Halogen-Bonded Supramolecular Capsules in the Solid State, in Solution, and in the Gas Phase

Article abstract of DOI:10.1002/anie.201610884

Supramolecular capsules were assembled by neutral halogen bonding (XB) and studied in the solid state, in solution, and in the gas phase. The geometry of the highly organized capsules is shown by an X-ray crystal structure which features the assembly of t

Full text of DOI:10.1002/anie.201610884

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201610884
German Edition: DOI: 10.1002/ange.201610884
Halogen-Bonded Capsules Very Important Paper
Halogen-Bonded Supramolecular Capsules in the Solid State, in
Solution, and in the Gas Phase
Oliver Dumele, Benedikt Schreib, Ulrike Warzok, Nils Trapp, Christoph A. Schalley, and
FranÅois Diederich*
In memory of Josꢀ Barluenga
Abstract: Supramolecular capsules were assembled by neutral
halogen bonding (XB) and studied in the solid state, in
solution, and in the gas phase. The geometry of the highly
organized capsules is shown by an X-ray crystal structure
which features the assembly of two XB hemispheres, geometri-
cally rigidified by H-bonding to eight MeOH molecules and
encapsulation of two benzene guests. To enhance capsular
association strength, tuning the XB donor is more efficient than
tuning the XB acceptor, due to desolvation penalties in protic
solvents, as shown for a tetraquinuclidine XB acceptor hemi-
sphere. With a tetra(iodoethynyl) XB donor and a tetralutidine
XB acceptor, the association in deuterated benzene/acetone/
reported on the first example of a XB capsule in solution
[5c]
(1···2, Figure 1).
XB donor 1 and XB acceptor 2 were
constructed from resorcin[4]arene cavitands and assembled to
form XB capsule 1···2 with a substantial association constant
À1
À1
of K = 5370m (DG = À4.85 kcalmol ), despite the use of
a
XB-competitive solvents, such as deuterated benzene/ace-
tone/methanol 70:30:1 at 283 K.
5
À1
methanol 70:30:1 at 283 K reaches K = (2.11 Æ 0.39) ꢁ 10 m
a
À1
(
DG = À6.9 Æ 0.1 kcalmol ). The stability of the XB capsules
in the gas phase was confirmed by electrospray ionization mass
spectrometry (ESI-MS). A new guest binding site was uncov-
ered within the elongated iodoethynyl capsule.
S
ince the first covalent container molecules were introduced
[
1]
by Cram et al. in 1985, different interactions, such as
[2]
[3]
hydrogen bonding, coordinative bonds, ionic interac-
tions, and only recently halogen bonding, have been
[
4]
[5]
Figure 1. Halogen-bonded supramolecular capsules. 1···2 (R=n-
[5c]
undecyl) studied in solution and in the gas phase. 1 ···2 (R=n-
[
6]
C6
C6
employed to construct supramolecular capsules. Halogen
bonding (XB) is the attractive non-covalent interaction
between the electrophilic site of a bound halogen atom and
a Lewis base. Supramolecular architectures based on XB
interactions have evolved over the recent years in crystal
hexyl) studied in the solid state.
[
7]
Herein, we report a study of XB capsules in the solid state,
in solution, and in the gas phase. Each phase reveals different
aspects of the fourfold XB through the use of complementary
analytical techniques, such as single-crystal X-ray crystallog-
raphy, NMR binding studies, and electrospray ionization mass
spectrometry (ESI-MS), in addition to structural variations of
the XB donor and acceptor motifs.
[8]
[9]
engineering, supramolecular materials, in the construction
[
10]
[11]
[12]
of rotaxanes,
catenanes,
anion receptors,
also become an important tool in medicinal chemistry to
macrocyclic hosts,
helical
[
13]
[14]
[15]
foldamers,
and catalysts.
XB has
[16]
develop more active and selective ligands.
Recently, we
X-ray analysis of dimeric XB capsules is challenging as it
is often difficult to obtain suitable single crystals necessary for
high quality crystallographic data on supramolecular com-
[
*] Dr. O. Dumele, B. Schreib, Dr. N. Trapp, Prof. Dr. F. Diederich
Laboratorium fꢀr Organische Chemie
ETH Zurich
Vladimir-Prelog-Weg 3, 8093 Zurich (Switzerland)
E-mail: diederich@org.chem.ethz.ch
plexes beyond
a
molecular weight of approximately
À1 [5a,e,17]
2
,000 gmol .
