Host-guest complexation of antioxidative caffeic and ferulic acid amides with a functionalized cyclophane

Article abstract of DOI:10.1007/s10847-012-0134-8

Host-guest complexation has been studied by ¹H NMR on the benzyl and phenethyl amides of ferulic and caffeic acids as the guests in chloroform and acetonitrile; the counter host is a cyclophane which integrates four phenylene rings, amino and a

Full text of DOI:10.1007/s10847-012-0134-8

J Incl Phenom Macrocycl Chem (2012) 74:407–413
DOI 10.1007/s10847-012-0134-8
ORIGINAL ARTICLE
Host–guest complexation of antioxidative caffeic and ferulic acid
amides with a functionalized cyclophane
Claudia Viru e´ s
•
Zaira Dom ´ı nguez
•
Magali Salas
•
•
Rosa Elena Navarro
Motomichi Inoue
•
Enrique F. Vel a´ zquez
•
Samuel Cruz
Javier Hern a´ ndez
•
Received: 15 February 2011 / Accepted: 24 February 2012 / Published online: 17 March 2012
Ó Springer Science+Business Media B.V. 2012
Abstract Host-guest complexation has been studied by
1
H NMR on the benzyl and phenethyl amides of ferulic and
Keywords Antioxidants ꢀ Caffeic acid ꢀ Ferulic acid ꢀ
Hydroxycinnamic acid derivatives ꢀ Cyclophanes ꢀ
Host-guest complexes
caffeic acids as the guests in chloroform and acetonitrile;
the counter host is a cyclophane which integrates four
phenylene rings, amino and amide groups in the macro-
cyclic framework and bears four pendant methyl acetate
ester arms. CAPE, one of the best known natural antioxi-
dants, also has been studied for comparison. Among the
guests studied, ferulic acid benzyl amide shows NMR
shifts due to the formation of a host-guest complex in
chloroform. The complexation occurs in two steps with the
Introduction
Caffeic and ferulic acids (Scheme 1) and their esters belongto
the family of hydroxycinnamic acid derivatives distributed
widely in the plant kingdom, and are potential natural anti-
oxidants that could prevent oxidative rancidity in foods and
oxidative damages in vivo relating to diseases such as cancer,
diabetes, and cardiovascular, Alzheimer’s, and Parkinson’s
diseases [1–12]. Our exploration into antibacterial and anti-
fungal properties in foodstuff has found the antibacterial
activity of caffeic acid phenethyl ester (well-known with
abbreviation CAPE) on some strains of Staphylococcus aur-
eus [13, 14]. Further, wehave studied the potential application
of CAPE in the control of Alternaria alternate, fungus that
causes major economic losses in fruit and vegetables har-
vested [15]. Since the ester group is metabolically labile [16,
17], the amide derivatives of caffeic acid have been synthe-
sized, which have high antioxidative capacity as well [18].
Notwithstandingparticular attention onthe bioactivities, these
natural and synthetic hydroxycinnamic acid derivatives have
disadvantages related to the insolubility in water and the bare
solubility in organic solvents of low polarity.
-
1
formation constants K = [HG]/[H][G] = 6 M
1
and
2
-2
b = [HG ]/[H][G] = 87 M . Two guest molecules are
2
2
bound on the surface of the macrocyclic framework of a
host molecule by two hydrogen bonds, NH(host ami-
de)ꢀꢀꢀO=C(guest amide) and C=O(host ester)ꢀꢀꢀHO(guest
phenol). The latter hydrogen bond may protect the bioac-
tive site, i.e., phenol OH, of guest molecules captured in
the complex against undesirable oxidation. This feature is
observed only for ferulic acid benzyl amide in chloroform;
the cyclophane ester interacts with this amide, distinctively
from the other hydroxycinnamic acid derivatives.
