Advantages of organic halogen bonding for halide recognition

Article abstract of DOI:10.1080/10610278.2015.1118101

The synthesis of a bidentate halogen bonding receptor and a nearly isostructural hydrogen bonding analogue is described. Crystal structures reveal the interactions of each receptor with anions in the solid state, while NMR titrations elucidate bidentate binding and association constants in solution. Of the two, the halogen bonding receptor demonstrates stronger, water resistant halide binding in competitive solvents.

Full text of DOI:10.1080/10610278.2015.1118101

Supramolecular Chemistry
ISSN: 1061-0278 (Print) 1029-0478 (Online) Journal homepage: http://www.tandfonline.com/loi/gsch20
Advantages of organic halogen bonding for halide
recognition
Nicholas B. Wageling, George F. Neuhaus, Ariana M. Rose, Daniel A. Decato &
Orion B. Berryman
To cite this article: Nicholas B. Wageling, George F. Neuhaus, Ariana M. Rose, Daniel A. Decato
& Orion B. Berryman (2015): Advantages of organic halogen bonding for halide recognition,
Supramolecular Chemistry, DOI: 10.1080/10610278.2015.1118101
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Date: 31 December 2015, At: 23:10

Supramolecular chemiStry, 2015
http://dx.doi.org/10.1080/10610278.2015.1118101
Advantages of organic halogen bonding for halide recognition
Nicholas B. Wageling‡, George F. Neuhaus‡, Ariana M. Rose, Daniel A. Decato and Orion B. Berryman
Department of chemistry and Biochemistry, university of montana, missoula mt, uSa
ARTICLE HISTORY
ABSTRACT
received 5 october2015
accepted 24 october2015
The synthesis of a bidentate halogen bonding receptor and a nearly isostructural hydrogen bonding
analogue is described. Crystal structures reveal the interactions of each receptor with anions in the
solid state, while NMR titrations elucidate bidentate binding and association constants in solution.
Of the two, the halogen bonding receptor demonstrates stronger, water resistant halide binding in
competitive solvents.
KEYWORDS
halogen bonding; anion
recognition; Nmr titration
1. Introduction
XB interactions, it has been suggested that XB is less sus-
ceptible to solvent inhibition than HB (15). For example,
Hunter recently reported a comparison of inorganic XB and
organic HB in a range of solvents.(15a) This investigation
concluded that HB strength diminished with increasing
solvent polarity while the XB remained relatively unper-
turbed. However, this study contained structurally diverse
inorganic XB and organic HB donors (elemental iodine and
4-(phenylazo)phenol). If this trend holds for organic XB
donors it would be of great interest due to their structural
versatility. Using an imidazolium-based organic XB or HB
donor on an identical scaffold provides an opportunity to
directly compare organic XB and C–H HB (16) in solution.
To date, only five experimental investigations (14b, 17) and
one computational study (18) have compared isostructural
imidazolium-based organic XB and HB donors.1 Herein, we
demonstrate that bidentate XB receptor 1 exhibits greater
binding affinity for halide guests and maintains stronger
interactions in the presence of water than a HB counter-
part. These results support that XB is a tractable approach
In the expanding field of anion recognition (1), potent
receptors have found application in chemical sensing (2),
anion transport (3), ion extraction (4), and catalysis (5).
However, producing tight and selective anion receptors
is challenging due to the low charge to radius ratio, pH
dependence and high hydration energy of anions as com-
pared to cations (6). Furthermore, applications in biologi-
cal (7) and environmental systems necessitate that anion
receptors function in competitive, polar and aqueous envi-
ronments. To overcome these obstacles, an array of strate-
gies are currently employed including: hydrogen bonding
(HB) (8), electrostatics (9), metal-complexation (10), and
hydrophobic interactions (11). In contrast, even though the
halogen bond (XB) is a robust noncovalent interaction, it
has been relatively under studied in solution.
The stringent linear directionality of the XB (12)
has been elegantly exploited in receptors to bind ani-
onic guests, including halides (13) and oxo-anions (14).
Because polarisation and charge-transfer contribute to
CONTACT orion B. Berryman
‡these authors contributed equally.
