Substituent effects in double-helical hydrogen-bonded AAA-DDD complexes

Article abstract of DOI:10.1002/chem.201103001

Two series of DDD and AAA hydrogen-bond arrays were synthesized that form triply-hydrogenbonded double-helical complexes when combined in CDCl₃ solution. Derivatization of the DDD arrays with electron- withdrawing groups increases the complex association constants by up to a factor of 30 in those arrays examined. Derivatization of the AAA arrays with electron donating substituents reveals a similar magnitude effect on the complex stabilities. The effect of substitution on both types of arrays are modeled quite satisfactorily (R² > 0.96 in all cases) as free energy relationships with respect to the sums of their Hammett substituent constants. In all, the complex stabilities can be manipulated over more than three orders of magnitude (>20 kJmol^-1) using this type of modification.

Full text of DOI:10.1002/chem.201103001

DOI: 10.1002/chem.201103001
Substituent Effects in Double-Helical Hydrogen-Bonded AAA-DDD
Complexes
Hong-Bo Wang, Bhanu P. Mudraboyina, and James A. Wisner*[a]
Abstract: Two series of DDD and
AAA hydrogen-bond arrays were syn-
thesized that form triply-hydrogen-
bonded double-helical complexes when
combined in CDCl3 solution. Derivati-
zation of the DDD arrays with elec-
tron-withdrawing groups increases the
complex association constants by up to
a factor of 30 in those arrays examined.
Derivatization of the AAA arrays with
electron donating substituents reveals a
similar magnitude effect on the com-
plex stabilities. The effect of substitu-
tion on both types of arrays are mod-
eled quite satisfactorily (R2 > 0.96 in
all cases) as free energy relationships
with respect to the sums of their Ham-
mett substituent constants. In all, the
complex stabilities can be manipulated
over more than three orders of magni-
tude (>20 kJmolÀ1) using this type of
modification.
Keywords: helical structures · hy-
drogen bonds · linear free energy
relationships · self-assembly · supra-
molecular chemistry
Introduction
required for main-chain supramolecular polymer applica-
tions.
Hydrogen bonds have been used to construct supramolec-
ular assemblies and materials that respond to environmental
changes such as temperature, pH, and solvent.[1] A milestone
in this area was the development by Meijer and co-workers
of supramolecular polymers based on self-complementary 2-
ureido-4[1H]-pyrimidinone units.[2] Since the introduction of
these materials, reversible hydrogen-bonded polymers have
been extensively investigated.[3] One of the key factors this
work has highlighted is the requirement of a high stability
constant (ꢀ105 mÀ1) for the hydrogen-bonded motif in the
formation of main-chain supramolecular polymers.[4] The
binding strengths of multiple-point hydrogen-bond arrays
used in these applications are highly dependent on the num-
bers and arrangement of hydrogen-bonding donors (D) and
acceptors (A).[5] As the number of hydrogen bonds increas-
es, cooperativity generally results in an increasing associa-
tion constant.[6] Complementary systems including four or
more hydrogen bonds often exhibit strong binding proper-
ties, however their design can be complicated by a number
of factors such as difficult or expensive syntheses,[7] intramo-
lecularly hydrogen-bonded conformers,[8] tautomerism[9] or
undesirable self-association.[10] Triple hydrogen-bond sys-
tems potentially offer three complementary binding arrays
(ADA-DAD, AAD-DDA and AAA-DDD) but only AAA-
DDD complexes have been shown to provide the stability
There are very few examples of AAA-DDD complexes.
