Unusual para-substituent effects on the intramolecular hydrogen-bond in hydrazone-based switches

Article abstract of DOI:10.1039/c2cc35860c

A "V"-shaped Hammett plot shows that resonance-assisted hydrogen bonding does not dictate the strength of the intramolecular hydrogen bond in the E isomers of hydrazone-based switches because it involves an aromatic pyridyl ring.

Full text of DOI:10.1039/c2cc35860c

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COMMUNICATION
Unusual para-substituent effects on the intramolecular hydrogen-bond in
hydrazone-based switchesw
a
b
b
b
a
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Xin Su, Mart Lokov, Agnes Kutt, Ivo Leito* and Ivan Aprahamian*
Received 27th June 2012, Accepted 31st August 2012
DOI: 10.1039/c2cc35860c
A ‘‘V’’-shaped Hammett plot shows that resonance-assisted hydrogen
bonding does not dictate the strength of the intramolecular hydrogen
bond in the E isomers of hydrazone-based switches because it
involves an aromatic pyridyl ring.
Hydrogen bonding is a universal phenomenon that is of particular
interest to chemists because of its prevalent influence on chemical
reactivity, properties, and processes.1 Although the study of
Scheme 1 The equilibrium between the E and Z isomers of the
hydrazone-based switches and the corresponding Hammett constants
(sp) for the para-substituents,10 in addition to the measured pKa values11
in acetonitrile (CH3CN). The H-bond fragments HN–NQC–CQN and
HN–NQC–CQO are indicated in red.
H-bonds has been going on for decades, the nature of H-bonding,
especially intramolecular H-bonding, is still intriguing.1b In 1989,
Gilli et al. proposed the resonance-assisted hydrogen bonding
(RAHB) theory in order to explain the unique strength of the
intramolecular H-bond in acetylacetone (HOCRQCR–CRQO)
fragments.2 Based on this theory p-delocalization in the frag-
ments involved in intramolecular H-bonding can lead to the
strengthening of these bonds.3 In recent years RAHB theory
has been expanded to include N–HÁ Á ÁO,4 O–HÁ Á ÁS5 and
N–HÁ Á ÁN6 H-bonded systems, thus broadening its impact on
H-bonding theory.7 Even though the RAHB theory has been
widely accepted8 and validated in various H-bonding fragments,7b
its scope is still not completely defined. For instance, its effect
has not been thoroughly assessed in intramolecularly H-bonded
fragments involving heterocyclic aromatic groups.9
Our interest in developing hydrazone-based switches12 has
led us to the synthesis of various intramolecularly H-bonded
compounds (Scheme 1). What is interesting and unique in these
systems is that they not only possess the classical RAHB fragment
HN–NQC–CQO in the minor Z isomer, but also feature another
six-membered H-bonded network (HN–NQC–CQN) in the
major E isomer.12 The latter involves a heteroatom which is part
of the aromatic pyridyl ring. There are only few examples of
RAHB studies focused on the N–HÁÁÁN H-bond fragment,6 and
none of these involve an aromatic ring. The fact that these
molecular switches exist in solution as a mixture of isomers
offers us a unique opportunity to directly compare two
different intramolecularly H-bonded fragments and study the
effect of incorporating an aromatic heterocycle as part of the
H-bonded fragment on RAHB.
We therefore decided to systematically investigate the
structure–property relationship of a series of para-substituted
phenylhydrazones in terms of their intramolecular H-bond
strength (Scheme 1 and Scheme S1, ESIw). The substituents on
the phenyl ring range from typical electron donating groups
(EDGs) to typical electron withdrawing ones (EWGs). The
electronic properties of these sustituents are usually quantified
by the Hammett substituent constant s (in the case of para-
substituents, sp), which describes their electron-donating
or electron-withdrawing capabilities.10 Generally speaking,
the higher the absolute value of s, the stronger the electron-
donating/withdrawing ability of a substituent. The influence of
substituents on the H-bond strength is usually used to decipher
the nature of the studied bond.
The linear free-energy relationship (LFER)13 between H-bond
strength and s has been reported for a few O–HÁÁÁO14 and
N–HÁ Á ÁO4a RAHB systems, reflecting the validity of this
type of analysis. In our system, the H-bond strength
of HN–NQC–CQO fragments can be characterized and
quantified by the chemical shifts of the N–H protons in the
Z configuration (dN–H,Z). Usually the stronger the H-bond the
more downfield shifted is the N–H proton signal.4a A plot of
a Department of Chemistry, Dartmouth College, Hanover,
New Hampshire 03755, USA. E-mail: ivan.aprahamian@dartmouth.edu
b Institute of Chemistry, University of Tartu, Ravila 14a, 50411 Tartu,
Estonia. E-mail: ivo.leito@ut.ee
w Electronic supplementary information (ESI) available: Experimental
procedures, NMR spectra, pKa measurements and crystal structure
data for compounds p-NMe2, p-OnHex, p-Cl, p-Br and p-NO2. CCDC
885513–885517. See DOI: 10.1039/c2cc35860c
d
N–H,Z of the different derivatives vs. the appropriate sp values
yields an excellent linear relationship (R2 = 0.985, Fig. S1,
ESIw) between these two variables (Fig. 1). As can be seen
from the plot the N–H chemical shift decreases from 11.85 to
11.16 ppm as sp increases. This trend demonstrates that the
H-bond becomes weaker as we move from EDGs to EWGs.
c
10490 Chem. Commun., 2012, 48, 10490–10492
This journal is The Royal Society of Chemistry 2012

