Halogen bonding of (iodoethynyl)benzene derivatives in solution

Article abstract of DOI:10.1021/ol502099j

Halogen bonding (XB) between (iodoethynyl)benzene donors and quinuclidine in benzene affords binding free enthalpies (δG, 298 K) between -1.1 and -2.4 kcal mol^-1, with a strong LFER with the Hammett parameter σ_para. The enthalpic dri

Full text of DOI:10.1021/ol502099j

Letter
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Halogen Bonding of (Iodoethynyl)benzene Derivatives in Solution
Oliver Dumele,†,§ Dino Wu,†,§ Nils Trapp,† Nancy Goroff,‡ and Francois Diederich*,†
̧
†Laboratorium fur Organische Chemie, ETH Zurich, Vladimir-Prelog-Weg 3, 8093 Zurich, Switzerland
̈
‡Department of Chemistry, SUNY Stony Brook, Stony Brook, New York 11794-3400, United States
S
* Supporting Information
ABSTRACT: Halogen bonding (XB) between (iodoethynyl)benzene donors and
quinuclidine in benzene affords binding free enthalpies (ΔG, 298 K) between −1.1
and −2.4 kcal mol−1, with a strong LFER with the Hammett parameter σpara. The
enthalpic driving force is compensated by an unfavorable entropic term. The binding
affinity of XB acceptors increases in the order pyridine < CO < SO < PO <
quinuclidine. Diverse XB packing motifs are observed in the solid state.
Here, we investigate (iodoethynyl)benzene derivatives as XB
donors (Scheme 1) in benzene solution by performing NMR
alogen bonding (XB) is the noncovalent interaction of
Hthe electrophilic part of a halogen and a Lewis base. The
electron-donating entity, the XB acceptor, binds with its
electron lone pair to the electropositive region of the XB donor,
corresponding to the σ* orbital of the C−X bond, often
referred to as the σ hole.1,2 Important geometric boundary
conditions for efficient XB are A···X−C angles near 180° and
an A···X contact distance below the sum of the van der Waals
radii (A = XB acceptor). Halogen bonding has emerged as a
reliable motif in supramolecular architectures,3,4 and in catalysis
by C−X activation.5 The interaction is also abundant in
biological complexation.6,7 Nevertheless, only a limited number
of systematic quantitative XB studies in solution have
appeared.8−10 Here, we present a systematic study of halogen
bonding by (iodoethynyl)arenes and demonstrate the linear
free enthalpy relationship (LFER) of their XB with the
Hammett parameter σpara. Binding strengths to different XB
acceptors, thermodynamic profiles, and intermolecular solid-
state interactions are analyzed.
In 1981, Laurence et al. investigated changes in the IR
spectra of Lewis bases in dilute solution in the presence of
iodoethynyl derivatives R−CC−I with various substituents
directly attached to the acetylene.8 They observed good linear
correlations between log Ka (association constant) and the
Hammett parameter σpara for the substituent, with the most
Lewis acidic organoiodines demonstrating the strongest
interactions.8 Almost 30 years later, Taylor et al. studied the
XB properties of perfluorinated iodoarenes and iodoalkanes as
XB donors with a set of XB acceptors, using 19F NMR binding
titrations in cyclohexane.9 The scope of XB donors in this study
was limited to perfluorinated materials, as fluorine substituents
increase the polarization of arene or alkane C−X bonds,
creating a more positive σ-hole potential. A modest linear
correlation between log Ka and σpara was observed (r2 = 0.82),
although computational modeling predicted a very strong one
for fluorinated iodoarenes (ab initio study: r2 = 0.98).11
Scheme 1. Halogen Bonding of para-Substituted
(Iodoethynyl)benzene Derivatives with Lewis Bases
binding titrations with a focus on tuning XB donor strength by
distant para-substituents on the aromatic ring. Iodoalkynes
undergo XB in the solid state with a variety of acceptors,12 and
their XB donor abilities2a,b were ranked to be as strong as
pentafluoroiodobenzene by solid-state IR investigations.13 In
early work, Goroff et al. observed large solvent-dependent
changes in the 13C NMR chemical shift of the signal
corresponding to the C(1)-atom in iodoalkynes and demon-
strated through computational and experimental studies that
this effect resulted directly from XB interactions with the
solvents, acting as an XB acceptor.14 Taking advantage of these
interactions, diiodobuta-1,3-diyne was aligned in a designed
bis(nitrile)oxalamide XB acceptor matrix and shown to
undergo topochemical polymerization to form poly(diiodo-
diacetylene) in a crystal-to-crystal transformation.15 Iodoethyn-
yl motifs are also present in the lead structure of the
commercial antimycotic drug haloprogin,16a,c of which the
mechanism of action is still unknown.16b
By varying the para-substituent, remote from the iodine atom
(Scheme 1), we assumed that the environment at the XB
Received: July 17, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol502099j | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
binding site remains unchanged in the different complexes
formed. XB donors 1a−j and 2 were synthesized following
published procedures (see Supporting Information (SI) for
synthetic procedures)17 and are air-stable for days. Quinucli-
dine was selected as a Lewis base because of its very high XB
acceptor abilities.18
Binding constants were determined by NMR titrations
conducted in C6D6 (see SI for details). XB binding energies
could be determined for the entire scope of para-substituents
with σpara ranging from −0.83 to +0.78 (Table 1). Experimental
Table 1. Association Constants Ka and Binding Free
Enthalpy ΔG for XB Complexes of (Iodoethynyl)benzenes
1a−j and 2 with Quinuclidine in C6D6 at 298 K
Figure 1. Correlation between binding free enthalpies ΔG and
Hammett parameters σpara of different para-substituted (iodoethynyl)-
benzenes 1a−j with quinuclidine in C6D6 at 298 K.