JC .. HV ei rr nu a´e´ ns d (e &z ) ꢀ Z. Dom ´ı nguez (&) ꢀ M. Salas ꢀ S. Cruz ꢀ
Unidad de Servicios de Apoyo en Resoluci o´ n Anal ´ı tica,
Universidad Veracruzana, Apartado Postal 575,
Some of unfavorable properties, such as low solubility
and chemical instability, of a substance are expected to be
improved by construction of its host-guest complexes with
appropriate receptors; even new functions such as molec-
ular-sensing and controlled release of a drug may be
developed. Cyclodextrins and functionalized cyclophanes
are typical hosts that can construct a variety of complexes
in which a host molecule binds a guest molecule of
91190 Xalapa, Veracruz, Mexico
e-mail: cvirues@uv.mx
Z. Dom ´ı nguez
e-mail: zdominguez@uv.mx
R. E. Navarro ꢀ E. F. Vel a´ zquez ꢀ M. Inoue
Departamento de Investigaci o´ n en Pol ´ı meros y Materiales,
Universidad de Sonora, Apartado Postal 130,
8
3000 Hermosillo, Sonora, Mexico
123

4
08
J Incl Phenom Macrocycl Chem (2012) 74:407–413
O
This cyclophane acid is insoluble in organic solvents, but
its methyl ester (2) in Scheme 1) is soluble in common
organic solvents to bind simple organic acids with hydro-
gen bonding at the amide group in chloroform [32]. The
cyclophane acid ester is, therefore, expected to function as
a receptor toward the amide derivatives of caffeic and
ferulic acids through multi-point hydrogen bonding, on the
basis of the mutual sizes of the host and guest molecules.
The present paper reports that, among the target guests
shown in Scheme 1 with abbreviations, ferulic acid benzyl
amide (FaBzAm) shows clear evidence for the formation of
a host-guest complex in which two FaBzAm molecules
are bound on the surface of the macrocyclic framework of a
cyclophane ester molecule.
HO
HO
caffeic acid
ferulic acid
OH
O
CH O
3
OH
HO
HO
O
O
CAPE
O
N
HO
HO
H
HO
CaBzAm
O
CH O
3
( )
N
n
H
HO
n = 1: FaBzAm, n = 2: FaPeAm
Experimental
O
O
O
c
a
RO C
CO R
2
2
Cyclophane acid ester 2 was prepared by esterification
of cyclophane acid 1 with iodomethane [32–34]; the
cyclophane acid was synthesized by a reaction between
ethylenediaminetetraacetic (EDTA) dianhydride and
bis(4-aminophenyl) ether [29], and dried in vacuum at
N
N
N
N
N
H
H
e
H
H
b
d
N
N
N
RO C
CO R
2
2
O
O
O
R = H: 1, cyclophane acid
R = CH : 2, cyclophane acid ester
80 °C for 8 h before use. The amide-based guests, CaB-
3
zAm, FaBzAm and FaPeAm, were prepared from the
Scheme 1 The guests: caffeic and ferulic acid derivatives (above).
The host: cyclophane acid ester 2 (below)
appropriate acids and amines by using benzotriazol-1-yl-
oxytris(dimet-hylamino)phosphonium
hexafluorophos-
phate (BOP) as a coupling agent, and purified on a silica
gel column [18]. CAPE was synthesized from caffeic acid
and phenethyl alcohol in the presence of p-toluene sulfonic
acid as a catalyst [35]. The formation and purity of all
appropriate polarity and dimension within the hydrophobic
cavity or on the hydrophilic exterior surface [19–25].
Regarding hydroxycinnamic acid esters and amides, how-
ever, a report on their host-guest complexes has not
been found in our bibliographic search; only caffeic acid
has been reported to form an inclusion complex with
b-cyclodextrin [26]; as other polyphenol guests, some
flavonoids have been found to be encapsulated by
b-cyclodextrin, and the possible improvement of the
pharmaceutical functions has been pointed out [27]. This
fact has prompted us to search for cyclophane-type hosts
capable of binding hydroxycinnamic acid derivatives in
non-aqueous media. Among host-guest binding forces,
hydrogen bonding is predominant in organic solvents [28].
From this viewpoint, our special interest has been directed
to the complexation of the amide derivatives, because
amide group is capable of forming strong hydrogen bonds
to assemble supramolecules and play important roles in
biological systems.
