Tetraaza-2,2′-biphenylophanes: Larger is not always more flexible. The role of intramolecular H-bonding in polyazamacrocycles

Article abstract of DOI:10.1016/S0040-4039(02)00121-1

Intramolecular H-bonding can explain the trends in conformational flexibility for tetraaza-2,2′-biphenylophanes obtained by NMR and molecular dynamics calculations.

Full text of DOI:10.1016/S0040-4039(02)00121-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1817–1819
Tetraaza-2,2%-biphenylophanes: larger is not always more
flexible. The role of intramolecular H-bonding in
polyazamacrocycles
M. Isabel Burguete,a Beatriu Escuder,a Enrique Garc´ıa-Espan˜a,b Laura Lo´pez,a Santiago V. Luis,a,*
Juan F. Miraveta and Manel Querola
aDepartamento de Qu´ımica Inorga´nica y Orga´nica, Universitat Jaume I, 12080 Castello´n, Spain
bDepartamento de Qu´ımica Inorga´nica, Universitat de Valencia, 46100 Burjassot, Valencia, Spain
Received 21 November 2001; accepted 16 January 2002
Abstract—Intramolecular H-bonding can explain the trends in conformational flexibility for tetraaza-2,2%-biphenylophanes
obtained by NMR and molecular dynamics calculations. © 2002 Elsevier Science Ltd. All rights reserved.
During the last two decades macrocyclic polyamines
have been extensively studied by different research
groups.1,2 This type of compounds can interact with
anions, cations and with neutral molecules, and the
supramolecular species formed are of great interest in a
variety of areas. In particular, tetraazamacrocycles have
received special attention, being cyclam and related
compounds probably the better known example. In our
group we have been specially interested in azamacrocy-
cles containing aromatic units derived from benzene,
naphthalene, anthracene and biphenyl.3 The presence of
biphenyl subunits in the macrocycles is particularly
interesting as a result of the dynamic properties associ-
ated with this aromatic moiety as demonstrated, for
example, by Rebek in the development of allosteric
receptors.4
experiments and molecular dynamics calculations,
putting special emphasis on the information about host
preorganization that can be obtained from those
studies.
Synthesis of 2,2%-biphenylentetraazamacrocycles 1–8
(Chart 1) was carried out according to the general
method described by us for the preparation of N-tosyl-
ated-polyaza[n]paracyclophanes.3a In this case, drop-
wise addition of 2,2%-bis(bromomethyl)biphenyl dis-
solved in CH3CN over a refluxing suspension of the
appropriate pertosylated polyamine and an excess of
K2CO3 in CH3CN yielded the pertosylated macrocycles
1–4. The corresponding N-deprotected derivatives 5–8
were obtained after the treatment of 1–4 with HBr/
AcOH or Na/Hg.
The introduction of 2,2%-biphenylene units can be used
advantageously for the study of the dynamic properties
of a macrocycle by NMR spectroscopy. The informa-
tion that can be gained in this way about the preorgani-
zation of the receptors is very relevant for a better
understanding of the host–guest interactions. Thus, for
instance, the presence of conformational constraints
such as intramolecular H-bonding, that can be very
important in polyazamacrocycles, are amenable to
study using this approach. Our aim is to report on the
preparation of 2,2%-biphenylenetetraazamacrocycles and
the study of their dynamic properties based on NMR
* Corresponding author. Tel.: +34964728236; fax: +34964728214;
e-mail: luiss@qio.uji.es
Chart 1.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00121-1

