Molecular rotors as simple models to study amide NH-aromatic interactions and their role in the folding of peptide-like structures

Article abstract of DOI:10.1021/jo701552b

(Chemical Equation Presented) The conformational behavior of designed macrocyclic naphthalenophanes (1a,b and 2a,b) derived from amino acids (Phe and Val) has been used for studying NH...π interactions. The cycles having 16- and 17-membered rings showed a dynamic process within the NMR time scale, produced by the flipping of the aromatic naphthalene moiety with respect to the macrocyclic main plane. We used the temperature dependence of ¹H NMR to obtain activation parameters of the energetic barrier for the process (variable temperature NMR and line shape analysis). The rate of the movement clearly depends on the macrocyclic ring size and, more interestingly, on the nature of the peptidomimetic side chain, the energetic barrier being higher for the compounds bearing aromatic side chains. A largely negative entropic contribution to the free energy of activation was observed, with clear differences due to the side chain nature. Molecular modeling studies suggest that the aromatic rings interact with intramolecularly H-bonded amide NH groups, protecting them from solvation and thus leading to a larger unfavorable activation entropy. This NH...π interaction has been exploited for the preparation of new systems (1c and meso-1b) with designed conformational preferences, in which aromatic rings tend to fold over amide NH groups. Thus, these minimalistic molecular rotors have served us as simple model systems for the study of NH...π interactions and their implication in the folding of peptide-like molecules.

Full text of DOI:10.1021/jo701552b

Molecular Rotors as Simple Models to Study Amide NH-Aromatic
Interactions and Their Role in the Folding of Peptide-like Structures
Ignacio Alfonso,*,† M. Isabel Burguete, Francisco Galindo, Santiago V. Luis,* and
Laura Vigara
Departamento de Qu´ımica Inorga´nica y Orga´nica, UAMOA, UniVersidad Jaume I, CSIC,
Campus del Riu Sec, AVenida Sos Baynat, s/n, E-12071, Castello´n, Spain
iarqob@iiqab.csic.es; luiss@qio.uji.es
ReceiVed July 16, 2007
The conformational behavior of designed macrocyclic naphthalenophanes (1a,b and 2a,b) derived from
amino acids (Phe and Val) has been used for studying NH‚‚‚π interactions. The cycles having 16- and
17-membered rings showed a dynamic process within the NMR time scale, produced by the flipping of
the aromatic naphthalene moiety with respect to the macrocyclic main plane. We used the temperature
dependence of 1H NMR to obtain activation parameters of the energetic barrier for the process (variable
temperature NMR and line shape analysis). The rate of the movement clearly depends on the macrocyclic
ring size and, more interestingly, on the nature of the peptidomimetic side chain, the energetic barrier
being higher for the compounds bearing aromatic side chains. A largely negative entropic contribution
to the free energy of activation was observed, with clear differences due to the side chain nature. Molecular
modeling studies suggest that the aromatic rings interact with intramolecularly H-bonded amide NH
groups, protecting them from solvation and thus leading to a larger unfavorable activation entropy. This
NH‚‚‚π interaction has been exploited for the preparation of new systems (1c and meso-1b) with designed
conformational preferences, in which aromatic rings tend to fold over amide NH groups. Thus, these
minimalistic molecular rotors have served us as simple model systems for the study of NH‚‚‚π interactions
and their implication in the folding of peptide-like molecules.
Introduction
at the molecular level.1 Despite the obvious problem of
oversimplification, we can obtain important information about
the source and characteristics of weak interactions, such as
hydrogen bonding, cation-π interactions, or solvophobic
Models are very attractive to chemists, as they allow
understanding of intrinsically complicated biological systems
* Corresponding authors. Phone: +34 964728239; fax: +34 964728214.
† Present address: Department of Biological Organic Chemistry, IIQAB-CSIC,
Jordi Girona 18-26, E-08034, Barcelona, Spain.
(1) For a very recent discussion on this topic, see: Kool, E. T.; Waters,
M. L. Nat. Chem. Biol. 2007, 3, 70-73.
10.1021/jo701552b CCC: $37.00 © 2007 American Chemical Society
Published on Web 09/21/2007
J. Org. Chem. 2007, 72, 7947-7956
7947

Alfonso et al.