© 2015 taylor & Francis
orion.berryman@umontana.edu

2
N. B. WAGelING eT Al.
to anion recognition in competitive biological and envi-
ronmental systems.
2.4. General procedure for iodination
6 or 6a (1 equiv) was dissolved in dry THF and sparged
with dry N2 before cooling to −50 °C. To the slightly yellow
mixture, n-Buli (2.5 M in hexanes, 2.5 equiv) was added
dropwise, and was allowed to stir at –50 °C for 30 min.
A sparged solution of I2 (0.76 M in THF, 2.3 equiv) was
added to the solution dropwise, turning the solution red.
The reaction mixture was allowed to warm to rt over 2 h
and allowed to stir for an additional 22 h under N2. The
solvent was then removed and the concentrate was dis-
solved in DCM, washed with saturated aqueous sodium
thiosulfate, followed by DI water and finally brine. The
organic layer was dried over anhydrous MgSO4, filtered
and concentrated. The product was purified by flash col-
umn chromatography on normal phase silica.
2. Experimental section
2.1. General information
All materials were obtained from commercial sources
and used without further purification. NMR spectra were
recorded on a 500 or 400 MHz spectrometer. Chemical
shifts (δ) are expressed as ppm. For the 19F NMR spectra,
C6F6 (δ = –164.9 ppm) was used as an internal standard.
Signal splitting patterns are indicated as s, singlet; d, dou-
blet; t, triplet; m, multiplet; b, broad. Coupling constants
(J) are given in Hz. High-resolution mass spectrometry was
performed on an electrospray ionization mass spectrom-
eter with a time-of-flight detector.
2.5. General procedure for methylation
4, 4a, 5, 5a, 6 or 6a (1 equiv) was dissolved in dry DCM
and sparged with dry N2. MeOTf (4 equiv) was then added
dropwise to the solution, and it was allowed to stir under
N2 overnight. The product was filtered and purified by
recrystallisation.
2.2. General procedure for N-arylation
Salicylaldoxime (0.2 equiv), imidazole (1.2 equiv), Cs2CO3 (2.0
equiv), and Cu2O (0.1 equiv) were added to an oven dried
Schlenk tube under an inert atmosphere (dry N2). A sparged
solution of 1-bromo-3-(tert-butyl)-5-iodobenzene (8) (pre-
paredbyaknownprocedure(19)), or1-bromo-3-iodobenzene
(8a) (1 equiv, 0.8 M in total reaction mixture) dissolved in dry
acetonitrile was then added to the Schlenk tube using a can-
nula and the clear reaction mixture with Cu2O and Cs2CO3
suspension was raised to 50 °C in an oil bath and left to stir
for 25 h. The solution was then allowed to cool to rt before
diluting with DCM and filtering through diatomaceous earth.
The product was then purified by flash column chromatogra-
phy using normal phase silica, and/or by vacuum distillation
at 1 Torr.
2.6. General procedure for anion titrations
Stock solutions of 1, 2 and 3 were prepared in the given
solvent. Aliquots (0.500 ml) from each stock solution were
transferred via gas-tight syringe into three separate NMR
tubes sealed with rubber septa. The stock solutions were
then used to make host/guest solutions corresponding to
their experiment number. After obtaining free-host spectra
of 1, 2 and 3, aliquots of corresponding guest solution (con-
taining 1, 2, or 3 and TBA+X– at specified concentrations)
were added to their respective NMR tubes. A spectrum was
obtained after each addition. A constant host concentra-
tion was maintained, while TBA+X– concentrations in the
NMR tube gradually increased throughout the titration (see
data in SI). HypNMR 2008 (20) was used to fit the binding
isotherms for multiple signals (1: Ha, Hb, and Hc; 2: Ha, Hb,
Hc, Hd, He, Hf, and Hg; 3: Ha, Hb, Hc, and Hd) simultaneously.