Multicomponent ionic XB architectures
[5b,d,18]
with different XB linker units have been reported,
however, no discrete, neutral, halogen-bonded dimeric cap-
sule has been resolved by X-ray analysis until now. Suitable
crystals were obtained for 1 ···2 , an analogue of 1···2 with
M. Sc. U. Warzok, Prof. Dr. C. A. Schalley
Institut fꢀr Chemie und Biochemie der Freien Universitꢁt
Takustrasse 3, 14195 Berlin (Germany)
C6
C6
Dr. O. Dumele
shorter side chains, by slow vapor diffusion (26 days) from
Present address: Department of Chemistry, Northwestern University
a benzene/MeOH/CS solvent system. The solid state struc-
2145 Sheridan Rd, Evanston, IL 60208 (USA)
2
ture (C2/c, Figure 2) depicts a remarkably ordered 12-
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
components assembly [(benzeneꢀ1 ·4MeOH)]···[(benz-
C6
À1
1002/anie.201610884.
eneꢀ2 ·4MeOH)] with a molecular weight of 4492 gmol .
C6
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had not been achieved before, despite
[
23]
their attractive XB abilities.
We further intended to strengthen
the XB ability of the XB donor hemi-
sphere 1 by installing iodoethynyl(te-
trafluorophenyl) moieties to afford
hemisphere 4 (Figure 3A). (Iodoethy-
nyl)benzene derivatives exhibit supe-
rior XB donor abilities in solu-
[15d,22c,24]
[25]
tion
and in the solid state.
In fact, pentafluoro(iodoethynyl)ben-
zene···quinuclidine is among the stron-
gest neutral monodentate XB pair in
À1
solution (K = 117m , cyclohexane,
a
Figure 2. Single-crystal X-ray structure of XB capsule 1 ···2 . The supramolecular assembly
[22c]
C6
C6
2
98 K).
Initial calculations further
consists of twelve individual components: donor hemisphere 1 , acceptor hemisphere 2 , each
encapsulating one benzene molecule (green), and each cavitand is rigidified by four MeOH
C6
C6
suggested that the modifications out-
lined above might increase the binding
Gibbs energies of the altered capsule
molecules. ORTEP ellipsoids are set at 40% probability at 100 K. C gray, N blue, O red,
host
[19]
I purple, F yellow, Cguest green.
[
21]
dramatically.
Binding experiments
to determine K for capsule 1···3 by
F NMR binding titration revealed a—for XB interactions
a
1
9
The capsular geometry is in agreement with our initially
predicted model obtained by density functional theory (DFT)
unprecedented—slow exchange process relative to the
F NMR time scale (in deuterated benzene/acetone/metha-
[5c]
19
calculations. The two XB donor and acceptor hemispheres
undergo head-to-head assembly as earlier determined in our
nol 70:30:1, 283 K). When 3 was added to a solution of 1,
1
9
19
solution studies by F NMR titrations and 2D-HOESY NMR
a new set of F NMR signals for the capsular complex 1···3
[5c]
experiments.
The four halogen bonds have a length of
emerged (Figure 3B) and the association constant was
d(I···N) = 2.82 ꢀ and are shorter than the sum of the van-der-
determined to an unexpectedly modest value of K
=
a,1···3
4
À1
À1
Waals radii of the interacting atoms by about 20%. The CÀ (1.03 Æ 0.11) ꢁ 10 m
(DG = À5.3 Æ 0.1 kcalmol , see the
1
9
I···N angles are nearly linear (2 ꢁ 1718, 2 ꢁ 1788), as expected
for the strongly directional XB interactions. Each hemisphere
complexes one benzene guest deep inside the resorcin-
Supporting Information, Section S4). F Diffusion-ordered
[
26]
NMR spectroscopy (DOSY)
confirmed the presence of
1···3 by a significantly lower diffusion constant relative to
single cavitand 1 (see the Supporting Information, Table S12).
As we initially hoped to substantially strengthen the XB
association with 1···3 as compared to 1···2, we turned to
analyze the enthalpy–entropy compensation for the binding
process by vanꢂt Hoff analysis. The formation of capsule 1···3
is enthalpy-driven with an unexpectedly low binding enthalpy
[
4]arene scaffold and each hemisphere is stabilized by four
MeOH solvent molecules bridging the benzimidazole walls of
the cavitand by a circular hydrogen bonding array, as initially
[20]
shown by Rebek and co-workers.