contacts. Among others, hydrogen bonds implicating both the
π-cloud of aromatic systems and amide NH bonds have been
deeply studied in the past decade,2 as they are present in many
proteins3 and peptides4 and have been used for molecular
recognition in synthetic receptors.5 However, the use of these
noncovalent contacts for conformational control6 and the
development of model systems for studying the process7 have
been less exploited. The understanding of these noncovalent
interactions is of great importance, as there are some biological
processes that are closely related, such as protein binding to
specific ligands8 or the regulation of molecular recognition of
DNA.9
On the other hand, amino acid derived macrocyclic com-
pounds have recently attracted much attention in the fields of
synthetic,10 bioorganic,11 medicinal,12 and supramolecular chem-
istry.13 Their cyclic structure usually confers on them a three-
dimensional organization of the amino acid residues in a
preferred conformation,14 allowing them to host small molecules
and ions,15 with interesting potentials in molecular recognition
or in the design of new chemosensors.16 Thus, the conforma-
tionally well-defined disposition of functional groups make them
ideal probes for the study of noncovalent interactions in relation
to solvent exposure and folding properties and, consequently,
for designing model systems. Regarding that, we have recently
reported on the study of conformational properties of macro-
cyclic peptidomimetic cyclophanes containing a p-phenylene
unit.17 The energetic barrier for the rotation of the aromatic ring
with respect to the macrocyclic main plane showed a close
relationship with the intramolecular H-bond pattern and the
solvent accessibility to the pseudo-peptidic moiety. These
properties were exploited for the description of a methanol-
dependent molecular rotor, a simple device that was used as a
proof-of-concept simple model. Additionally, the effect of the
aromatic rings of the side chains was correlated to the ability
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7948 J. Org. Chem., Vol. 72, No. 21, 2007

Molecular Rotors as Models to Study NH-Aromatic Interactions
SCHEME 1. Molecular Structures (with Atom Numbering)
and Naphthalene Dynamic Process of 1a,b and 2a,b
identity of the signals as well as the exchanging nuclei were
confirmed by a set of 1-D NOESY experiments at low
temperatures and are in good agreement with the dynamic
flipping of the naphthalene group with respect to the macrocyclic
main plane, as it would mainly affect the signals close to the
C1-C2 bond. Coalescence temperatures (Tc) for different signals
of 1a,b and 2a,b are given in Table 1, as well as the free energies
of activation (∆Gq) at the coalescence temperature.22
By comparing the values in Table 1, very interesting trends
were found. The enlargement of the macrocyclic structure by
one methylene decreases the conformational energy barrier by
ca. 4 kcal/mol, in reasonable agreement with reported data on
polyamino cyclophanes.17,24 Considering the data with the parent
p-cyclophane derivatives,17 a slightly lower rotational barrier
was found for the naphthalenophanes. This apparently surprising
result can be explained by steric factors. The size of the moiety
passing through the macrocyclic cavity for the rotation of the
phenylene and the flipping of the naphthalene moieties is
essentially the same. However, the naphthalene derivatives
experience an additional steric repulsion between H2 and H9
protons (see modeled structures). This interaction destabilizes
the corresponding ground states and leads to a lower energetic
barrier for the conformational process.
of these groups to prevent amide solvation, probably due to a
stabilizing NH‚‚‚π noncovalent interaction. Intrigued by these
observations, we have prepared a second generation of pepti-
domimetic macrocycles, implementing a naphthalene aromatic
ring in their structure. Considering the behavior observed
previously, these compounds will show a dynamic flipping
process of the naphthalene ring within the NMR time scale
(Scheme 1). Besides, the naphthalene group will have multiple
effects. First of all, it will break the C2 symmetry of the
compounds in the slow movement regime, as the aromatic ring
tends to set perpendicular to the macrocyclic plane (Scheme
1). Second, this aromatic system with an increased diamagnetic
anisotropy will induce a larger anisocrony of the diastereotopic
protons of the pseudo-peptidic macrocycle. Last, but not least,
the aromatic surface will produce a more efficient desolvation
of the intramolecularly H-bound amide NH protons. Thus, we
envisioned 1a,b and 2a,b as good candidates for the detection
of NH‚‚‚π interactions through the deep knowledge of their
conformational behavior. The understanding of these processes
would be valuable for the design of new molecular devices,18
either with internal or with external control of the disposition
and dynamics of some parts of the system. On the other hand,
they serve as very simple models for studying the role of NH-
aryl interactions in conformational flexibility and stability, in a
deep relationship with solvent exclusion,19 and, therefore, with
a three-dimensional structure of biomolecules and protein
folding processes.20
Apart from the higher conformational rigidity of the smaller
cycles, an effect of the side chain nature is also noteworthy.
Thus, by comparing entries 3 versus 8 and 4 versus 9 in Table
1, we can conclude that the phenylalanine derivatives lead to
less flexible cycles, at least regarding the ring inversion process.
This energy barrier difference is larger in the smaller macro-
cycles, being almost abolished for the 17-membered rings. The
i
smooth energy gap obtained when changing Pr into Bn was
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Results and Discussion
Variable Temperature Nuclear Magnetic Resonance (VT-
NMR) Study. For the study of the conformational process
1
proposed in Scheme 1, we performed a H NMR analysis of
1a,b and 2a,b at different temperatures (VT-NMR).21 Interest-
ingly, due to the large diamagnetic anisotropy produced by the
naphthalene ring, several proton signals of the compounds split
off at temperatures below coalescence, within the slow exchange
regime. This fact has allowed us to use different NMR signals
as molecular probes for the study of conformational processes.
A representative example is shown in Figure 1, in which 2a
showed seven signals with a typical coalescence behavior. The
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Garc´ıa-Espan˜a, E.; Luis, S. V.; Miravet, J. F. J. Org. Chem. 1994, 59, 1067-
1071.
J. Org. Chem, Vol. 72, No. 21, 2007 7949

Alfonso et al.
FIGURE 1. 1H NMR spectra of 2a (500 MHz, CDCl3) at selected temperatures. Atom numbering is as in Scheme 1. In the inset, the experimental
(left) and simulated (right) partial NMR spectra of protons at C2 are shown. Temperatures (K) and computed exchange rates (s-1) are also given
for every trace. Simulated spectra were obtained with the gNMR program.23
also observed previously in related examples and was correlated
to the different solvation of amide NH groups.17 When compar-
ing energetic barriers calculated from the coalescence of
different signals of the same compound, we found a very good
fitting for the larger rings. Merging different entries, we
estimated an averaged ∆Gq ) 13.7 kcal/mol for 2a (see entries
10-16 in Table 1) and ∆Gq ) 14.0 kcal/mol for 2b (see entries
17-21 in Table 1), the individual values obtained for each
proton signal being within experimental error ((0.4 kcal/mol).