2.3. General procedure for Suzuki–Miyaura cross-
coupling
PdCl2(PPh3)2 (0.1 equiv), and 1,3-phenylenediboronic acid
(0.5 equiv) were added to a Schlenk flask under an inert
atmosphere (dry N2). Sparged solutions of 7, 7a, 8 or 8a
in DMF (1 equiv, 0.1 M in total reaction mixture) and TBAF
(1 M inTHF, 7.8 equiv) were then added to the Schlenk flask
with a cannula. The yellow mixture was then heated to
90 °C in an oil bath. The reaction turned black after 10 min,
and was allowed to stir at 90 °C under N2 overnight. After
cooling to rt, the volatiles were removed by rotary evap-
orator leaving a black oil that was dissolved in DCM and
filtered through diatomaceous earth. The filtrate was con-
centrated on rotary evaporator and the resultant black oil
was purified by flash column chromatography on normal
phase silica.
2.6.1. 1-(3-bromo-5-(tert-butyl)phenyl)-1H-imidazole (7)
Prepared from 8 by following the general procedure for
N-arylation. Yellow oil: 85.7% yield; eluent conditions
1.5% (v/v) NH4OH (14.8 M, aq.) 3:2 hexanes:etOAc; 1H
NMR (500 MHz, CDCl3) δ 7.83 (s, 1H), 7.52 (t, J = 1.6 Hz,
1H), 7.37 (t, J = 1.9 Hz, 1H), 7.31 (t, J = 1.7 Hz, 1H), 7.26 (s,
1H), 7.21 (s, 1H), 1.35 (s, 9H). 13C[1H] NMR (125 MHz, CDCl3)
δ 155.39, 138.22, 135.60, 130.60, 127.93, 123.10, 121.96,
118.28, 117.64, 35.17, 31.07. HRMS (eSI-TOF) m/z: 279.0491
(M + 1H)+ 50%, 281.0472 (M + 2 + 1H)+ 50%, C13H15BrN2
(calc. 278.04).

SUPRAMOleCUlAR CHeMISTRY
3
2.6.2. 1-(3-bromophenyl)-1H-imidazole (7a)
2.6.6. 3,3″-bis(2-iodo-1H-imidazol-1-yl)-1,1′:3′,1″-
Prepared from 8a by following the general procedure for
N-arylation. Yellow oil: 84% yield; bp: 190–200 °C, ~1 Torr.
1H NMR (500 MHz, CDCl3) δ = 7.86 (s, 1H), 7.56 (t, J = 2.0 Hz,
1H), 7.51–7.49 (m, 1H), 7.37–7.32 (m, 2H), 7.27 (s, 1H), 7.22
(s, 1H). 13C[1H] NMR (125 MHz, CDCl3) δ = 138.5, 135.6,
131.3, 130.9, 130.7, 124.7, 123.5, 120.1, 118.2. HRMS (eSI-
TOF) m/z: 222.9865 (M + 1H)+ 50%, 224.9845 (M + 2 + 1H)+
50%, C9H7BrN2 (calc. 221.98).
terphenyl (4a)
Prepared from 6a by following the general procedure for
iodination. White solid: 52% yield; eluent conditions 1.5%
1
(v/v) NH4OH (14.8 M, aq.) 1:1 hexanes:acetone. H NMR
(500 MHz, CD2Cl2) δ = 7.89 (s, 1H), 7.81 (d, J = 7.8 Hz, 2H),
7.70–7.67 (m, 4H), 7.63–7.59 (m, 3H), 7.39 (d, J = 7.9 Hz,
2H), 7.32 (d, J = 1.3 Hz, 2H), 7.19 (d, J = 1.2 Hz, 2H). 13C[1H]
NMR (100 MHz, CDCl3) δ = 142.43, 140.56, 139.11, 133.22,
130.05, 129.93, 127.97, 127.09, 126.25, 125.84, 125.75,
124.93, 90.42 HRMS (eSI-TOF) m/z: 307.9805 (M + 2H)2+
C24H16I2N4 (calc. 613.94).
2.6.3. 1,1′-(5,5″-di-tert-butyl-[1,1′:3′,1″-terphenyl]-
3,3″-diyl)bis(1H-imidazole) (6)
Prepared from 7 by following the general procedure for
Suzuki–Miyaura cross-coupling. White solid: 60% yield;
eluent conditions 0.25% (v/v) MeOH, 1.5% (v/v) NH4OH
(14.8 M, aq.) in etOAc; mp: 207–210 °C. 1H NMR (400 MHz,
DMSO-d6) δ 8.39 (d, J = 1.4 Hz, 2H), 8.06 (t, J = 1.8 Hz,
1H), 7.90 (t, J = 1.3 Hz, 2H), 7.82–7.76 (m, 4H), 7.68 (t,
J = 1.5 Hz, 2H), 7.64–7.59 (m, 3H), 7.12 (d, J = 1.3 Hz, 2H),
1.41 (s, 18H). 13C[1H] NMR (100 MHz, DMSO-d6) δ 153.50,
141.81, 140.71, 137.43, 135.91, 129.70, 129.46, 126.83,
126.26, 122.60, 118.46, 116.80, 116.73, 34.98, 31.05.