a
b
compd
R
σpara
Ka /M−1
ΔG /kcal mol−1
1a
1b
1c
1d
1e
1f
1g
1h
1i
(CH3)2N−
iPrO−
CH3O−
CH3−
H−
Cl−
CH3CO−
F3C−
NC−
−0.83
−0.45
−0.27
−0.17
0
6.3 0.6
8.1 0.8
9.8 1.5
−1.1 0.1
−1.2 0.1
−1.3 0.1
−1.4 0.2
−1.5 0.1
−1.5 0.0(3)
−1.8 0.1
−1.7 0.1
−1.9 0.2
−1.9 0.2
−2.4 0.0(3)
−2.8
We found that the observation of the chemical shifts of
multiple NMR nuclei provides a good understanding of
secondary influences, apart from the direct XB association. In
this regard, we determined binding constants from at least two
independent titrations, whereas the substrates were titrated in
both direction: (1) addition of the XB donor to a constant
concentration of XB acceptor, and (2) vice versa, which
exhibited significant differences in binding constants (see SI for
detailed analysis and discussion regarding that issue).
We subsequently explored the variation of the XB acceptors.
Exploiting the iodoalkynes with the strongest XB donor
abilities, we were able to monitor and quantify the halogen
bonding interaction with weaker acceptor molecules, such as
tert-amides (Table 2). Among the oxygen-bearing acceptors,
the earlier reported order of decreasing binding strength of PO
> SO > CO is obeyed.18 Amide and urea carbonyl acceptors are
the weakest among all studied examples. Our results are in
11
12
14
20
17
25
25
60
117
3
2
1
3
4
7
8
3
0.23
0.50
0.54
0.66
0.78
1j
O2N−
c
2
C6F5−CCI
−
−
c
d
2
C6F5−CCI
a
Determined at 298 K in C6D6 by nonlinear least-squares curve fitting
of 1H NMR binding titration data to a 1:1 binding isotherm following
the ortho-protons of the (iodoethynyl)benzene and both CH2 groups
b
of quinuclidine. See SI for full details. Calculated from averaged Ka.
c
d
No substituent parameter available for comparison. Association
19
constant determined from
F
ortho
NMR chemical shift in cyclohexane
at 298 K (assumed error ∼20%).
Table 2. Association Constants Ka (M−1) of Representative
XB Acceptors with 1j and Pentafluoroiodobenzene
parameters (temperature, solvent, concentrations, XB acceptor
batch, spectrometer) were strictly maintained to be constant to
allow for precise comparison of data. Ka values (Table 1) range
from 6.3 0.6 M−1 for the dimethylamino (DMA)-substituted
XB donor to 25
8 M−1 for the nitro-substituted one. For
comparison, the highest XB strength was measured for 2 as the
donor, showing Ka values of 60 3 M−1 in C6D6 and 117 M−1
in cyclohexane. Remarkably, even DMA- or isopropoxy-
substituted substrates showed measurable association strength
despite unfavorable donor effects.
The binding free enthalpies ΔG and substituent parameters
σpara are in good linear correlation (Figure 1, r2 = 0.97; for
further details of data analysis, see SI). This correlation
confirms that the para-substituent is in electronic communica-
tion with the iodoethynyl group through the aromatic system.
Compared to the variation of the direct acetylenic substituent R
in R−CC−I in the study by Laurence et al., which gave
comparably good linear correlations,8b the influence of the
para-substituent at the aromatic ring is significant. It
demonstrates that substituent effects of even distant conjugated
groups influence the σ-hole potential substantially, resulting in a
remarkable span in binding free enthalpy Δ(ΔG) = 0.8 0.2
kcal mol−1. A comparison to the results by Taylor et al. shows
that (iodoethynyl)arenes follow a more linear trend than
tetrafluoroiodoarenes when the 4-substituent is varied.9 A lower
degree of linear correlation between ΔG and the Hammett
parameter σmeta was observed (Figure S55).
a
Association constant in C6D6 at 298 K; errors of 20% are generally
b
assumed. Association constant in cyclohexane at 298 K; values taken
c
1
from ref 9. For comparison, this value derives from the H NMR
chemical shift for Hortho of the XB donor, in contrast to the value
reported in Table 1.