However, discrepancies above the experimental error were found
for the smaller macrocycles (compare, for instance, entries 1
and 3-and 4 or 6 and 8- and 9 in Table 1). Interestingly, these
differences are observed for signals presenting very different
coalescence temperatures, which depend on both energetic
barrier of the conformational process and frequency difference
between exchanging nuclei at the slow exchange regime.22 This
trend suggested that ∆Gq is strongly dependent on the temper-
ature, in other words, that the energetic barrier is entropically
driven. To check this proposal, the activation parameters were
measured by performing full line shape analyses of the protons
at C2 in 1a,b (Figures 2 and 3) and 2a (Figure 1, inset). For
2b, a serious signal overlapping prevented accurate computer
simulation of the spectra. Besides, this analysis allows us to
know the temperature dependence of the conformational energy
barrier itself. Arrhenius activation energies (Ea) or enthalpic
(∆Hq) and entropic (∆Sq) contributions to the free energy of
activation were obtained either by ln(k) versus 1/T or Eyring
plots, respectively (Table 2).22
As predicted, values in Table 2 show a strong temperature
dependence of the free energy of activation for this conforma-
tional process.25 Thus, the value of the entropy of activation is
negative in all cases. Besides, ∆Sq is larger for the smaller
cycles, being predominant over ∆Hq in its contribution to ∆Gq.
As entropy can be seen as the thermodynamic measurement of
(25) This entropic contribution has been previously reported in related
systems: (a) Chang, M. H.; Masek, B. B.; Dougherty, D. A. J. Am. Chem.
Soc. 1985, 107, 1124-1133. (b) Chang, M. H.; Dougherty, D. A. J. Am.
Chem. Soc. 1983, 105, 4102-4103.
7950 J. Org. Chem., Vol. 72, No. 21, 2007

Molecular Rotors as Models to Study NH-Aromatic Interactions
TABLE 1. Frequency Difference (δν, Hz), Coalescence
Molecular Modeling. For a clearer picture of the more stable
conformations of these peptidomimetic naphthalenophanes, a
Monte Carlo random conformational search with MMFF force
field minimization was performed for every compound.27 The
global minima of energy thus obtained for every macrocycle
are shown in Figure 4.
Temperature (Tc, K) and Energetic Barrier at Tc (∆Gq , kcal/mol)
c
for Conformational Process of Napthalenophanes 1a,b and 2a,b
Using Different Proton Signals
1H NMR
signal
δνa
∆Gq
c
entry compd
(Hz) Tc (K) (kcal/mol)b,c
solvent
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
1a
1a
1a
1a
1b
1b
1b
1b
1b
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
2b
H9
23.8
323
370
375
378
343
343
383
403
413
293
283
294
297
295
287
293
295
297
308
297
280
16.4
17.3
17.6
17.6
18.2
17.8
18.2
19.1
19.3
13.7
13.8
13.5
13.6
13.8
13.5
13.6
14.2
14.0
14.3
14.0
13.7
DMSO-d6
DMSO-d6
DMSO-d6
DMSO-d6
DMSO-d6
DMSO-d6
DMSO-d6
DMSO-d6
DMSO-d6
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
All of them showed the naphthalene moiety perpendicular
to the macrocyclic main plane, in good agreement with reported
crystal structures and molecular modeling studies on similar
compounds.17,26 This disposition would set the peptidomimetic
chain on top of the anisotropy cone of the naphthalene ring,
explaining the observed upfield shift of the corresponding
signals, which is especially important for the amide NH protons.
Amide protons are H-bonded to the amino nitrogens, forming
five-membered rings in all the derivatives. Additionally, for the
smaller cycles 1a,b, there is an interesting CdO‚‚‚HsN
hydrogen bond, forming a seven-membered ring, which re-
sembles the γ-turn conformation found in peptide structures.28
On the other hand, the minima for the phenylalanine deriv-
atives (1b and 2b) tend to set the π-cloud of the aryl moieties
of the side chains close to the H-bound amide protons, being
especially of note for compound 1b. This suggests the possibility
of an NH‚‚‚π stabilizing interaction. Actually, measured dis-
tances on 1b between the amide NH and the center of the closest
C-C bond of the aromatic rings (2.67-3.05 Å) imply a
naphthyl‚‚‚amide NH‚‚‚phenyl sandwich disposition. This sce-
nario would explain the more efficient desolvation of the
H-bound amide NH groups in 1b, leading to a much larger ∆Sq
value. We also have used molecular modeling for the qualitative
visualization of the solvation differences between 1a and 1b.