HRMS (eSI-TOF) m/z: 238.1465 (M + 2H)2+, C32H34N4 (calc.
474.28).
2.6.7. 1-(3″,5-di-tert-butyl-5″-(1H-imidazol-1-yl)-
[1,1′:3′,1″-terphenyl]-3-yl)-2-iodo-1H-imidazole (5)
Prepared from 4 by following the general iodination proce-
dure (monoiodination occurs as a side product in the iodi-
nation step). White solid: 17% yield; eluent conditions 1.5%
(v/v) NH4OH (14.8 M, aq.) 2:3 hexanes:etOAc; mp: 140 °C
(decomposition). 1H NMR (400 MHz, CD3CN) δ 8.05 (s, 1H),
8.03 (t, J = 1.7 Hz, 1H), 7.89 (t, J = 1.7 Hz, 1H), 7.79–7.74
(m, 3H), 7.69 (t, J = 1.8 Hz, 1H), 7.64–7.57 (m, 3H), 7.55 (t,
J = 1.9 Hz, 1H), 7.50 (t, J = 1.8 Hz, 1H), 7.46 (d, J = 1.3 Hz,
1H), 7.16 (d, J = 1.3 Hz, 1H), 7.13 (s, 1H), 1.43 (s, 18H). 13C[1H]
NMR (125 MHz, CD3CN) δ 155.03, 154.42, 143.10, 142.56,
142.04, 141.66, 139.75, 138.81, 133.28, 130.58, 127.96,
127.82, 127.18, 126.22, 125.65, 124.31, 124.22, 123.65,
91.54, 35.91, 31.39, 31.36. HRMS (eSI-TOF) m/z: 301.0948
(M + 2H)2+, C32H33IN4 (calc. 600.17).
2.6.4. 3,3″-di(1H-imidazol-1-yl)-1,1′:3′,1″-terphenyl
(6a)
Prepared from 7a by following the general procedure
for Suzuki–Miyaura cross-coupling. Yellow oil: 78% yield;
eluent conditions 2.5% (v/v) MeOH, 1.5% (v/v) NH4OH
(14.8 M, aq.) in etOAc. 1H NMR (400 MHz, CDCl3) δ = 7.95
(s, 2H), 7.81 (t, J = 2.5 Hz, 1H), 7.66–7.64 (m, 6H), 7.62–7.57
(m, 3H), 7.42 (dt, J = 9.5 Hz, 2.0 Hz, 2H), 7.36 (s, 2H), 7.25 (s,
2H). 13C[1H] NMR (100 MHz, CDCl3) δ = 143.1, 140.9, 138.1,
135.8, 130.62, 130.58, 129.9, 127.1, 126.6, 126.3, 120.8,
120.6, 118.5. HRMS (eSI-TOF) m/z: 363.1604 (M + 1H)+
C24H18N4 (calc. 362.15)
2.6.8. 1,1′-(5,5″-di-tert-butyl-[1,1′:3′,1″-terphenyl]-
3,3″-diyl)bis(2-iodo-3-methyl-1H-imidazol-3-ium)
trifluoromethanesulfonate (1)
Prepared from 4 by following the general procedure for
methylation. White solid: 72% yield; Recrystallized from
1
CHCl3; mp: 218 °C (decomposition). H NMR (500 MHz,
CD3CN) δ 8.03 (t, J = 1.6 Hz, 2H), 7.99 (t, J = 1.6 Hz, 1H), 7.83
(d, J = 2.1 Hz, 2H), 7.77 (dd, J = 7.6, 1.9 Hz, 4H), 7.68–7.63
(m, 3H), 7.55 (t, J = 1.8 Hz, 2H), 3.93 (s, 6H), 1.44 (s, 18H).