The central unit of
capsule 1 ···2 is unable to bind guest molecules owing to the
C6
C6
intrusion of the aromatic units into the cavity (see the
Supporting Information, Figure S3). Independently, Sure and
Grimme calculated detailed structural features of this XB
capsule by applying optimized D3-dispersion methods to
DFT calculations (2% deviation in the d(N···I) distances, see
À1
of DH = À5.0 kcalmol and a nearly vanishing entropy (DS
À1 À1
ꢁ 0 kcalmol K ). This situation is in marked contrast to the
[
22c,27]
thermodynamic profiles of neutral XB interactions,
such
as in the complexation of 1···2 with a larger binding enthalpy
[21]
À1
the Supporting Information, Section S3).
of DH = À12.6 kcalmol and a compensating entropic pen-
À1
The capsular assembly is solely based on fourfold halogen
bonding and provides a platform to investigate XB in solution
with the aim of exploring the upper limit of XB association
constants and to uncover new aspects of that interaction in
solution. To investigate the influence of different XB donor
and acceptor motifs, we introduced two distinct structural
changes from the original XB capsule 1···2 with the intention
of enhancing association between the hemispheres. The
weakly Lewis basic lutidyl moieties of the XB acceptor
cavitand 2 were exchanged with quinuclidyl residues, one of
alty of TDS = À7.8 kcalmol (same solvent and same tem-
[
5c]
perature).
The X-ray analysis of 3 revealed the origin of the slow
1
9
complexation on the F NMR time scale and the modest
increase in capsular stability despite the much stronger XB
¯
acceptor moiety. The crystal structure (P1) shows a 10-
component assembly consisting of cavitand 3 solvated by
eight ordered MeOH molecules and an enclosed benzene
molecule. Four of the MeOH molecules participate in the
mentioned circular H-bonding array, stabilizing the confor-
mation of the benzimidazole cavity walls. The other four
solvate the strongly H-bond-accepting quinuclidine N-atoms
(d(O···N) = 2.7–2.8 ꢀ; Figure 3C). The energy barrier for the
desolvation of these N-atoms upon capsule formation is
substantial and leads to the observed slow exchange kinetics
on the NMR time scale.
[
22]
the strongest organic XB acceptor motifs known, to afford
tetraquinuclidyl cavitand 3 (Figure 3A; for synthetic details,
see the Supporting Information, Section S2). The vertical
fourfold alignment of the nitrogen atoms was confirmed by an
X-ray crystal structure of 3 (Figure 3C). Synthetic incorpo-
ration of quinuclidyl derivatives into XB acceptor scaffolds
2
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dine···MeOH N···HO H-bonds are exchanged by strong N···I
halogen bonds, yielding only a moderate enthalpy gain for
capsule formation. Gratifyingly, the release of the quinucli-
dine-bound MeOH molecules into bulk solvent fully com-
pensates for the entropy losses upon capsular assembly. The
multidentate XB of highly preorganized hemispheres to
capsules thus provides unique insight into solvent effects on
[
27]
the assembly in the presence of competitive solvents.
Theoretical Gibbs energy predictions overestimated the
À1 [21]
binding strength for 1···3 (DGtheo = À9.6 kcalmol ), prob-
ably due to limitations on including explicit solvent molecules.
We anticipated that solvent would be less competitive in
the formation of tetra(iodoethynyl) capsule 2···4. Indeed, the
1
9
F NMR binding titration of 4 with 2 occurred at fast
exchange kinetics and provided a greatly enhanced XB
association, with an association constant of K
= (2.11 Æ
a,2···4
5
À1
À1
0
.39) ꢁ 10 m
(DG = À6.9 Æ 0.1 kcalmol ) in deuterated
benzene/acetone/methanol 70:30:1, 283 K (Figure 3D). To
our knowledge, this is the highest binding constant reported
for any neutral organic XB system and can be largely
attributed to the strong XB donor ability of the iodoethynyl
moieties.
All attempts to characterize the hypothetically strongest
iodoethynyl···quinuclidyl XB capsule 3···4 by NMR binding
titration resulted so far in either precipitation of the material
or degradation. The degradation could occur presumably by
alkyne de-iodination via iodine transfer to the quinuclidyl N-
atom, followed by protic degradation pathways.