The computed solvent-accessible surfaces for both minima (see
Supporting Information) showed clear differences, highlighting
the more hindered accessibility of DMSO molecules to the
amide groups in 1b due to the presence of the aromatic rings.
amide-NH 220.8
H2A
H2B
H9
200.0
231.5
9.4
H10
15.8
amide-NH 175.8
H2A
H2B
H9
184.8
251.6
171.0
64.0
H7
amide-NH 282.5
H2A
H2B
H3
H5
H9
265.8
229.5
147.5
185.0
97.6
amide-NH 166.5
H2A
H2B
H3
240.6
151.8
55.2
a Measured at the low-temperature spectra. b Calculated using the ap-
proximated formula for ∆Gq at the temperature of coalescence. c Estimated
error (0.4 kcal/mol.
molecular disorder, the negative value of ∆Sq should mean that
the transition state (TS) must be more ordered than the ground
state (GS). This molecular order could come from a less flexible
TS than the GS or from an increasing solvation from the GS to
the TS. More interestingly, the effect of the side chains is mainly
entropic (see entries 1 and 2 in Table 2), the ∆Gq value being
identical for both derivatives 1a and 1b at 298 K. Upon heating,
the very large entropic contribution to ∆Gq for 1b increases
the energetic barrier much more than for 1a, highlighting their
differences at the coalescence temperatures. Comparing rings
of the same size, the change in the internal molecular order
from the GS to the TS should be very similar; the entropic
difference between 1a and 1b is most likely related to the
solvation properties of both. These results must be carefully
considered if the measurements have been performed in very
different solvents but are completely correct when comparing
results measured in the same solvent (entries 1 and 2 in Table
2). In these macrocyclic systems, hydrogen bonding abilities
play a very important role in the conformational preferences
and have to be taken into account.17 With this regard, the amide
NH chemical shifts of 1a,b showed little differences when the
1H NMR spectra acquired either in CDCl3 or in DMSO-d6 were
compared [δ(DMSO-d6) - δ(CDCl3) ) 0.49-0.51 ppm]. These
data support the efficient shielding of the pseudo-peptidic moiety
from solvent molecules. Accordingly, the corresponding bis-
(aminoamide) portion would present an intramolecular H-
bonding pattern, as initially observed with related systems.17,26
Moreover, as the flipping of the naphthalene ring with respect
to the macrocycle implies the breaking of the intramolecular
H-bonging pattern, the more efficient the prevention of the
solvation of the amide NH is, the larger the barrier for the ring
inversion is.17 With this rationale in mind, the larger ∆S‡ value
for 1b than for 1a would imply a more efficient desolvation of
the amide bond in the phenylalanine derivative.
Conformational Control by NH‚‚‚π Interactions. Since the
results obtained for the macrocycles 1a,b and 2a,b suggested
the participation of NH‚‚‚π interactions in the conformational
stability of the compounds, we envisioned other derivatives to
demonstrate the utility of this effect to design a preferred
conformation and folding of the structures. We used 1b as the
starting point because it showed the more efficient NH‚‚‚π
interaction by molecular modeling and VT-NMR (largest
entropic contribution to the energetic barrier). With this aim,
we synthesized 1c and meso-1b (Scheme 2), which can be seen
as variations of the previously studied 1b. Thus, 1c would be
(27) All the molecular modeling was performed using: Spartan ’04;
Wavefunction, Inc.: Irvine, CA, 2004. For MMFF force field calculations,
see: Halgren, T. A. J. Comput. Chem. 1996, 17, 490-519 and the other
papers in this issue. For quantum mechanics calculations, see: Kong, J.;
White, C. A.; Krylov, A. I.; Sherrill, D.; Adamson, R. D.; Furlani, T. R.;
Lee, M. S.; Lee, A. M.; Gwaltney, S. R.; Adams, T. R.; Ochsenfeld, C.;
Gilbert, A. T. B.; Kedziora, G. S.; Rassolov, V. A.; Maurice, D. R.; Nair,
N.; Shao, Y.; Besley, N. A.; Maslen, P. E.; Dombroski, J. P.; Daschel, H.;
Zhang, W.; Korambath, P. P.; Baker, J.; Byrd, E. F. C.; van Voorhis, T.;
Oumi, M.; Hirata, S.; Hsu, C.-P.; Ishikawa, N.; Florian, J.; Warshel, A.;
Johnson, B. G.; Gill, P. M. W.; Head-Gordon, M.; Pople, J. A. J. Comput.
Chem. 2000, 21, 1532-1548.
(28) (a) Li, X.; Yang, D. Chem. Commun. 2006, 3367-3379. (b) Jimenez,
A. I.; Ballano, G.; Cativiela, C. Angew. Chem., Int. Ed. 2005, 44, 396-
399. (c) Vass, E.; Hollo´si, M.; Besson, F.; Buchet, R. Chem. ReV. 2003,
103, 1917-1954. (d) Guruprasad, K.; Rao, M. J.; Adindla, S.; Guruprasad,
L. J. Pept. Res. 2003, 62, 167-174. (e) Improta, R.; Barone, V.; Kudin, K.
N.; Scuseria, G. E. J. Am. Chem. Soc. 2001, 123, 3311-3322. (f) Marraud,
M.; Aubry, A. Biopolymers 1996, 40, 45-83. (g) Rose, G. D.; Gierasch,
L. M.; Smith, J. A. AdV. Protein Chem. 1985, 37, 1-109. (h) Toniolo, C.
Crit. ReV. Biochem. 1980, 9, 1-44.
(26) Becerril, J.; Bolte, M.; Burguete, M. I.; Galindo, F.; Garc´ıa-Espan˜a,
E.; Luis, S. V.; Miravet, J. F. J. Am. Chem. Soc. 2003, 125, 6677-6686.
J. Org. Chem, Vol. 72, No. 21, 2007 7951

Alfonso et al.