definitely not consistent with RAHB theory! To reaffirm the
trend in H-bond strength we examined the crystal structures of
several derivatives in their E configuration (Fig. S7, ESIw),
since the donor–acceptor atom distance can be used to evaluate
the H-bond strength.15 Derivatives with either EDGs or
EWGs have shorter NÁ Á ÁN distances compared to that in
p-H, indicating that they also have stronger H-bonds. In
addition, the NÁ Á ÁN distances in these compounds range from
2.603(2) to 2.658(2) A, which are longer than those in reported
N–HÁ Á ÁN RAHB systems. The CQN bond lengths in these
derivatives range from 1.305(2) to 1.315(4) A, indicating that
they retain their double bond character, while the N–N bond
lengths range from 1.316(1) to 1.327(3) A, affirming their
single bond character.6 These results rule out RAHB induced
hydrazone-azo tautomerization16 in these systems.17 Thus,
neither 1H NMR spectroscopy nor X-ray crystallography
results show any evidence of RAHB in the HN–NQC–CQN
fragment. This observation can be attributed to the relatively
high energy of the resonance form, H+NQN–CQCQNÀ, in
which the aromaticity of the pyridyl group is diminished.
This conclusion is not straightforward, especially when one
takes into account reported examples in which aromaticity is
compromised for the sake of RAHB.9,18 The difference
between these systems and ours is the position of the acceptor
atom; it is directly attached to the aromatic ring in the former,
and is part of the ring in the latter. This distinction seems to be
responsible for the observed differences in behavior, and can
be important when analyzing RAHB phenomena in hetero-
cyclic systems, such as base pairs.19
Fig. 1 The plot of dN–H,Z (CD3CN) of the different derivatives (in
their Z configuration) vs. the corresponding sp values, and the
resonance structures in the N–HÁ Á ÁO RAHB system.
This observation is consistent with RAHB theory, i.e., the reso-
nance structures HN–NQC–CQO 2 H+NQN–CQC–OÀ
strengthen the H-bonding through p-delocalization.4a The
presence of an EDG in the phenyl ring enhances the electron
density and increases the H-bond strength, whereas EWGs lead to
the opposite effect. On the other hand and without RAHB
facilitation, the trend in the change of H-bond strength would
have been completely the opposite since EDGs will decrease
the acidity of the N–H proton, thus weakening the H-bonding.
It is noteworthy that the influence of RAHB is so significant
that it surpasses the increase in N–H acidity in the derivatives
with EWGs.
To validate our hypothesis and better understand the
unexpected trend observed for the H-bond strength in the E
isomers, we sought to determine the basicity of the pyridyl
group in these derivatives. We first studied the influence of the
phenyl ring para-substituents on the pyridyl ring by examining
the chemical shifts of the pyridyl proton H5 (dH5, Scheme 1).
The LFER in the plot of dH5 vs. sp clearly shows that the
electronic properties of the substituents on the phenyl ring
affect the pyridyl group (Fig. S3, ESIw). Going from p-NMe2
to p-NO2 the values increase from 8.68 to 8.75 ppm. The
positive slope shows that the EWGs lead to the expected
downfield shift. This observation demonstrates that the
pyridyl ring is in conjugation with the phenyl one,12d and thus
its basicity can be modulated by the p-substituents.
On the other hand the plot of the N–H chemical shifts
(dN–H,E) of the HN–NQC–CQN fragment in the E isomers
vs. the appropriate sp values affords a ‘‘V’’-shaped curve
instead of a straight trend line (Fig. 2). A decrease from
14.78 to 14.55 ppm is observed when going from p-NMe2 to
p-H, followed by an increase (14.55 to 14.77 ppm) going from
p-H to p-NO2. A roughly linear relationship between dN–H,E
and sp is observed in both sections (Fig. S2, ESIw). With p-H
as the lowest point in the curve, it is clear that both EDGs and
EWGs are making the H-bond stronger. This observation is
The basicities of the molecular switches (pKa values of their
conjugate acids) were determined using the previously
described methodology,20 and are presented in Scheme 1
(Table S2, ESIw).11 As shown previously,12 protonation of
the pyridyl group to yield the conjugate acid leads to the
switching of the molecule into the protonated Z isomer. The
pKa values show a roughly linear correlation with the sp values
(Fig. S4, ESIw); however, a ‘‘V’’-shaped pattern is again
observed when these values are plotted against dN–H,E
(Fig. S5, ESIw). Thus, there is no straightforward relation
between the pKa values of the compounds and the strength of
the intramolecular H-bond in the E isomer. In order to better
understand the nature of the substituent effect in these
systems, we looked deeper into the factors that can modulate
their H-bond strength, i.e., inductive and resonance effects.
When we correlated the pKa values with the field-inductive
Fig. 2 The plot of dN–H,E (CD3CN) of the different derivatives (in
their E configuration) vs. the corresponding sp values, and the
forbidden resonance in the HN–NQC–CQN fragment.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 10490–10492 10491