B
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Letter
good agreement with the earlier study of related acceptors
interacting with C6F5I as the XB donor (Table 2).9
Thermodynamic quantities for selected XB complexes were
1
determined by van’t Hoff analysis of variable-temperature H
NMR titration data. The association between quinuclidine and
iodoalkynes is promoted by a favorable negative enthalpic term
ΔH, partially compensated by an unfavorable negative entropic
term TΔS (Figure 2). Interestingly, when the aryl substituent is
Figure 3. Single crystal X-ray structures of (A) 1i, (B) 1g, (C) 1c, and
(D) 4,5-bis(iodoethynyl)-1,2-dimethoxybenzene (3). Atomic displace-
ment parameters obtained at 100 K are drawn at 50% probability level.
Distances are indicated in Å with the percent of below van der Waals
distance in parentheses (for details see SI). Parts of the second
molecules in (A) and (B) are omitted for clarity.
Figure 2. Thermodynamic parameters of halogen bonding between
aryl-substituted iodoethynyls and quinuclidine, derived from van’t Hoff
analyses (see SI for details). TΔS is calculated at 298 K. Gray solid
investigations and experimental charge density measurements
from high-resolution single-crystal X-ray diffraction of these
diverse XB motifs are in progress.
a
lines as reference for TΔS and −ΔH values of 1e···quinuclidine. In
b
C6D6. In C6H12.
In summary, we employed para-substituted (iodoethynyl)-
benzene derivatives as XB donors and found a strong LFER
with σpara in the complexation to the XB acceptor quinuclidine.
Binding free enthalpies −ΔG for 1:1 complexes in C6D6 vary
between 1.1 (Me2N−) and 1.9 kcal mol−1 (O2N−). The XB
acceptor strength varies in the order pyridine < CO < SO
< PO < quinuclidine.18 Thermodynamic profiles revealed
that the enthalpic gain from the established halogen bond is
partially compensated by a substantial unfavorable entropic
term. Crystal structures showed diverse XB motifs of self-
associating (iodoethynyl)benzene derivatives in the solid state.
The results demonstrate the versatility of (iodoethynyl)-
benzene derivatives as strong XB donors, without the need
for aromatic perfluorination, which should make them attractive
components in drug design and synthetic supramolecular
systems.
varied from electronically neutral (−Ph) to electron deficient
(−C6F5), the increased gain in binding free enthalpy −ΔG
mostly originates from a more favorable enthalpic term. The
positive σ-hole potential becomes enhanced and a stronger
halogen bond forms, while the entropic costs are less affected.
Furthermore, 2 was found to exhibit a higher association
constant in cyclohexane compared to C6D6 (Table 1). C6D6···
C6F5CCI quadrupolar interactions and C6D6···σ-hole inter-
actions both become perturbed upon halogen bonding. In other
words, the XB donor is better solvated in C6D6 than in C6H12,
and the resulting desolvation accounts for a more favored
entropic term −TΔS in C6D6. At the same time, loss of σ-hole
stabilization by C6D6 solvation reduces the overall enthalpic
gain, as compared to C6H12.
In our previous biological study involving the enzyme hcatL,7
we observed a large gain in protein−ligand affinity even upon
formation of halogen bonds between backbone amide CO
and modest XB donors “X−C6H4−ligand”. It is clear that the
entropic costs are paid in this case by the complexation of the
large ligand at the active site of hcatL and the full additional
enthalpic gains of XB are harvested without much additional
loss in entropy.
In the crystalline state, the (iodoethynyl)arenes with
additional XB acceptor moieties expectedly exhibit pronounced
halogen bonding (Figure 3).1b,19 Short XB contacts, with I···A
distances below the sum of the van der Waals radii and C−I···A
angles in the range of 148°−175°, are observed. Thus, XB has a
dominant influence on the crystal packing, which is in
agreement with the observed solution-phase binding free
enthalpies of 1−2 kcal mol−1, well within the range of packing
energies previously observed for pairwise aromatic interactions
in crystals.20 Four different XB motifs were found: linear CN···
I, bent CO···I, orthogonal CC···I, and a three-center O··I··
O halogen bond (see SI for details). Quantum chemical
ASSOCIATED CONTENT
* Supporting Information
■
S
Synthetic procedures, analytical data of synthesized com-
pounds, NMR titration curves, further detailed analysis of
binding constant determination, Job plots, X-ray crystal
structure data, CIF files, 1H and 13C NMR spectra. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: diederich@org.chem.ethz.ch.
Author Contributions
§O.D. and D.W. contributed equally.
Notes
The authors declare no competing financial interest.
C
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Letter
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ACKNOWLEDGMENTS
■
The work was supported by the ETH Research Council. O.D.
acknowledges a Kekule
Chemischen Industrie (Germany). We thank Michael Solar
́
fellowship from the Fonds der
(ETH Zurich) for his help with collecting X-ray structures. We
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