1
substances were confirmed by H NMR.
NMR spectra were obtained with a Varian Mercury 300
spectrometer operating at 300 MHz at a temperature of
30 °C; the internal reference was TMS. The complexation
was studied in CHCl -d (99.9% atom D) and CH CN-d
3
3
3
(99.8% atom D); both solvents were supplied from Aldrich,
and were dried over molecular sieve when necessary.
Titration of FaBzAm was performed by changing the total
concentration of the guest [G] from 20 to 160 mM
t
-
3
(mM = mmol dm ) at the constant total concentration of
the host [H] of 5 mM in CHCl -d; for the majority of other
host - guest systems, [H] was 2.5 mM, and [G] from 10
t
3
t
t
to 80 mM because of the low solubility.
Results and discussion
Previously, we have synthesized cyclophanes function-
alized with amide group and pendant carboxyl group, and
have found that these ‘‘azacyclophane acids’’ form inclu-
sion complexes with bioactive amines such as dopamine,
histamine and tryptamine in aqueous media [29–31]. A
representative is cyclophane acid 1 shown in Scheme 1.
NMR titrations of the host-guest systems
The caffeic acid derivatives are soluble enough for NMR
titration only in acetonitrile among common deuterated
solvents, and the ferulic acid derivatives are soluble in
1
23

J Incl Phenom Macrocycl Chem (2012) 74:407–413
409
chloroform; only FaBzAm is soluble in both solvents.
Titrations were carried out in the appropriate solvents by
changing the total concentration of the guests [G] while
t
the total concentration of the macrocyclic host [H] was
t
kept constant. Table 1 shows the shifts D of host protons
H
with reference to d in the absence of a guest at selected [H]t
and [G] : D = d ([G] )-d (0) where d ([G] ) is the
t
H
H
t
H
H
t
chemical shift d of a host proton at a guest concentration
H
of [G] , and d (0) is d at [G] = 0. Among the guests
t
H
H
t
studied, FaBzAm causes significant changes in dH in
CHCl -d, and plots of D ([G] ) against [G] give titration
3
H
t
t
curves characteristic of complex formation as shown in
Fig. 1. Other amide guests cause very small changes in dH.
Even FaBzAm little influences d in CH CN-d indicating
H
3
3
a solvent effect (Table 1). The study of complex formation
has been extended to CAPE for comparison, because it is
the most-studied antioxidant among hydroxycinnamic acid
derivatives. Although the amide NH of the host exhibits a
considerable NMR shift in the presence of CAPE, the shifts
of the CH protons were too small for concluding complex
formation (Table 1). Thus, only FaBzAm in chloroform
provides convincing evidence for complex formation. The
present work, therefore, has focused on this host-guest
complexation.
Formulation and determination of formation constants
The host molecule is composed of two equivalent moieties
whose size is comparable to that of a guest molecule.
Potentially, therefore, each host molecule is capable of
1
Fig. 1 a Changes in H NMR d of the cyclophane ester host in the
presence of guest FaBzAm in CHCl = d ([G] )-