Zimmerman and co-workers described the first neutral
AAA-DDD complex (Ka >105 mÀ1), but it is unstable due to
a hydride shift from one component to the other.[11] Leigh
and co-workers demonstrated that modification of the AAA
component in this system could be used to improve the sta-
bility of the complex and observed extremely high associa-
tion constants.[12] Cationic DDD subunits can also form even
more stable complexes with AAA components, although
currently reported systems are likely sensitive to the charac-
ter of the counter anion, proton transfer and solvent depen-
dent pKa changes.[13]
As an alternative, we have recently described an AAA-
DDD hydrogen-bond system that is based on a different
design in which oligoheterocyclic strands wrap around one
another to form a double-helical complex.[14–16] In the ab-
sence of the AAA partner, the DDD components we initial-
ly synthesized displayed very poor solubility in non-polar
solvents due to intermolecular hydrogen-bonding. The solu-
bility can be greatly improved by using sterics to restrict
access to the sulfone functional group. The resulting methy-
lated analogue (Scheme 1, 6a) was markedly more soluble
but exhibited an association constant (Ka) of only 3700mÀ1
(RT in CDCl3). However, using the same synthetic approach
the skatole (3-methylindole) subunits of this design are
easily derivatized at their respective 5-positions with elec-
tron-withdrawing groups to improve the hydrogen-bond-do-
nating character of the corresponding NH protons. We were
interested in synthesizing several DDD and AAA analogues
of this reported system to determine the effect of electron-
withdrawing and -donating substituents on the stabilities of
their resultant complexes. These observations were antici-
pated to provide a gauge of what upper limit the stability of
[a] H.-B. Wang, B. P. Mudraboyina, Prof. J. A. Wisner
Department of Chemistry, The University of Western Ontario
1151 Richmond St., London, ON, N6A 5B7 (Canada)
Fax : (+1)519-661-3022
E-mail: jwisner@uwo.ca
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201103001.
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Chem. Eur. J. 2012, 18, 1322 – 1327

FULL PAPER
Scheme 1. Synthesis of DDD hydrogen bond arrays. Reagents and conditions: a) NaOH, EtOH/H2O, NaOAc, 08C to RT, 8 h; b) formic acid, reflux,
16 h; c) Zn(CN)2, DMF, [PdACHTUNTGRNEUNG(PPh3)4], reflux, 2 days; d) PhNMe3Br3, THF, reflux, 1.5 h; e) KSAc, DMF, 12 h; f) NaHCO3, cysteamine hydrochloride,
CH3CN, 12 h; g) Et3N, CH3CN, 12 h; h) meta-chloroperbenzoic acid (mCPBA), DMF, À258C to RT., 12 h; i) NH4OAc, glacial acetic acid, microwave,
1808C, 3 h.
these complexes could be manipulated to within the con-
fines of this particular design.
Results and Discussion
Synthesis: The synthesis of the DDD hydrogen bonding
arrays (Scheme 1) was initiated using a Japp–Klingeman/
Fischer indole approach[17] employing the diazonium salts of
anilines containing the desired substituents and either
methyl 2-ethylacetoacetate or the one carbon homologue
methyl 2-ethyl-3-oxopentanoate to yield 5-substituted
acetyl- or propionylskatoles 1a–d. The 5-cyanoskatoles 2
Scheme 2. Synthesis of AAA hydrogen-bond arrays. Reagents and condi-
tions: a) i) nBuLi, 2-dimethylaminoethanol, hexane, 08C, 1 h, ii) Bu3SnCl,
were obtained by Pd-catalyzed cyanation of the bromides 1c
and 1d. Acylskatole derivatives 1 and 2 were then a-bromi-
THF, À788C to RT, 1 h, 40%; b) 2,6-diiodo-3,5-lutidine, [Pd
ACHTUNGTRNEN(UNG PPh3)4], tol-
nated and the resulting bromides 3 converted to their corre-
sponding mercaptans 4. Thioethers 5 were generated by sub-
stitution of 3 by 4, oxidized to the resultant sulfones and cy-
clized with ammonium acetate to give 6a–i as final DDD
products substituted with electron-withdrawing groups on
one or both of the skatole rings. Unfortunately, the dinitrile
6i was completely insoluble in chloroform and could not,
therefore, be evaluated alongside the other DDD molecules
in the present study. It should also be noted that all of our
attempts to cyclize sulfones that would result in 2,6-dime-
thylthiazinedioxide products (i.e., elaboration of the thioeth-
ers generated from substitution of 3b, 3c, 3e by 4b and 4d)
were unsuccessful despite the investigation of a wide variety
of reagents and conditions that typically yield the desired
transformation.
uene, reflux, 5 days, 41%; c) i) nBuLi, hexane, THF, À788C, 1 h, ii) I2,
THF, À788C to RT, 14 h, 45%; d) conc. HNO3, conc. HSO4, 708C, 12 h,
72%; e) PCl3, CHCl3, reflux, 12 h, 90%; f) 2-tributyltinpyridine, [Pd-
AHCTUNTGREGUN(NN PPh3)4], toluene, reflux, 16 h, 86%; g) 10% Pd/C, hydrazine hydrate,
EtOH, reflux, 1.5 h, 91%.
coupling of the deoxygenated nitro derivative 12. The terlu-
tidine 9 was similarly provided by Stille coupling of 2-tribu-
tyltin-4,5-lutidine to 2,6-diiodo-3,5-lutidine that is easily de-
rived by deoxygenation of 10.