FIGURE 2. Partial (protons at C2 carbon) VT-NMR spectra of 1a (5 mM, DMSO-d6, 300 MHz): experimental (left) and simulated (right). Values
of temperature (T, K) and interconversion rate (k, s-1) are also given for every trace. Simulated spectra were obtained with the gNMR program.23
FIGURE 3. Partial (protons at C2 carbon) VT-NMR spectra of 1b (5 mM, DMSO-d6, 300 MHz): experimental (left) and simulated (right). Values
of temperature (T, K) and interconversion rate (k, s-1) are also given for every trace. Simulated spectra were obtained with the gNMR program.23
TABLE 2. Activation Parameters for 1a,b and 2a
Ea
entry compd (kcal/mol)a (kcal/mol)a K-1 mol-1
∆Hq
∆Sq (cal
∆Gq
(298)
b
)
(kcal/mol)a solvent
1
2
3
1a
1b
2a
11.5
8.9
9.7
10.8
8.1
9.1
-18.3
-27.0
-15.3
16.2
16.2
13.7
DMSO-d6
DMSO-d6
CDCl3
a Estimated error (0.15 kcal/mol. b Estimated error (0.5 cal K-1 mol-1
.
the result of the elimination of one phenyl ring in one side chain
of 1b, while meso-1b was designed to check the effect of spatial
disposition of side chains. Additionally, since the pseudo-
peptidic chain has been constructed by the assembly of two
different amino acids (Phe and Ala for 1c or D/L-Phe for meso-
1b), the average C2 symmetry in the fast exchange regime was
broken. As a consequence, the flipping proposed on these
derivatives (Scheme 2) would produce two different diastereo-
isomers regarding the planar chirality of the naphthalenophane.
FIGURE 4. Minima of energy for 1a,b and 2a,b. Hydrogen bonding
interactions are red dashed lines.
7952 J. Org. Chem., Vol. 72, No. 21, 2007

Molecular Rotors as Models to Study NH-Aromatic Interactions
SCHEME 2. Molecular Structures and Proposed Conformational Equilibria for 1c and meso-1b
One of them would set the naphthalene and the aromatic side
chains in opposite sides of the macrocycle (anti or type I in
Scheme 2), and the other would locate both aromatic groups
toward the same macrocyclic face (syn or type II in Scheme
2). As the energy barrier for the inversion of the 16-membered
ring is expected to be similar to those measured for 1a,b, both
diastereomers (I and II) will interconvert slowly in the NMR
time scale, making their corresponding 1H NMR signals
observable at room temperature. Besides, these two diastereo-
isomers would display different abilities to set the proposed
NH‚‚‚π interactions, as a consequence of the geometrical
disposition of the naphthyl and phenyl groups. Taking this into
account, we anticipated the syn-II isomer to be favored, its
relative stability being an indirect measurement of the role of
NH‚‚‚π interactions in the folding of the model compounds.
According to our design, the 1H NMR spectrum of 1c showed
a complicated group of signals as an indication of the presence
of two species in solution, which were characterized by
bidimensional COSY, TOCSY, and NOESY experiments (Sup-
porting Information). Detailed analysis of the 2-D NOESY
spectrum confirmed the presence of both rotamers I and II
connected through EXSY cross-peaks (Supporting Information)
and allowed the partial assignment of their corresponding proton
signals. Careful integration of some of these signals rendered a
2:3 mole ratio of I/II diastereoisomers (500 MHz, 303 K,
DMSO-d6). This would mean that ∆G(303K) ) 0.25 kcal/mol
favorable to the syn-II isomer. Additionally, we estimated from
VT-NMR experiments the energetic barrier for the intercon-
Fortunately, NMR analysis of meso-1b was even more
illustrative, as its H NMR spectrum showed a unique, very
1
simple, and symmetric structure in solution (both in DMSO-d6
and in CDCl3), which remains unaltered up to 403 K (300 MHz,
DMSO-d6), suggesting a very stable conformation. With the help
of a full set of 1-D NOESY experiments, we were able to
unambiguously assign this species to be the syn-II diastereomer
(Figure 7). For instance, selective irradiation on H9 produced
NOE enhancements on H10, amide NH, and one of the
diastereotopic protons on C2, H2A. On the other hand, irradia-
tion on the diastereotopic counterpart, H2B, produced a NOE
effect on H7 and H3, the CR proton. Besides, the amide NH
proton resonates at low chemical shifts (Figure 5), due to the
shielding effect of the anisotropy cones of the aromatic rings.
These data confirm that both aromatic groups point toward the
same face of the macrocyclic ring and that the amide group is
close to the naphthalene ring, thus preventing solvent acces-
sibility to the NH protons. Regarding that, the temperature factor
of the amide NH chemical shift in DMSO-d6 was found to be
notably small, ∆δNH/∆T ) -2.30 ppb/K.29 Besides, the
1
chemical shift difference of this H NMR signal in CDCl3 or
DMSO-d6 [δ(DMSO-d6) - δ(CDCl3) ) 0.39 ppm] was also
small. All these data support the existence of a strong intramo-
lecular hydrogen bond pattern even in a very competitive solvent
and a poor solvent accessibility to the amide NH protons, in
good agreement with the proposed conformation and our initial
design.