-d at 30 °C: D
(0) as a function of guest concentration [G] (in 10 M) at the
3
H
H
t
-3
d
H
t
-
3
binding up to two guest molecules to yield an HG -type
2
constant host concentration [H] 5 9 10 M. The solid lines show
t
the best fits based on the model of two-step complex formation of
complex:
HG
H]
= 6.0 M
proton b
2
. b Mol fractions f calculated for H, HG and HG
2
species against
t
(5 9 10 M) on the basis of the formation constants
H þ G ꢀ HG
HG þ G ꢀ HG2
ð1Þ
ð2Þ
-3
[
K
-
1
-1
1
and K
2
= 16.6 M
H
determined from the D of
The formation constant of each step and the overall
1
Since a single H NMR signal is observed for every pair
of equivalent protons throughout the titrations, the reaction
equilibrium is rapid compared with the NMR observation
time scale. In such a fast exchange case, the chemical shift
of a proton is given by an average of the values intrinsic of
species that coexist in a reaction, as follows:
constant of HG are defined by:
2
K1 ¼ ½HGꢁ=½Hꢁ½Gꢁ
ð3Þ
ð4Þ
ð5Þ
K2 ¼ ½HG2ꢁ=½HGꢁ½Gꢁ
2
b ¼ ½HG2ꢁ=½Hꢁ½Gꢁ ¼ K1 ꢀ K2
2
1
Table 1 H NMR shifts of the cyclophane ester host (2) in the
[G]
a guest, D
abbreviation of the guests see Scheme 1); T = 30 °C
t
; shift of proton H(n) is given with reference to d in the absence of
presence of caffeic and ferulic acid derivatives as guests at a given
and that of a guest
H
= d ([G] )-d (0) (for labeling proton n and the
H
t
H
-
3
total concentration (in 10 M) of the host [H]
t
Guest
Solvent
[H]
t
:[G]
t
NH CH (a)
2
CH
2
(b)
CH
2
(c)
ArH(d)
ArH(e)
OCH
3
FaBzAm
CDCl
CD CN
CDCl
3
5.0:80
2.5:80
2.5:80
2.5:50
2.5:80
0.010
0.010
0.013
0.010
0.025
–0.022
–0.005
–0.007
–0.002
0.000
–0.028
–0.009
–0.011
–0.005
–0.003
–0.031
–0.001
–0.007
0.004
–0.009
–0.001
–0.002
–0.004
–0.001
–0.013
–0.007
–0.005
–0.005
–0.004
–0.010
–0.003
–0.006
–0.002
–0.002
3
FaPeAm
CaBzAm
CAPE
3
CD
CD
3
CN
CN
3
0.015
123

4
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J Incl Phenom Macrocycl Chem (2012) 74:407–413
ꢀ
Here, the subscript j stands for the jth sample solution of
ꢁ
ꢀ
ꢁ
one another. These facts suggest that the successive
formation of two species HG and HG2 is reasonable
rather than the formation of a single species HG.
DHj ½Gꢁtj
¼
DHC1½HGꢁ þD ½HG ꢁ =½Hꢁ
ð6Þ
j
HC2
2 j
t
a total concentration of guest [G] , D
is the chemical
tj
HC1
Binding sites in the complex
shift change D of the host in complex HG with reference
H
to d of the free host, and DHC2 is that in complex HG2:
H
The major binding forces of host-guest complexes in
organic solvents originate from hydrogen bonding [28].
One of the most convincing evidences for hydrogen
bonding is given by the down-field NMR shift (or an
increase in d) of the participating acidic proton [32, 37].
DHC1 = d (HG)-d (H), and D
= d (HG )-d (H),
H
H
HC2
H
2
H
where d (H) is equated to dH at [G] = 0. On the basis
H
tj
of mass balances, [H] = [H] ? [HG] ? [HG ] and
t
2
[
G] = [G] ? [HG] ? 2[HG ], Eqs. 3 and 4 lead to the
t 2
following cubic equation of [G].