Complexation of 6 with 7: The interaction between each of
the eight DDD arrays that were soluble in CDCl3 (6a–h)
1
and the AAA array 7 was observed using H NMR spectros-
The complementary terpyridyl-based AAA hydrogen-
bond arrays studied were elaborated from lutidine-N-oxide
in three to five linear steps depending on the absence or
nature of substitution at the 4’-position (Scheme 2). The
nitro- and amino substituents of 13 and 14 were installed
first through nitration of common intermediate 10 and later
reduction of the nitroterpyridine 13 obtained from Stille
copy. A CDCl3 solution of each of 6a–h was titrated with 7
and the resulting change in chemical shift of the three N-H
protons was used to determine the binding constant (KX,Y
)
by non-linear curve fitting of the data to a simple 1:1 bind-
ing model (Table 1).[18] In all cases, the three N-H protons of
6 undergo large downfield shifts upon addition of excess 7
(4.02ꢀDdmax ꢀ2.36 ppm) indicating a strong hydrogen bond
Chem. Eur. J. 2012, 18, 1322 – 1327
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1323

J. A. Wisner et al.
Table 1. Changes in the chemical shifts of N-H protons (Ddmax), Hammett substituent constants (sp), associa-
tion constants (KX,Y), and free energies of complexation (DG), between each of 6a–h and 7 determined by
1H NMR in CDCl3 at 298 K (experimental errors in brackets).
However, there is
a clear
linear free-energy relationship
between the magnitude of the
complex stability and the elec-
tronic character of the substitu-
ents on the indole rings. It is
apparent that, as one might
expect, the installation of elec-
tron-withdrawing substituents
at the 5-positions of either ska-
tole ring system in 6 results in a
predictable increase in the sta-
bility of the complex with 7. A
plot of the sum of the Hammett
substituent constants for X and
6a
6b
6c
6d
6e
6 f
6g
6h
X, Y
H, H
Br, H H,
Br, CO2Et H, CN
Br, CN
CO2Et,
CO2Et
2.78[a]
3.94[b]
4.02[c]
0.88
CN,
CO2Et
3.90
CO2Et
Ddmax [ppm]
3.00[a]
2.79[b]
3.51[c]
0.00
2.60[a] 3.09[a]
3.88[b] 2.71[b]
3.22[c] 3.56[c]
2.86[a]
2.46[b]
3.21[c]
0.70
2.72[a]
2.36[b]
3.02[c]
0.71
2.80[a]
2.36[b]
3.93[c]
0.97
3.19
3.29[c]
1.15
Ssp
KX,Y [MÀ1
0.26
0.44
[d]
]
3.7ꢁ103 7ꢁ103 1.1ꢁ104 2.6ꢁ104
2.9ꢁ104
4.9ꢁ104
5.4ꢁ104
1.1ꢁ105
(Æ180)
A
R
(Æ1.1ꢁ103)
(Æ1.6ꢁ103)
A
(Æ1.7ꢁ103)
A
DG [kJmolÀ1
DDG
]
À20.4
À25.2
À25.5
À26.8
À27.0
À28.8
0
4.8
5.1
6.4
6.6
8.4
[kJmolÀ1
]
[a] Change in the chemical shift of thiazine dioxide N-H proton. [b] Change in the chemical shift of X-substi-
tuted indole N-H proton. [c] Change in the chemical shift of Y-substituted indole N-H proton. [d] Values are
averages and errors reported beneath are twice the standard deviations calculated from triplicate measure-
ments.
Y (Ssp) against log(KX,Y/KH,H
)
displays
a linear correlation
with 1=1.3 and R2 =0.99
(Figure 2). The positive value
interaction with all three sites. A molecular model of the
complex (geometry optimized at the Hartree–Fock 6-31G*
level of theory) between 6a and 7 illustrates the presumed
arrangement of the two arrays in the complex (Figure 1).
of 1 indicates that electron-withdrawing groups stabilize the
developing partial negative charge on the nitrogen atom of
the skatole rings that forms as a result of the hydrogen-
bonding interaction. Though electron-donating groups have
not been specifically explored in this context it is reasonable
to assume that the linear relationship observed here extends
to these cases as well.