This structural arrangement was also obtained by molecular
modeling studies27 (Monte Carlo search and MMFF force field
minimization), which showed the preference of the macrocycle
to adopt the syn-II structure, being 3.5 kcal/mol more stable
than the anti-I diastereoisomer (Figure 6A and Table 3). The
minimum found for syn-II also showed internuclei distances in
version to be ∆Gq
) 19.2 kcal/mol, in good agreement
(373K)
with that observed for 1b. Monte Carlo conformational searches27
on 1c also showed syn-II as a more stable conformation than
anti-I, although the computed energetic difference (MMFF force
field) was much higher than the experimental one. However,
the energy minima thus obtained also show the H-bonding
pattern and NH‚‚‚π interactions previously found for 1b
(Supporting information). Thus, both experimental NMR data
and modeling reflect the preference of the aromatic rings to set
to the same face of the macrocycle, probably interconnected
through aryl-NH-aryl contacts.
(29) It was not possible to accurately measure the corresponding amide
NH temperature factor for all the other compounds due to exchange
produced by ring inversion. (a) Alonso, E.; Lo´pez-Ortiz, F.; Del Pozo, C.;
Peralta, E.; Mac´ıas, A.; Gonza´lez, J. J. Org. Chem. 2001, 66, 6333-6338.
(b) Belvisi, L.; Gennari, C.; Mielgo, A.; Potenza, D.; Scolastico, C. Eur. J.
Org. Chem. 1999, 389-400.
J. Org. Chem, Vol. 72, No. 21, 2007 7953

Alfonso et al.
tion by computing the solvent-accessible surface (Figure 6B).
In this conformation, the aromatic rings create an electron-rich
desolvated cavity, perfectly suited to host the intramolecular
H-bonded amide NH group. This calculation agrees with both
the low chemical shift and the temperature factor of NH protons
in a highly competitive solvent, such as DMSO.
We have performed additional theoretical calculations to
understand the nature of the NH‚‚‚π contacts in our most
efficient model, meso-1b, in spite of the controversial debate
about the origin of weak interactions.30 Previous theoretical
calculations31 found that amide-aromatic interactions mainly
emerge from a combination of dispersion and electrostatic
forces, which both have an electronic origin. Then, we optimized
the system using more accurate DFT quantum calculations at
the B3LYP/6-31G(d) level of theory. Full optimization of both
diastereoisomers of meso-1b yielded two minima with geom-
etries only slightly different from those obtained by MMFF force
field calculations and characterized by the disposition of the
amide NH bonds perpendicular to the naphthalene main plane
(Figure 7A). These T-shaped geometries maximize the attractive
interaction between the electric dipole of the amide groups and
the quadrupole of the aromatic ring, and they are expected to
be favored by quantum calculations in the gas phase. Interest-
ingly, DFT calculations rendered a closely similar energy
difference, ∆E ) 3.7 kcal/mol, favorable to the syn-II diaste-
reoisomer, in good agreement with the molecular mechanics
approach. Thus, the MMFF force field seems to reflect the
NH‚‚‚π interactions in a reasonable fashion, at least for a first
approximation. On the other hand, the DFT energy difference
would render a population of >99% of the syn-II isomer up to
403 K, in a perfect agreement with the observation of only this
rotamer by VT-NMR experiments within our accessible tem-
perature range.
FIGURE 5. Selected 1-D NOESY experiments (500 MHz, 303 K,
CDCl3) of meso-1b obtained by selective pulse field gradient irradiation
(bold arrow) on H9 (blue trace) or H2B (red trace).
To better visualize the NH‚‚‚π stabilizing contacts, we used
two different graphical representations. First of all, the CPK
model of the minimum found for the syn-II isomer of meso-1b
at the B3LYP/6-31G(d) level of theory showed clear van der
Waals contacts between both the amide NH atoms and the
aromatic π-cloud of the naphthyl ring (Figure 7B). This
observation follows the existence of dispersion forces between
both moieties of the system. A further representation of the weak
NH‚‚‚π interactions can be performed using the electron density
of the whole molecule, available from the electronic configu-
ration obtained by the B3LYP/6-31G(d) calculations.32 As this
stabilizing contact has an important electrostatic contribution,
we mapped the electrostatic potential (ESP) onto the global
electron density surface, different contours being evaluated for
illustrative purposes.33 The electron-rich areas (mainly π-electron
densities and electron lone pairs) are qualitatively represented
in red, while the electron-poor areas (mainly polarized hydrogen
atoms) are in blue. Electron density surfaces at different
isosurface values (Isoval) are shown in Figure 7C. The electron
density isosurface at Isoval ) 0.002 au represents >98% of
the electronic charge and reflects a close similarity to the CPK
FIGURE 6. (A) Minimized structures for anti-I and syn-II diastere-
oisomers of meso-1b, with hydrogen bonds as red dashed lines. (B)
Front and side views of syn-II geometry displaying the solvent-
accessible surface. The solvent excluded amide NH protons are in
yellow.
agreement with the experimental NOEs and presented two
intramolecularly H-bonded amide protons, surrounded by the
aromatic rings. A careful analysis of the structural differences
between both geometries (I and II) showed a closer contact of
the amide hydrogen atoms with the naphthyl ring for the syn-II
isomer (Table 3). Consequently, the theoretical calculations
nicely reflect the stabilization effect of the amide NH-aryl
contacts and also give an explanation for the complete diaste-
reoselectivity obtained in solution.