ESI-MS experiments were selected as a mild method to
characterize the presence and stability of XB capsules in the
[
28]
gas phase.
Obtaining ESI-MS signals from neutral XB
capsules remained unsuccessful in both the positive and
negative ionization mode. As the capsule was shown to host
six-membered aromatic and heteroaliphatic guests, N-meth-
ylpyridinium was chosen as a permanently charged guest to
[
28a,d]
charge-tag
electrospray ionization of equimolar solutions of XB capsules
···2, 1···3, and 2···4 with N-methylpyridinium tosylate guest
the halogen-bonded capsules. Positive-mode
1
G·OTs resulted in mass spectra showing the intact hetero-
dimeric capsules with one bound guest G as singly charged
Figure 3. A) Structural tuning of the XB hemispheres in capsule 1···2
to tetraquinuclidyl cavitand 3 and to tetra(iodoethynyl) cavitand 4. The
+
+
+
ions [G@(1···2)] , [G@(1···3)] , and [G@(2···4)] at m/z 4733,
4749, and 4830, respectively (Figure 4). Exact masses and
isotopic patterns match those calculated. No homodimeric
complexes were observed indicating that the heterodimeric
capsules are indeed formed due to specific XB interactions of
the different cavitand hemispheres (see the Supporting
Information, Section S6).
binding constants K of the corresponding capsules 1···3, 1···2, and
a
2
···4 are given in the boxes (all in C D /(CD ) CO/CD OD 70:30:1,
6 6 3 2 3
1
9
2
83 K). B) F NMR spectra of 1 (c =1.024 mm) with increasing
0
amounts of added component 3. Determination of K by integration
a
ratios bound/free (inset values) at slow exchange rates. C) X-ray crystal
structure of 3 in complex with benzene and showing eight ordered
MeOH solvent molecules, with four of them solvating three of the
strongly basic quinuclidyl moieties. The front residue is not solvent-
exposed owing to its shielded position in the crystal packing; distances
To further explore the guest affinity of 1···3 and 2···4 in
solution, we studied 1,4-dioxane and 1,4-dithiane as
[
19]
19
[2c,29]
in ꢂ. D) F NMR binding titration of 4 with 2. The complexation-
induced change of chemical shift of the signals for the F atoms ortho
guests.
As a solvent system, we chose the reported
[
D ]mesitylene with 2% of 3,5-dimethylbenzyl alcohol at
12
to the iodoethynyl substituents is plotted (c (4)=85.5 mm) and fitted
o
2
83 K to compare new binding data of capsules 1···3 and 2···4
1
to a 1:1 isotherm. E) H NMR spectrum of 1,4-dithiane encapsulated
with the reported capsule 1···2 (see the Supporting Informa-
in 2···4 in [D ]mesitylene (+2% 3,5-dimethylbenzyl alcohol) at 283 K.
1
2
[5c]
tion, Section S5).
The iodoethynyl capsule 2···4 hosts one additional guest (turquois
marked area) compared to 1···2 or 1···3.
1
Guest binding rates are slow on the H NMR time scale
and encapsulation of guests is indicated by a large upfield shift
1
of the H NMR resonances into the negative ppm range. XB
The moderate, only twofold increase in stability of capsule
capsule 1···3 binds two molecules of 1,4-dioxane. Each 1,4-
1···3 compared to 1··2 is largely because the strong quinucli-
dioxane guest tumbles in the cavity at fast rates and each gives
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phase. The first X-ray crystal structure of a neutral dimeric
XB capsule evidenced a fourfold XB geometry between the
two hemispheres and encapsulation of two benzene guests.
Two novel structural modifications of the XB donor and
acceptor motif uncovered large solvent effects on XB capsule
formation. The quinuclidyl residues in the free hemisphere 3
are strongly solvated by MeOH molecules undergoing
OH···N hydrogen bonding. As a result, the formation of the
XB capsule 1···3 was found to have a modest association
constant in deuterated benzene/acetone/methanol 70:30:1 at
2
83 K and self-assembly occurs at slow exchange rates on the
F NMR time scale. In contrast, the tetra(iodoethynyl)
1
9
cavitand 4 undergoes strong association to the tetralutidyl
5
À1
cavitand 2 (K = (2.11 Æ 0.39) ꢁ 10 m ) at fast exchange rates.