À
Á
À
The amide NH signal of the host shows an increase in D
H
3
2
½
Gꢁ þ 1=K2 þ 2½Hꢁ ꢂ½Gꢁ ½Gꢁ þ 1=b þ ½Hꢁ =K2
t
t
2
t
with increasing the concentration of FaBzAm (Fig. 1 and
Table 1). This observation indicates the participation of the
amide proton in the hydrogen bonding. The most probable
counter H-bonding site in the guests is amide C=O to form
NH(host)ꢀꢀꢀO=C(guest) binding. This hydrogen bond has
Á
ꢂ½Gꢁ =K2 ½Gꢁ ꢂ ½Gꢁ =b ¼ 0
ð7Þ
t
t
2
For given K and K , the cubic equation is solved
2
1
numerically, providing [H], [HG] and [HG ] successively,
2
and then the spectral change DHj is calculated by Eq. 6 for
assumed DHC1 and DHC2 values. A set of four parameters,
1
been confirmed by H NMR of FaBzAm in the presence of
the host; Table 3 represents changes in d, D = d ([H] )-
G
G
t
K , K , D
and DHC2, that reproduces best an observed
titration curve has been determined by a non-linear least-
1
2
HC1
d (0), at selected concentrations [G] and [H] in CHCl -
G
t
t
3
d. The significant positive D value observed for CH(2) of
G
squares fitting [36]. The D values caused by FaBzAm in
H
FaBzAm supports the formation of NH(host)ꢀꢀꢀO=C(guest),
because the hydrogen bond lowers electron density in the
conjugated system O=C–CH(2)= in the guest. Potential
H-donating sites in FaBzAm include phenol OH and amide
CHCl -d are large enough for determination of the
3
formation constants, and the titration curves are
reproduced well with parameters given in Table 2 as
shown in Fig. 1. The formation constants determined from
the different protons agree with one another in a deviation
NH. Evidence for hydrogen bonding (i.e., positive D ) is
G
found for the OH proton; by contrast, the amide NH proton
shifts toward a direction opposite to that predicted for
hydrogen bonding (Table 3). The hydrogen bonding at the
of about 10%; the means are \ K [ = 6.0 ± 0.7 and
1
\
assumed to form, the formation constant K and the shift
K [ = 14.7 ± 2.0. When only a 1:1 complex HG is
2
OH group is consistent with the negative D values of H(5,
G
D ([G] ) are readily formulated [29]. Although the
Hj
t
6, 9) of the o-methoxyphenol ring on which electron den-
resulting D ([G] ) reproduced each of observed titration
Hj
t
sity is increased as a result of partial proton donation of
phenol OH to an electron donor atom in the host. The
counter H-accepting site in the host is either amino nitro-
gen or ester C=O oxygen. Hydrogen bonding at the amino
nitrogen would lead to an increase in d of the adjacent
curves with a tolerable deviation, the fitness between the
shapes of the observed and calculated titration curves was
poor compared with that for the two-step complex
formation. In addition, the constants K determined for
different protons showed a deviation as large as 100% from
protons NCH (a, b, c) [38]. To the contrary, these protons
2
1
-1
-1
-2
Table 2 Formation constants K
shifts d of cyclophane protons for HG and HG
the cyclophane ester host (2) and guest FaBzAm, and the shifts, DHCn
of the complexes, with reference to the free cyclophane: K
n
and b
2
determined from H NMR
M
= [HG]/[H][G]; K
2
/M = [HG
([G]t = ?)-d (0) for complex HG, and DHC2
. Solvent, CHCl
-d; T = 30 °C
2 2 2
]/[HG][G]; b /M = [HG ]/
2
2
complexes between
[H][G] ; DHC1 is d
that for HG
H
H
,
2
3
1
/
Proton
NH
K
1
K
2
b
2
D
HC1
D
HC2
5.1
5.5
6.0
6.3
7.1
6.0
16.8
13.9
16.6
15.5
13.1
12.0
85
76
0.013
0.031
CH
CH
CH
2
(a)
2
(b)
2
(c)
-0.031
-0.030
-0.036
-0.012
-0.014
-0.063
-0.078
-0.083
-0.040
-0.030
100
97
ArH(e)
OCH
93
3
72
The averages over the values of different protons: \ K
formation constant is in the range 5–10%
1
[ = 6.0 ± 0.7; \ K
2
[ = 14.7 ± 2.0; \ b [ = 87 ± 11. The uncertainty of each
2
1
23

J Incl Phenom Macrocycl Chem (2012) 74:407–413
411
show decreases in d upon complex formation (Fig. 1 and
Table 1). When the ester C=O of a host molecule forms a
hydrogen bond with the phenol OH of a guest molecule, the
o-methoxyphenol ring of the guest can orient in such a way
and C=O(host ester)ꢀꢀꢀHO(guest phenol). A possible
molecular arrangement involving these hydrogen bonds is
visualized in Fig. 2: two guest molecules are located on the
opposite hemispheres of the host molecule for steric rea-
that its ring plane faces the CH (a, b, c) groups of the host.