(30) Dunitz, J. D.; Gavezzotti, A. Angew. Chem., Int. Ed. 2005, 44,
1766-1787.
(31) Duan, G.; Smith, V. H., Jr.; Weaver, D. F. J. Phys. Chem. A 2000,
104, 4521-4532.
(32) Hehre, W. J. A Guide to Molecular Mechanics and Quantum
Chemical Calculations; Wavefunction Inc.: Irvine, CA, 2003.
(33) This approach has been very recently used to study sugar-aromatic
weak interactions: Terraneo, G.; Potenza, D.; Canales, A.; Jime´nez-Barbero,
J.; Baldridge, K. K.; Bernardi, A. J. Am. Chem. Soc. 2007, 129, 2890-
2900.
Also, in this case, we tried to qualitatively study the solvent
exposure of the amide NH protons in the most stable conforma-
7954 J. Org. Chem., Vol. 72, No. 21, 2007

Molecular Rotors as Models to Study NH-Aromatic Interactions
TABLE 3. Selected Structural Data of the Two Minimized Geometries (MMFF) Found for meso-1b
structure
H atom
d[NsH‚‚‚N]a
d[NsH‚‚‚Ph]b
d[NsH‚‚‚Nap]b
E (kcal/mol)c
anti-I
(R)-CR-CONH
(S)-CR-CONH
avd
2.37
2.38
2.38
2.41
2.28
2.35
2.95
2.89
2.92
2.81
3.07
2.94
2.85
2.87
2.86
2.84
2.69
2.74
129.6
syn-II
(R)-CR-CONH
(S)-CR-CONH
avd
126.1
a Distance (Å) from amide H to the amino nitrogen, forming a five-membered ring. b Distance (Å) from amide H to the center of the closest aryl C-C
bond. c Computed energy using the MMFF force field implemented in Spartan 04. d Averaged value (Å) between both amide hydrogen atoms.
FIGURE 7. (A) Minimized B3LYP/6-31G(d) geometries for both diastereoisomers of meso-1b. (B) CPK model for syn-II diastereoisomer. (C)
ESP mapped onto the global electron density [B3LYP/6-31G(d)] at different isosurface values (Isoval) for the syn-II minimum of meso-1b.
representation. The relative ESP around the amide protons
clearly indicates contact with the naphthalene ring, confirming
their mutual bonding interaction. The surface at Isoval ) 0.003
au, encompassing a smaller electron density and accordingly
closer to the nucleus, still shows important overlapping between
both NH groups and naphthyl moieties. The contact with one
of the amide NH atoms is lost at Isoval ) 0.005 au, suggesting
a lower limit of ca. 3.1 kcal/mol for the energy of the interaction
with both groups. The isosurface at 0.007 showed the contact
of naphthalene with only one of the amide protons. Moving
yet closer to the nucleus, at Isoval ) 0.009 au, no contact
between the amide NH groups and the naphthyl ring was
observed. Interestingly, we have to move much closer to the
nucleus, at Isoval ) 0.02 au, to eliminate the amide-amine
intramolecular H-bond, highlighting that this interaction is
stronger than the amide NH‚‚‚π contact. Besides, this analysis
allowed an estimation of the extent of the NH‚‚‚π interactions
in this system, located within 0.005-0.009 au or 3.1-5.6 kcal/
mol. These values are in good agreement with our experimental
and theoretical results, as well as with published calculations
on benzene-formamide complexes.31
amino acids (Val and Phe) has been studied by VT-NMR and
molecular modeling. The flipping rate of the naphthalene moiety
occurs within the NMR time scale range, which has allowed us
to deeply study this dynamic process. From the VT-NMR
experiments, clear tendencies have been observed depending
on the macrocyclic ring size and, more interestingly, the nature
of the side chain of the peptidomimetic fragment. In general,
macrocycles bearing aromatic side chains tend to be less flexible
related to the ring inversion process. The negative values of
∆Sq are noteworthy, which is most likely due to a higher
solvation of the TS as compared to the GS. This observation is
especially important for the derivatives bearing aromatic side
chains. Molecular modeling suggested the participation of amide
NH‚‚‚π interactions on the preferred conformations, which lead
to a more efficient desolvation of the pseudo-peptidic moiety
due to the presence of aromatic rings.
To confirm our proposal, we designed and prepared new
derivatives (1c and meso-1b) in which the flipping process
would lead to different diastereoisomers regarding the planar
chirality of the naphthalenophane ring. Careful NMR analysis
of these derivatives confirmed the major presence of the
corresponding rotamers showing both aryl groups (naphthyl and
benzyl) toward the same side of the macrocyclic main plane,
surrounding the peptidic NH bonds. This stereoselectivity is
Conclusion
The conformational behavior of 16- and 17-membered ring
macrocyclic naphthalenophanes (1a,b and 2a,b) derived from
1
moderate for 1c but complete for meso-1b. The H NMR data
J. Org. Chem, Vol. 72, No. 21, 2007 7955

Alfonso et al.
(∆Gq ) at the coalescence temperature (Tc) were obtained from the
for meso-1b in different solvents and temperatures suggested
that amide NH is implicated in a strong intramolecular hydrogen
bond and immersed in a desolvated environment. Besides,
molecular mechanics showed good agreement with experimental
results and confirmed the participation of amide NH‚‚‚π
interactions in the stabilization of the major diastereoisomers.