1818
M. I. Burguete et al. / Tetrahedron Letters 43 (2002) 1817–1819
As it was mentioned previously, one of the most inter-
esting features of 2,2%-biphenylene macrocycles is the
dynamic properties associated with the rotation
through the CꢀC bond that connects the two phenyl
units. As depicted in Scheme 1, variation of the
biphenyl dihedral angle (q) can result eventually in the
exchange of enantiomeric conformers A and B. In
favorable cases, such equilibrium can be monitored by
variable temperature NMR experiments. For example,
the slow (on the NMR time scale) exchange between A
1
and B conformers results in non equivalent H NMR
signals for benzylic protons labeled as H1 and H1% in
Scheme 1 (AB system), while a fast exchange would
yield equivalent resonances for these protons (A2
system).
As could be expected, the dynamic behavior detected
for pertosylated macrocycles 1–4 by NMR (CDCl3, 300
MHz, 298 K), is explained simply by the size of the
macrocycles involved. As shown in Fig. 1, macrocycle 1
1
displays benzylic H NMR signals corresponding to an
AB system and two doublets are observed (J=13 Hz,
1
Dl=1.1 ppm). The H NMR of 2 and 3 also presents
an AB system for the benzylic signals but the lower
chemical shift difference detected reflects the faster
exchange process that is taking place. Macrocycle 4
shows a singlet for the benzylic protons at 298 K
indicating a fast exchange at this temperature.
Figure 1. 1H NMR spectra (300 MHz, 298 K) of the benzylic
protons of N-pertosylated compounds 1–4 and the corre-
sponding N-deprotected derivative 5–8 in CDCl3.
1
When macrocycles 5–8 were studied by H NMR in
CDCl3 (300 MHz, 298 K), interesting information
regarding their conformational flexibility was obtained
by analysis of the above mentioned benzylic type pro-
tons (see Fig. 1).
two propylenic spacers, did not show a singlet for the
benzylic protons as expected but two doublets (J=13
Hz, Dl=0.1 ppm) which did not change upon heating
to 333 K, a situation similar to that observed for
macrocycle 5.
For the smallest macrocycle 5, which contains three
ethylenic spacers, the spectrum shows two doublets
(J=13 Hz, Dl=0.26 ppm) as a result of coupling
between the non equivalent geminal protons in a situa-
tion analogous to that found for 1. The appearance of
these signals did not change upon heating to 333 K
(just below the boiling point of chloroform). Reason-
ably, the equilibrium depicted in Scheme 1 is faster for
larger macrocycles such as 6 and 7 as demonstrated by
their NMR spectra. The benzylic signals of 6 (which
presents an additional methylene group in the chain
when compared to 5) at 298 K are almost a singlet
(coalescence temperature 304 K), while 7 (which con-
tains three propylenic spacers) shows a singlet at that
temperature (coalescence occurs at 263 K). However,
the largest macrocycle 8, containing one butylenic and
This behavior is, at first sight, rather surprising but can
be understood in terms on the role that intramolecular
hydrogen bonding plays in the conformational flexibil-
ity of the studied macrocycles. As a matter of fact,
when molecular dynamics calculations were carried out
departing from the minimum energy structure found by
extensive conformational search (MACROMODEL
7.0,5 OPLS/AA, GB/SA simulation of chloroform as
the solvent) it was found that macrocycle 8 presents a
strong tendency to form an intramolecular H-bond
between its central amino groups.
As illustrated in Table 1, 30% of the sampled structures
during a 2000 ps simulation present a H-bond between
the amino groups separated by a butylenic spacer. The
study of macrocycle 7, presenting only one methylene
unit less than 8, results in fewer H-bonded structures
(19%) that also correspond to the interaction between
central amino groups. For the smaller macrocycles 5
and 6 intramolecular H-bonding is found to be much
less important.
The described calculations are in agreement with the 1H
NMR spectra mentioned previously and indicate that,
for a size of the polyamine chain large enough, the
presence of a butylenic separator between two amino
groups is a most favorable situation for intramolecular
Scheme 1.

M. I. Burguete et al. / Tetrahedron Letters 43 (2002) 1817–1819
1819
Table 1. Percentages of intramolecularly H-bonded struc-
tures found in the Molecular Dynamics simulations for
compounds 5–8a
Compound
% of H-bonded structures
5
6
7
8
3b
0
19c
30c
a OPLS/AA force-field, GB/SA simulation of solvent, simulation
time=2000 ps, 100 structures were sampled, H-bond presence was
determined according to the standard cutoffs.
Figure 3. Conformations of the central propylenediamine unit
of 7 and butylenediamine unit of 8 as found in the lowest
energy structures obtained by molecular mechanics (OPLS/
AA).
b H-bond between benzylic amino groups.
c H-bond between central amino groups.
H-bonding in these macrocycles. In order to illustrate
graphically the notable effect that this constraint
imposes to the conformational space of the macrocy-
cles, a superimposition of the structures sampled during
the molecular dynamics simulation for macrocycles 7
and 8 is shown in Fig. 2. It seems clear that this
restricted mobility correlates with the spectroscopic
data mentioned above.
This can be explained due to the strong electrostatic
repulsion in the would exist at the transition state for
the exchange process depicted in Scheme 1 and the
stiffening that protonation causes resulting in highly
preorganized hosts.
Acknowledgements
More information can be obtained by a detailed analy-
sis of the lowest energy structures obtained after exten-
sive Monte Carlo conformational search. As it can be
seen in Fig. 3, for both compounds 7 and 8 the most
stable structure presents an intramolecular H-bond
bridging the central amino groups. The H-bond in 8 is
specially stable due to the formation of a seven-mem-
bered ring that permits an almost linear disposition of
the three atoms involved, which, in addition, results in
shorter bond distances that in the case of 7. For the
latter molecule, the corresponding six-membered cyclic
disposition implies a H-bond disposition distorted from
the ideal 180° angle.
We are grateful to CICYT (BQV2000-1424-C03) for
financial support.
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Figure 2. Superimposition of 100 structures sampled during
the Molecular Dynamics simulation carried out for com-
pounds 7 and 8.