13C[1H] NMR (100 MHz, CD3CN) δ 155.40, 143.17, 141.21,
138.31, 130.97, 128.27, 127.73, 127.68, 127.57, 127.04,
124.16, 123.45, 121.99 (q, J = 318 Hz), 101.78, 40.76, 36.12,
31.32. 19F NMR (376 MHz, CD3CN) δ –79.70. HRMS (eSI-TOF)
m/z: 378.0587 M2+, C34H38I2 N42+ (calc. 756.12, triflate anions
omitted).
2.6.5. 1,1′-(5,5″-di-tert-butyl-[1,1′:3′,1″-terphenyl]-
3,3″-diyl)bis(2-iodo-1H-imidazole) (4)
Prepared from 6 by following the general procedure for
iodination. White solid: 58% yield; eluent conditions 1.5%
(v/v) NH4OH (14.8 M, aq.) 3:2 hexanes:etOAc (note: product
degrades on normal phase silica); mp: 157 °C (decompo-
sition). 1H NMR (500 MHz, CD3CN) δ 8.01 (t, J = 1.6 Hz, 1H),
7.89 (t, J = 1.6 Hz, 2H), 7.76 (dd, J = 7.7, 1.7 Hz, 2H), 7.64–7.59
(m, 3H), 7.50 (t, J = 1.8 Hz, 2H), 7.45 (d, J = 1.2 Hz, 2H), 7.16
(d, J = 1.1 Hz, 2H), 1.42 (s, 18H). 13C[1H] NMR (125 MHz,
CD3CN) δ 154.48, 142.53, 141.73, 139.81, 133.31, 130.70,
127.88, 127.10, 126.24, 125.64, 124.34, 123.66, 91.53, 35.94,
31.42. HRMS (eSI-TOF) m/z: 364.0431 (M + 2H)2+, C32H32I2N4
(calc. 726.07).
2.6.9. 1,1′-([1,1′:3′,1″-terphenyl]-3,3″-diyl)
bis(2-iodo-3-methyl-1H-imidazol-3-ium)
trifluoromethanesulfonate (1a)
Prepared from 4a by following the general procedure for
methylation. White solid: 86% yield; filtered from reaction
and rinsed with DCM to give product. 1H NMR (400 MHz,
CD3CN) δ 8.26 (s, 2H), 8.16–8.11 (m, 7H), 7.87–7.81 (m,

4
N. B. WAGelING eT Al.
4H), 7.73–7.66 (m, 3H), 4.13 (s, 6H) 13C[1H] NMR (125 MHz,
CD3CN) δ 143.29, 140.63, 138.42, 131.65, 131.10, 130.68,
128.13, 127.78, 127.57, 126.84, 126.65, 126.33, 123.28,
120.73, 101.78, 40.73 (note: the peaks at 123.28 and 120.73
are from 19F coupling to the triflate carbon. The carbon
peak should split into a quartet, but only the two inside
peaks are observed, as the two outside peaks are below
the noise) 19F NMR (470 MHz, CD3CN) δ 79.68 HRMS (eSI-
TOF) m/z: 321.9961 M2+, C26H22I2 N42+ (calc. 643.99, triflate
anions omitted)
124.13, 123.39, 122.70, 119.74, 119.48, 101.70, 40.75, 37.20,
36.12, 36.10, 31.26, 31.24. 19F NMR (376 MHz, CD3CN) δ
-79.69. HRMS (eSI-TOF) m/z: 315.1095 M2+, C34H39IN42+ (calc.
630.22, triflate anions omitted).