Figure 1. Optimized (HF 6-31G*) structure of the complex formed be-
tween 6a and 7.
Figure 2. Plot of log(KX,Y/KH,H) versus Ssp for the interaction of 6a–h
with 7.
We could find no obvious correlations to draw between
either the electronic character of the substituents X and Y
(expressed as Hammett sp values)[19] or the stabilities of the
resulting complexes (KX,Y) with the dfree, dmax and Ddmax
values obtained from the titration curves. The effects are
therefore the result of a more complex relationship with the
chemical shifts of the NMR resonances than the simple
linear variance that one might expect.[20] The results imply
that the effect of X and Y on 6a–h is not only electronic
and perturbing the N-H hydrogen-bond acidities but also
conformational. We interpret the apparently random varia-
tion of the dfree, dmax and Ddmax values in the series of eight
donor molecules to indicate that, in their free states, they
have very different average conformations with respect to
their interplanar dihedral angles.
Complexation of 6a, 6c, 6g and 6h with 7, 9, 13 and 14:
Complex formation between four representative DDD mol-
ecules (6a, 6c, 6g and 6h) and the four AAA molecules 7,
9, 13 and 14 were examined in chloroform to provide a mea-
sure of the influence that electron-donating/withdrawing
groups attached to the acceptor components have on the
complex stabilities. In these cases, except those involving
complexation with 13, the association constants were deter-
mined using isothermal titration calorimetry (ITC) to estab-
lish not only the free energies but also the enthalpies and
entropies of complexation. In the case of 13, none of the
ITC experiments performed with 6a, 6c, 6g and 6h gave
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Chem. Eur. J. 2012, 18, 1322 – 1327

Double-Helical Hydrogen-Bonded AAA-DDD Complexes
FULL PAPER
satisfactory results due to a combination of weak binding
and solubility constraints. Consequently, these association
1
constants were instead determined using H NMR spectros-
copy in the manner described above. All of the titration
1
data (ITC and H NMR) were fit successfully to 1:1 binding
models. Examination of the results of these ITC and
1H NMR experiments reveals several trends.
As might be expected, a plot of the sum of the Hammett
substituent constants for X and Y (Ssp) against log(KX,Y
/
KH,H) displays a linear correlation for each of 7, 9, 13 and 14
yielding 1=1.3 for all four and R2 ꢀ0.97 (Figure 3a). Thus,
regardless of the AAA component examined, the complex
stability varies in the same way with the character of X and
Y in 6. A similar plot of the sum of the Hammett substituent
constants (Ssm/p) of 9, 13 and 14 (using 7 as the unsubstitut-
ed AAA reference) against log(Km/p/KH/H) with each of 6a,
6c, 6g and 6h also yielded a linear relationship with a simi-
lar correlation (Figure 3b). In all four of these cases, 1=
À1.4 and R2 ꢀ0.97 indicating the magnitude of the influence
of substitution on the AAA components towards complex
stability is nearly identical to that observed upon substitu-
tion of the DDD partner 7. This observation is somewhat
surprising considering the closer proximity of the substitu-
ents to the interacting atoms in the AAA versus DDD
arrays (i.e., three/four bonds distant (9, 13 and 14) vs. six
(6a, 6c, 6g and 6h)).[21] The negative value of 1 indicates
that electron-donating groups stabilize the developing par-
tial positive charge on the nitrogen atom of the pyridyl rings
in 7, 9, 13 and 14 as a result of the hydrogen-bonding inter-
action with 6.
Figure 3. a) Plot of log(KX,Y/KH,H) versus Ssp for the interaction of each
~
&
*
^
of 7 ( ), 9 ( ), 13 ( ), and 14 ( ) with 6a, c, g and h. b) Plot of log(Km/p
/
~
&
^
KH/H) versus Ssm/p for the interaction of each of 6a ( ), 6c ( ), 6g ( ),
*
and 6h ( ) with 7, 9, 13 and 14. Lines depict linear least squares fits for
each data set.