(sF) and resonance (sR) constants of the substituents10
(Fig. S6, ESIw) we obtained the following equation:21
4 (a) V. Bertolasi, L. Nanni, P. Gilli, V. Ferretti, G. Gilli, Y. M. Issa
and O. E. Sherif, New J. Chem., 1994, 18, 251–261; (b) P. Gilli,
V. Bertolasi, L. Pretto, A. Lycka and G. Gilli, J. Am. Chem. Soc.,
2002, 124, 13554–13567.
pKa = 12.3 À 2.0sR À 1.1sF (r2 = 0.97, S = 0.11) (1)
5 T. Steiner, Chem. Commun., 1998, 411–412.
6 (a) P. Simunek, V. Bertolasi, A. Lycka and V. Macha
Biomol. Chem., 2003, 1, 3250–3256; (b) P. Simunek, M. Svobodova
V. Bertolasi, L. Pretto, A. Lycka and V. Machacek, New J. Chem.,
2007, 31, 429–438.
´
cek, Org.
It can be seen that although both effects are operational, the
influence of the resonance effect is almost twice as strong.
Combining the pKa values with the information on the
strength of the intramolecular H-bond leads to the conclusion
that the para-substituents work in two different ways. The
EWGs first of all increase the N–H proton acidity, which is
more pronounced than the accompanied decrease in the basicity
of the pyridyl group leading to a stronger intramolecular
H-bond. On the other hand, the EDGs reduce the acidity of
the N–H proton; however, they concurrently lead to a larger
increase in the basicity of the pyridyl nitrogen, thereby leading
to an overall strengthening of the H-bond.
´
,
´
7 (a) L. Sobczyk, S. J. Grabowski and T. M. Krygowski, Chem. Rev.,
2005, 105, 3513–3560; (b) P. Gilli, L. Pretto, V. Bertolasi and
G. Gilli, Acc. Chem. Res., 2009, 42, 33–44.
8 For a different explanation as to why the H-bond in such systems is
´ ´
strong please see: (a) P. Sanz, O. Mo, M. Yanez and J. Elguero,
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11 The standard uncertainty (root mean square error) in pKa values is
estimated to be 0.1 unit, except for the p-MC, p-CN and p-NO2
derivatives where the standard uncertainties are 0.2, 0.2 and
0.5 unit, respectively.
12 (a) S. M. Landge and I. Aprahamian, J. Am. Chem. Soc., 2009,
131, 18269–18271; (b) X. Su and I. Aprahamian, Org. Lett., 2011,
13, 30–33; (c) X. Su, T. F. Robbins and I. Aprahamian, Angew.
Chem., Int. Ed., 2011, 50, 1841–1844; (d) S. M. Landge,
In summary, we have shown that the two H-bond fragments
HN–NQC–CQN and HN–NQC–CQO in a series of hydra-
zone-based switches adopt two distinct H-bonding motifs.
The HN–NQC–CQN fragment cannot take advantage of
RAHB enhancement, because that will diminish the aromatic
character of the pyridyl group. On the other hand, the
HN–NQC–CQO fragment follows RAHB theory. By mea-
suring the pKa values of the pyridyl ring and dissecting its
components, we were able to show that both electron donating
and withdrawing p-substituents strengthen the H-bond in the
HN–NQC–CQN fragment by inversely modulating the acidity
and basicity of the N–H and pyridyl nitrogens, respectively.
This work was supported by Dartmouth College, the
Burke Research Initiation Award, grant no. 9105 from the
Estonian Science Foundation and the UT Centre of excellence
‘‘High-Technology Materials for Sustainable Development’’
(SLOKT117T). The authors wish to thank Dr. Richard Staples
(Michigan State University) for X-ray analysis.
E. Tkatchouk, D. Benıtez, D. A. Lanfranchi, M. Elhabiri,
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R. P. Hughes and I. Aprahamian, Nat. Chem., 2012, 4, 757–762.
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stable than the hydraozone one by 5.9 kcal molÀ1
.
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21 The p-NO2 derivative was left out of the correlation because of the
very high uncertainty of its pKa value; the p-OnHex derivative was
left out because of the unavailability of its s constants. The
standard deviations of the intercept and the coefficients of sR
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c
10492 Chem. Commun., 2012, 48, 10490–10492
This journal is The Royal Society of Chemistry 2012