2
sons, and the methoxyphenol ring plane faces CH (a) and
2
In such a structure, the ring-current field induced by the
CH (b) groups. In acetonitrile, DH values are very small
2
methoxyphenol ring can result in D *-0.02 to -0.03
observed for protons H(a, b, c), because the ring-current
compared with those in chloroform except that the amide
proton shifts are comparable. Probably, the high polarity
of acetonitrile weakens hydrogen bonding between the
host and the guest, and alters relative molecular
orientations.
H
shift caused by a benzene ring may amount up to
-
2.2 ppm for a resonant proton that resides above the
aromatic ring plane in a distance of a van der Waals contact
˚
.9 A [39]. Thus, the NMR shifts of CH (a, b, c) protons
2
As CAPE causes very small shifts DH of the host, the
2
supports hydrogen bonding at the ester C=O of the host. All
of the observed NMR shifts consistently indicate that the
host-guest assembly is constructed by two-point hydrogen
bonding composed of NH(host amide)ꢀꢀꢀO=C(guest amide)
changes in d of the guests are not significant either; the
G
DG value of every proton of CAPE was of the order of
0.001 at [G] 4 mM and [H] 32 mM. In addition, the signal
t
t
of phenol OH of the guest was undetectable due to extreme
1
Table 3 H NMR shifts of proton H(n) of FaBzAm in the presence of the cyclophane ester host: the shifts are referenced to the corresponding d
G
-
, 4 9 10 M; [H]
3
-3
of the free guest, D
G
= d
G
([H]
t
)-d
G
(0); solvent, CHCl -d; [G]
3
t
t
, 32 9 10 M; T, 30 °C
Proton
D
G
Proton
D
G
Amide NH
CH(2)
–0.010
0.019
OH
0.214
–0.019
–0.017
–0.007
–0.023
H(5)
H(6)
H(9)
CH(3)
–0.010
–0.012
CH
2
(10)
Phenyl H
–0.008 to 0.012
3
OCH (17)
1
7
OCH3
1
5
8
O
H
1
4
16
9
4
H
7
H
N
1
2
10
1
3
5
1
3
2
6
1
1
O
H
FaBzAm
Fig. 2 View of host-guest
interaction concluded from the
1
H NMR shifts of FaBzAm
guest) and cyclophane acid
(
ester (host) in their complex: the
structure is drawn just to
visualize (1) two-point
hydrogen bonding, NH(host
amide)ꢀꢀꢀO=C(guest amide) and
C=O(host ester)ꢀꢀꢀHO(guest
phenol), and (2) the location of
2 2
CH (a) and CH (b) of the host
above the o-methoxyphenol ring
plane of the guest, with the aid
of molecular mechanics
MM ? on HyperChem
(
Professional Version Rel. 6.03,
Hypercube Inc., Gainesville,
FL, USA)
123

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-
2
line-broadening. No convincing evidence for complex
[G] = [G] , under [G] = [H] . The stability (*90 M )
t/2
t
t
formation has been obtained from d of the guest either.
of the present host-guest system gives a [G]t, 1/2 value of
about 0.1 M (or *3% (w/w)). This concentration is too
high for practical use. Still the present study has shown an
example for receptors capable of capturing a ferulic acid
derivative in a protective manner in lipophilic media.
G
Complexation properties of the host
In the FaBzAm-cyclophane complex, the absolute value
|
DHC1| of the HG species is approximately half the |DHC2|
Acknowledgments C.ꢀV. thanks CONACYT M e´ xico for a post-
doctoral fellowship. J. H. thanks CONACYT M e´ xico and COVECYT
M e´ xico for financial support (VER-2009-C03-127523).
value of the HG2 species (Table 2). The complexation
equilibrium and the accompanying molecular reorientation
occur rapidly compared with the NMR time scale, because
every proton in the host as well as in the guests exhibits a
1
single H NMR signal throughout the titrations. In such a
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2
have identical strength of local binding forces. This is the
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second molecule. As a result, the value of K is much large
2
than K , but local binding forces are unchanged in com-
1
3
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9
HG , which is stabilized by two-point hydrogen bonding
2
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composed of NH(host amide)ꢀꢀꢀO=C(guest amide) and
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