a
These findings imply for protic solvents that tuning of the XB
donor has a greater favorable impact on the strength of XB
systems than tuning of the XB acceptor. Through encapsu-
lation of an N-methylpyridinium guest as charge-tag, ESI-MS
experiments further verified the presence of XB capsules in
the gas phase. Guest binding in solution showed Gibbs
Figure 4. ESI-Q-TOF-HRMS spectra of host–guest complexes of XB
capsules a) 2···4, b) 1···3, c) 1···2 with d) N-methylpyridinium (G; 10–
1
00 mm in CH Cl plus 3–5% MeOH), and experimental and calculated
2 2
À1
binding energies down to À(15.3 Æ 1.5) kcalmol for three
isotopic patterns (inset). For a detailed discussion of non-labeled
signals, see the Supporting Information.
1,4-dithianes enclosed into the largest capsule 2···4. We expect
increased future incorporation of the reported XB motifs in
supramolecular architectures and the use of multidentate XB
to create efficient binding sites for molecular recognition,
transport, and supramolecular catalysis.
rise to a singlet in the negative ppm region (d = À0.72 ppm
H
1
and À0.76 ppm) of the H NMR spectrum with a total Gibbs
À1
binding energy of DG = À(12.2 Æ 1.2) kcalmol . Similarly,
two 1,4-dithiane guests bind to 1···3 with DG = À(10.9 Æ Acknowledgements
À1
1
(
.1) kcalmol , in agreement with guest binding in 1···2
À1
DG = À7.5 and À11.6 kcalmol for 1,4-dioxane and 1,4-
O.D. was supported by a Kekulꢃ fellowship (Fonds der
Chemischen Industrie) and the Studienstiftung des Deut-
schen Volkes. We are grateful for support by the ETH
Research Council (ETH-01 13-2), the Swiss National Science
Foundation (SNF 200020_159802), and the Deutsche For-
schungsgemeinschaft (SFB 765). We thank Anatol Schwab for
recording analytical HPLC chromatograms, Renꢃ Arnold and
Dr. Marc-Olivier Ebert for recording NMR spectra, Michael
Solar for carefully picking crystals and recording X-ray
structures, and Cornelius Gropp (all ETHZ) for valuable
comments on the manuscript.
[
5c]
dithiane, respectively). When Sure and Grimme explored
the inner space of capsule 1···2 by quantum chemical methods,
a third guest binding site was found near the iodophenyl
residues in 1, which appeared to be significantly less favorable
compared with the deeply buried binding sites of the bridged
[
21]
resorcin[4]arene scaffolds. With the incorporation of the
capsule-elongating ethynyl units in tetra(iodoethynyl) cav-
itand 4, this binding site becomes accessible to a third
molecule. Binding of three 1,4-dithiane guests inside the XB
1
capsule 2···4 was inferred by three H NMR signals in the
negative ppm region (Figure 3E). The overall Gibbs binding
energy for three 1,4-dithianes amounts to DG = À(15.3 Æ
Keywords: halogen bonding · host–guest complexation ·
mass spectrometry · supramolecular capsules · X-ray diffraction
À1
1
.5) kcalmol . The additional third binding site is a result
of the XB capsule assembly and has not been observed with
the monomeric cavitand hemispheres 1–4 in solution; only the
X-ray crystal structure of 1 showed two benzenes inside the
[5c]
cavitand hemisphere 1. When 1,4-dioxane—a guest known
to bind weaker to each hemisphere than its thio analogue—
was employed in the same encapsulation experiment with
[
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[
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ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
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Chemie
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Manuscript received: November 7, 2016
121, 7455 – 7456.
Final Article published: && &&, &&&&
6
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 7
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Halogen-Bonded Capsules
O. Dumele, B. Schreib, U. Warzok,
N. Trapp, C. A. Schalley,
F. Diederich*
&&&& — &&&&
Halogen-Bonded Supramolecular
Capsules in the Solid State, in Solution,
and in the Gas Phase
We got them all: The geometry of neutral
dimeric halogen bonding (XB) capsules is
shown by an X-ray crystal structure of
a 12-component assembly. The halogen
bond donor and acceptor hemispheres
were tuned and revealed unprecedented
solvent effects, suggesting a new
approach for raising the stability of XB
assemblies in protic solvents. Stability of
the XB capsules in the gas phase was
confirmed by ESI-MS.
Angew. Chem. Int. Ed. 2016, 55, 1 – 7
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
7
These are not the final page numbers!