Further DFT quantum mechanics calculations were also per-
formed, showing a very good agreement with both experimental
and MMFF data. The combination of CPK models and ESP
analysis onto the electron density surfaces allowed us to
characterize this NH‚‚‚π stabilizing contact as a combination
of dispersion and electrostatic interactions. By the combination
of all theoretical and experimental data, we limit this interaction
within the energetic range of 3.1-5.6 kcal/mol.
The study of amide NH‚‚‚π interactions in model systems is
of great interest for the understanding of these noncovalent
contacts in biological chemistry and molecular recognition
processes. From our studies, we found that both dispersion and
electrostatic interactions contribute to the bonding stabilization
energy, with solvent exclusion playing a fundamental role.
Besides, their use to induce a highly diastereoselective confor-
mational preference is, as far as we know, unprecedented.
Indeed, the cooperative operation of NH‚‚‚π weak interactions
and solvent exclusion make one of our simple models (meso-
1b) to exclusively fold into one of the possible diastereomeric
geometries, in the same manner as biomolecules often behave
in nature.
c
following formula: ∆Gq ) RTc[22.96 + ln(Tc/δν)].22 Fitting of
dynamic NMR line shapes at different temperatures was performed
with the gNMR program.23 The activation parameters were
calculated by the least-squares fitting of suitable plots of the
corresponding kinetic values obtained from the line-shape analysis
and the measured temperatures of the experimental spectra. As the
simulation could be carried out at several temperatures (eight or
more), the estimated error in ∆Gq is about (0.15 kcal/mol.36 To
obtain the minima of energy by molecular modeling, the conformer
distribution calculation option available in Spartan ‘04 was used.27
With this option, an exhaustive Monte Carlo search without
constraints was performed for every structure. The torsion angles
were randomly varied, and the obtained structures were fully
optimized using the MMFF force field. Thus, 100 minima of energy
within an energy gap of 10 kcal/mol were generated. These
structures were analyzed and ordered considering the relative
energy, the repeated geometries being eliminated. When different
diastereoisomers were possible (1c and meso-1b), we calculated
both rotamers separately to ensure the complete mapping of the
conformational energy hypersurface. For DFT calculations at the
B3LYP/6-31G(d) level of theory, full minimization and frequency
analysis were performed with Spartan ‘04.27 The ESP mapped onto
the global electron density surfaces was computed at Isoval ) 0.002,
0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.010, 0.015, and
0.020 au using the B3LYP/6-31G(d) wavefunction and with the
facilities also available in this package. The graphics of the CPK
model and ESP electron densities represented in Figure 7 were
displayed using Spartan ‘04.27
Experimental Section
Acknowledgment. This paper is dedicated to Prof. Vicente
Gotor on the occasion of his 60th birthday. Financial support
from the Spanish Ministerio de Educacio´n y Ciencia (CTQ2006-
15672-C05-02) and Bancaixa-UJI (P11B2004-38) is gratefully
acknowledged. I.A., F.G., and L.V. also thank MEC for financial
support (Ramo´n y Cajal program for I.A. and F.G. and
predoctoral F. P. U. fellowship for L.V.).
Compounds 1a,b and 2a,b were synthesized as previously
described,34 while 1c and meso-1b were prepared in a similar way,
by performing a macrocyclization reaction from the corresponding
open chain bis(amidoamine). More detailed descriptions of the
synthesis and characterization of 1c and meso-1b are given in the
Supporting Information. For the VT-NMR experiments, samples
were prepared by weighing the necessary amount of peptidomimetic
naphthalenophane and adding a known volume (typically 0.7 mL)
of the desired deuterated solvent. The final concentration was 5-10
mM in all the cases. To take advantage of the magnetic field value,
measurements requiring temperatures higher than room temperature
for observing coalescence were performed in an apparatus with a
proton resonance frequency of 300 MHz. Conversely, when cooling
Supporting Information Available: Experimental synthetic
details and characterization, including copies of 1H NMR, 13C NMR,
and gCOSY spectra for meso-1b and 1H NMR, 13C NMR, gCOSY,
TOCSY, and NOESY spectra for 1c (3:2 syn/anti diastereomeric
mixture); experimental and simulated partial NMR spectra for the
VT-NMR analysis; Arrhenius and Eyring plots; computed solvent-
accessible surfaces for 1a,b; and XYZ coordinates and energies of
the geometries for all obtained global minima. This material is
available free of charge via the Internet at http://pubs.acs.org.
1
was necessary to achieve decoalescence, a 500 MHz (also for H
NMR) magnetic field was used. The temperature of each NMR
spectrometer was calibrated by the methanol method in separate
experiments.35 The accuracy in the temperature measurement was
at least (1 K. The reversibility of the changes produced in NMR
signals was checked by repeated measuring at different tempera-
tures. The approximated values of the free energy of activation
JO701552B
(35) Braun, S.; Kalinowski, H.-O.; Berger, S. 150 and More Basic NMR
Experiments; Wiley-VCH: Weinheim, Germany, 1988.
(36) Bonini, B. F.; Grossi, L.; Lunazzi, L. J. Org. Chem. 1986, 51, 517-
522.
(34) Burguete, F; Galindo, F.; Izquierdo, M. A.; Luis, S. V.; Vigara, L.
Tetrahedron 2007, 63, 9493-9501.
7956 J. Org. Chem., Vol. 72, No. 21, 2007