-L-proline derivatives can be
used to achieve information on aggregation versus solvatochro-
mic properties of polar compounds. However, compound 2
shows a hypsochromic shift of the UV/Vis absorption maxima
with increasing concentration in protic solvents. A comprehen-
sive study of the solvent effects on the position of the
long-wavelength UV/Vis absorption band of the compounds
2–5 is presented. The UV/Vis absorption maxima have been
measured in a variety of protic and aprotic solvents, and
especially in RTILs. Overall, the four amino acid derivatives 2–5
Figure 3. Relationship between calculated and measured ~nmax values for
2 (28 solvents)
Table 4. Solvent-independent correlation coefficients a, b, and s of the Kamlet–Taft parameters a[89], b,[90] and p [90], respectively,
*
~
solute property of the reference system nmax;0, correlation coefficient (r), significance ( f), sd, and number of solvents (n) calculated for
the solvatochromism of compounds 2–5
~
nmax,0
Compound
a
b
s
n
r
f
sd
(2)a
(3)b
(4)b
(5)c
28.061 ꢁ 0.152
28.932 ꢁ 0.136
28.886 ꢁ 0.133
28.785 ꢁ 0.114
À0.879 ꢁ 0.173
À0.373 ꢁ 0.078
À0.408 ꢁ 0.077
À0.394 ꢁ 0.086
À1.198 ꢁ 0.164
À1.036 ꢁ 0.126
À1.143 ꢁ 0.124
À1.073 ꢁ 0.131
À2.232 ꢁ 0.212
À3.155 ꢁ 0.172
À3.123 ꢁ 0.169
À3.097 ꢁ 0.159
28
41
41
42
0.959
0.962
0.965
0.969
<0.0001
<0.0001
<0.0001
<0.0001
0.235
0.241
0.237
0.256
a Only in solvents in which no probe aggregation of 2 is observed.
b Insoluble in n-hexane and cyclohexane.
c Insoluble in water.
J. Phys. Org. Chem. 2008, 21 242–250
Copyright ß 2008 John Wiley & Sons, Ltd.
www.interscience.wiley.com/journal/poc

K. SCHREITER AND S. SPANGE
show a positive solvatochromism. The data have been analyzed
and interpreted in terms of empirically derived LSERs using the
Kamlet–Taft solvents parameter set. The results of correlation
analyses suggest that the influence of solvent dipolarity/
polarizability on the long-wavelength absorption maximum for
all compounds is more predominant. Also, the effect of b-term on
the bathochromic band shift is more pronounced than that of the
a term, particularly with regards to the dipeptide functionalized
4-nitroaniline derivatives 3 and 4, and the pinane derivative 5.
Furthermore, the solvatochromism of the compounds 3–5 was
25 8C): d ¼ 1.91–2.37 (m, 4 H, proH-3/4), 3.39–3.58 (m, 2 H, proH-5),
3
3
4.42 (dd, JH,H ¼ 8.7 Hz, JH,H ¼ 2.3 Hz, 1 H, proH-2), 6.58 (d,
3JH,H ¼ 9.2 Hz, 2 H, ArH), 8.07 (d, 3JH,H ¼ 9.2 Hz, 2 H, ArH). 13C NMR
(69.9 MHz, DMSO-d6, 25 8C): d ¼ 23.2, 30.2, 48.3, 60.3, 111.3, 125.9,
~
136.1, 151.4, 173.5. IR (KBr): n ¼ 3569 m (carboxylic OH), 2974 m,
—
2871 m, 1718 s (C O), 1601 s, 1515 s (NO ), 1313 vs (NO ),
—
2
2
1199 m, 1115 s, 827 m cmÀ1. Anal. Calcd for C11H12N2O4: C, 55.93;
H, 5.12; N, 11.86. Found: C, 55.82; H, 4.95; N, 11.86.
General procedure for preparation of 3–5
used to investigate the reliability of the Kamlet–Taft solvent
[90]
Compound 2 (0.500 g, 2.12 mmol) was dissolved in anhydrous
dichloromethane (100 ml), and the solution was cooled to 0 8C.
An equimolar amount of amine hydrochloride (2.12 mmol), DCC
(0.437 g, 2.12 mmol), triethylamine (0.215 g, 0.3 ml, 2.12 mmol),
and a 10th part of an equimolar amount of 4-N,N-dimethyla-
minopyridine (0.026 g, 0.21 mmol) were added. The mixture was
then allowed to warm up to room temperature and stirred for
24 h. The precipitate was filtered off and washed with
dichloromethane. The filtrate was washed with 10% HCl, 5%
aqueous NaHCO3, and saturated aqueous NaCl, dried over
MgSO4, and evaporated in vacuo. The residue was purified by
flash column chromatography (silica gel, dichloromethane/ethyl
acetate), affording 3–5 as yellow crystals.