The ITC experiments also allowed an examina-
Table 2. Association constants (Ka), free energies (DG), enthalpies (DH), and entro-
pies (TDS) of complexation, between each of 6a, 6c, 6g and 6h, and 7, 9, 13 and 14 in
CHCl3 at 298 K (experimental errors in brackets) determined by ITC (or 1H NMR ti-
tration where indicated).
tion of the relationship between the free energies
of complexation between 6 and 7, 9, and 14 and the
enthalpic and entropic contributions to binding
(Table 2). In all the cases tested, the driving force
for complexation is enthalpic, as should be expect-
ed from complementary hydrogen-bond association
between two molecules in a non-polar solvent such
as chloroform. The data demonstrate the difficulty
of rationalizing incremental free energy relation-
ships using enthalpic and entropic data in this
system. A plot of DH versus TDS (see the Support-
ing Information) does not display a linear correla-
tion that would indicate a straightforward entropy–
enthalpy compensation effect. The linearity of the
free energy data when examined with respect to
the sums of the Hammett substitutent parameters
in the present cases must therefore result from a
more complex compensation between entropic and
enthalpic contributions to binding.
[a]
Ka [MÀ1
]
DG [kJmolÀ1
]
DH [kJmolÀ1
]
TDS [kJmolÀ1
]
6a·7
6a·9
6a·13
6a·14
6c·7
3100 (Æ380)
À19.9 (Æ0.3)
À21.2 (Æ0.4)
À11.9 (Æ0.7)
À23.2 (Æ0.5)
À24.2 (Æ0.4)
À25.6 (Æ0.2)
À16.6 (Æ0.7)
À27.5 (Æ0.2)
À26.7 (Æ0.2)
À27.7 (Æ0.1)
À19.3 (Æ0.7)
À30.6 (Æ0.3)
À29.0 (Æ0.4)
À30.1 (Æ0.3)
À20.7 (Æ0.4)
À32.4 (Æ0.2)
À35.1 (Æ0.6)
À31.4 (Æ1.8)
–
À32.1 (Æ2.4)
À40.4 (Æ3.0)
À36.2 (Æ2.6)
–
À41.3 (Æ2.8)
- 33.8 (Æ1.6)
À29.5 (Æ1.8)
–
À42.7 (Æ3.2)
À45.2 (Æ2.8)
À42.4 (Æ2.6)
–
À15.2 (Æ0.7)
À10.2 (Æ1.8)
–
À8.9 (Æ2.5)
À16.2 (Æ3.0)
À10.6 (Æ2.6)
–
À13.8 (Æ2.8)
À7.1 (Æ1.6)
À1.8 (Æ1.8)
–
À12.1 (Æ3.2)
À16.2 (Æ2.8)
À12.3 (Æ2.6)
–
5200 (Æ760)
120 (Æ32)[b]
1.18 (Æ0.22)ꢁ104
1.76 (Æ0.26)ꢁ104
3.04 (Æ0.24)ꢁ104
800 (Æ240)[b]
6c·9
6c·13
6c·14
6g·7
6.6 (Æ0.54)ꢁ104
4.8 (Æ0.30)ꢁ104
7.3 (Æ0.32)ꢁ104
2400 (Æ720)[b]
2.3 (Æ0.30)ꢁ105
1.2 (Æ0.22)ꢁ105
1.9 (Æ0.26)ꢁ105
4200 (Æ620)[b]
4.8 (Æ0.23)ꢁ105
6g·9
6g·13
6g·14
6h·7
6h·9
6h·13
6h·14
À47.7 (Æ2.2)
À15.3 (Æ2.2)
[a] Values are averages and errors reported in brackets are twice the standard devia-
1
tions calculated from triplicate measurements. [b] Determined by H NMR titration in
CDCl3 at 298 K.
Conclusion
addition of electron-withdrawing groups to the 5-positions
We have synthesized two series of DDD and AAA hydro-
gen-bond arrays that form triply-hydrogen-bonded double-
helical complexes when combined in CDCl3 solution. The
of the skatole rings in the DDD arrays increase the complex
association constants by up to a factor of 30 in the cases
studied. These increases, expressed in terms of their free
Chem. Eur. J. 2012, 18, 1322 – 1327
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1325

J. A. Wisner et al.
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The authors would like to thank the University of Western Ontario
(Western Innovation Fund), the Natural Sciences and Engineering Coun-
cil of Canada (Discovery Grant program) and the Ontario Ministry of
Research and Innovation (Early Researcher Award) for the financial as-
sistance to conduct this research.
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