*
parameter b and p of RTILs from Ref.
.
EXPERIMENTAL SECTION
General remarks
Solvents from Merck, Fluka, Lancaster, and Aldrich were redi-
stilled over appropriate drying agents prior to use. Dichlor-
omethane was dried over calcium hydride and distilled under
argon. All the following ionic liquids were purchased in the
highest available grade from commercial sources and used
without further purification: Merck: 1-hexyl-3-methylimidazolium
chloride, 1-hexyl-3-methylimidazolium tetrafluoroborate, 1-hexyl-
3-methylimidazolium hexafluorophosphate. All commercial
reagents were used without further purification, they were
purchased from the following suppliers: Acros: L(À)-proline,
Lancaster: glycine methyl ester hydrochloride, L(À)-alanine
methyl ester hydrochloride, ABCR: 1-fluoro-4-nitrobenzene, DCC.
All mps were measured on a Boetius mp apparatus and were
uncorrected. The UV/Vis absorption spectra were obtained by
MCS 400 diode array UV/Vis spectrometer from Carl Zeiss, Jena,
N-(4-nitrophenyl)-L-prolylglycine methyl ester 3
(Dichloromethane/ethyl acetate, 1:1), 20% yield. M.p. 177–178 8C.
1H NMR (300 MHz, CD2Cl2, 25 8C): d ¼ 2.04–2.14 (m, 2 H, proH-3 or
proH-4), 2.25–2.33 (m, 2 H, proH-3 or proH-4), 3.34–3.43 (m, 1 H,
proH-5), 3.67 (s, 3 H, OCH3), 3.69–3.76 (m, 1 H, proH-5), 3.87–4.07
3
3
(m, 2 H, CH2CO), 4.20 (dd, JH,H ¼ 7.8 Hz, JH,H ¼ 3.4 Hz, 1 H,
3
proH-2), 6.60 (d, JH,H ¼ 9.3 Hz, 2 H, ArH), 6.60 (1 H, NH), 8.08 (d,
1
connected via glass-fiber optics. H NMR and 13C NMR spectra
3JH,H ¼ 9.3 Hz, 2 H, ArH). 13C NMR (75.5 MHz, CD2Cl2, 25 8C):
were measured at 20 8C on a Bruker Avance 250 NMR
spectrometer at 250 and 69.9 MHz and on a Varian Gemini
300 FT NMR spectrometer at 300 and 75.5 MHz, respectively. The
residue signals of the solvents (DMSO-d6, CD2Cl2, CDCl3) were
used as internal standards. The FT-IR spectra were measured by
means of diffuse reflection diluted with KBr at room temperature
in the wave number range from 400 to 4000 cmÀ1 on a
Perkin-Elmer Fourier transform 1000 spectrometer. Elemental
analysis was determined with a Vario-EL analysis.
d ¼ 24.1, 31.8, 41.2, 49.8, 52.6, 64.1, 112.3, 126.2, 138.7, 152.1,
—
170.3, 172.7. IR (KBr): ~n ¼ 3303 s (NH), 2965 m, 1747 s (C O),
—
—
—
—
1736 s (C O), 1655 vs (C O), 1556 m, 1518 m (NO ), 1334 vs
(NO2), 1217 s (COC), 1117 m, 823 m cmÀ1. C14H17N3O5 (307.292):
—
2
calcd C 54.72, H 5.58, N 13.67; found C 54.73, H 5.56, N 13.55.
N-(4-nitrophenyl)-L-prolylalanine methyl ester 4
(Dichloromethane/ethyl acetate, 1:1), 38% yield. M.p. 174–176 8C.
3
1H NMR (300 MHz, CDCl3, 25 8C): d ¼ 1.38 (d, JH,H ¼ 7.1 Hz, 3
H, CH3), 1.98–2.16 (m, 2 H, proH-3 or proH-4), 2.29–2.37 (m, 2 H,
proH-3 or proH-4), 3.35–3.44 (m, 1 H, proH-5), 3.67 (s, 3 H, OCH3),
3.70–3.77 (m, 1 H, proH-5), 4.18 (dd, 3JH,H ¼ 7.4 Hz, 3JH,H ¼ 4.0 Hz, 1
H, proH-2), 4.50–4.63 (m, 1 H, CH), 6.59 (d, 3JH,H ¼ 9.3 Hz, 2 H, ArH),
Correlation analysis
Multiple regression analysis was performed with Origin 5.0
statistical program.
3
6.59 (1 H, NH), 8.11 (d, JH,H ¼ 9.3 Hz, 2 H, ArH). 13C NMR
(75.5 MHz, CD2Cl2, 25 8C): d ¼ 18.1, 23.9, 31.4, 47.9, 49.5, 52.5, 63.8,
~
112.0, 126.0, 138.7, 151.6, 171.8, 172.7. IR (KBr): n ¼ 3303 s
N-(4-nitrophenyl)-L-proline (2)
—
—
—
(NH), 2954 m, 1750 s (C O), 1666 s (C O), 1601 s, 1535 m,
—
As mentioned above, the synthesis of 2 was previously
described.[54,56,59,91]
1515 m (NO2), 1312 vs (NO2), 1241 m (COC), 1111 s,
828 m cmÀ1. C15H19N3O5 (321.318): calcd C 56.07, H 5.96, N
13.08; found C 55.93, H 5.92, N 12.95.
An equimolar amount of L-proline (8.17 g, 0.071 mol) was
added at 25 8C to a mixture of 1-fluoro-4-nitrobenzene (10.00 g,
0.071 mol) and threefold molar amount of K2CO3 (29.02 g,
0.210 mol) in EtOH/H2O (100 ml, v/v ¼ 3/1). The mixture was
refluxed at 90 8C for 38 h and then cooled to room temperature
(rt). The mixture was poured into ice water and neutralized with
2 M HCl. The precipitate was filtered off, washed with H2O, and
recrystallized (EtOAc) to give 2 (14.43 g, 0.061 mol) as a yellow
solid. 86% yield. M.p. > 220 8C (dec). 1H NMR (250 MHz, DMSO-d6,
1-(4-Nitrophenyl)-N-[(2,6,6-trimethylbicyclo[3.1.1]
hept-3-yl)methyl]-pyrrolidin-2-carboxamide 5
(Dichloromethane/ethyl acetate, 20:1), 37% yield. M.p.
156–158 8C. 1H NMR (250 MHz, CDCl3, 25 8C): d ¼ 0.62 (m,
3
1 H, CH2), 0.92 (s, 3 H, CH3), 0.97 (d, JH,H ¼ 7.1 Hz, 3 H, CH3),
1.15 (s, 3 H, CH3), 1.33–1.40 (m, 1 H, CH2), 1.56–1.65 (m, 1 H, CH),
www.interscience.wiley.com/journal/poc
Copyright ß 2008 John Wiley & Sons, Ltd. J. Phys. Org. Chem. 2008, 21 242–250

SOLVATOCHROMIC PROBES
1.69–1.74 (m, 1 H, CH), 1.77–1.87 (m, 1 H, CH), 1.78–1.85 (m, 1 H,
CH), 1.88–2.06 (m, 1 H, CH2), 2.09–2.17 (m, 2 H, proH-3 or proH-4),
2.21–2.30 (m, 1 H, CH2), 2.32–2.37 (m, 2 H, proH-3 or proH-4),
3.09–3.18 (m, 1 H, CH2N), 3.27–3.34 (m, 1 H, CH2N), 3.35–3.44 (m, 1
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3
H, proH-5), 3.69–3.76 (m, 1 H, proH-5), 4.19 (dd, JH,H ¼ 7.7 Hz,
3JH,H ¼ 3.9 Hz, 1 H, proH-2), 6.14 (t, 3JH,H ¼ 6.1 Hz, 1 H, NH), 6.59 (d,
3JH,H ¼ 9.3 Hz, 2 H, ArH), 8.13 (d, 3JH,H ¼ 9.3 Hz, 2 H, ArH). 13C NMR
(69.9 MHz, CDCl3, 25 8C): d ¼ 21.9, 23.0, 24.1, 28.0, 31.6, 32.2, 33.7,
36.2, 38.8, 40.8, 41.4, 47.5, 47.8, 49.7, 64.3, 112.1, 126.2, 138.9,
—
~
151.8, 172.1. IR (KBr): n ¼ 3269 bs (NH), 2900 s, 1655 s (C O),
—
1598 s, 1567 m, 1515 m (NO2), 1312 s (NO2), 1108 m, 821 m cmÀ1
.
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C22H31N3O3 (385.500): calcd C 68.54, H 8.11, N 10.90; found C
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´
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Acknowledgements
We thank the Fonds der Chemischen Industrie, Frankfurt am
Main, and the Chemnitz University of Technology for financial
support. Further, we thank Dr M. El-Sayed for technical support on
synthesis of compound 2, Prof. Dr S. Reißmann, FSU Jena, for
helpful discussion and scientific support by the peptide coupling
reactions.
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