2.6.11. 1,1′-(5,5″-di-tert-butyl-[1,1′:3′,1″-terphenyl]-
3,3″-diyl)bis(3-methyl-1H-imidazol-3-ium)
trifluoromethanesulfonate (3)
Prepared from 6 using the general procedure for methyl-
ation. White solid: 96% yield; recrystallized from 1:3 hex-
anes:CHCl3; mp: 203 °C (decomposition). 1H NMR (400 MHz,
CD2Cl2) δ 9.56 (s, 2H), 8.11 (s, 1H), 8.00–7.98 (t, 2H), 7.88 (s,
2H), 7.75–7.69 (m, 4H), 7.65–7.61 (t, 1H), 7.46 (t, J = 1.6 Hz,
2H), 7.45–7.42 (t, 2H), 4.12 (s, 6H), 1.44 (s, 18H). 13C[1H] NMR
(125 MHz, CD2Cl2) δ 155.36, 143.56, 140.84, 136.82, 135.67,
130.10, 127.62, 127.15, 126.88, 124.51, 122.08, 119.40,
118.59, 54.00, 37.30, 35.82, 31.47. 19F NMR (376 MHz,
CD2Cl2) δ -81.36. HRMS (eSI-TOF) m/z: 252.1621 M2+,
C34H40 N42+ (calc. 504.32, triflate anions omitted)
2.6.10. 1-(3″,5-di-tert-butyl-5″-(3-methyl-1H-
imidazol-3-ium-1-yl)-[1,1′:3′,1″-terphenyl]-
3-yl)-2-iodo-3-methyl-1H-imidazol-3-ium
trifluoromethanesulfonate (2)
Prepared from 5 by following the general procedure for
methylation. White solid: 86% yield; recrystallized from
1
1:9 hexanes:CHCl3; mp 146 °C (decomposition). H NMR
(500 MHz, CD3CN) δ 9.00 (s, 1H), 8.04 (t, J = 1.6 Hz, 1H), 8.02
(t, J = 1.5 Hz, 1H), 7.96 (t, J = 1.6 Hz, 1H), 7.88 (t, J = 1.9 Hz,
1H), 7.84 (d, J = 2.1 Hz, 1H), 7.81–7.75 (m, 4H), 7.68–7.64
(m, 2H), 7.63 (t, J = 1.9 Hz, 1H), 7.56 (t, J = 1.8 Hz, 2H), 3.96
(s, 3H), 3.93 (s, 3H), 1.44 (d, J = 2.9 Hz, 18H). 13C[1H] NMR
(125 MHz, CD3CN) δ 155.77, 155.37, 143.48, 143.19, 141.33,
141.12, 138.20, 136.48, 136.47, 136.25, 130.89, 128.36,
128.26, 127.75, 127.69, 127.58, 127.15, 127.03, 125.18,
3. Results and discussion
Bidentate XB scaffold 1 and controls 2 and 3 were prepared
by regioselective N-arylation (21) of 8 with imidazole fol-
lowed by a twofold palladium catalysed Suzuki–Miyaura
cross-coupling (22) (Scheme 1). The conformational
Scheme 1. (a) imidazole(1 equiv), cu2o (10 mol%), Saldox (20 mol%), cs2co3 (2 equiv), mecN, 50 °c, 18 h, 86%; (b) 1,3-phenylenediboronic
acid (0.5 equiv), pdcl2(pph3)2 (10 mol%), tBaF/thF (2.5 m, 4 equiv), DmF, 90 °c, 72 h, 60%; (c) 1) n-Buli (2.6 equiv), thF, –78 °c, 30 min 2)
i2/thF (2.7 equiv), –78 °c→rt, 24 h, 4 58%, 5 17%; (d) meotf (4.2 equiv), Dcm, rt, 24 h, 1 72%, 2 86%, 3 96%.

SUPRAMOleCUlAR CHeMISTRY
5
and 171.86(9)°). Additionally, there are anion–heteroarene
interactions (24) contributing to crystal formation: each
triflate counteranion lies between two electron-deficient
imidazolium rings, forming contacts between the triflate
oxygen and the methylated nitrogen of the imidazolium.
Crystal packing reveals alternating layers of XB receptors
where the donor iodines from each layer are directed
towards each other forming a linear array of iodines
throughout the crystal (SI Figure S1). The counteranions
interpenetrate each layer forming ion pairing interactions
and XB that stitch together neighbouring layers.
In contrast, tert-butyl substituted HB receptor 3 adopts
a splayed out conformation in the solid state (Figure 2).
X-ray diffraction quality crystals were grown by vapour dif-
Figure 1. (colour online) crystal structure of 1a highlighting the
linear XB between the iodines (purple) and triflate oxygens.
fusion of THF into MeCN solution. 3 crystallizes in the P1
̅
space group with two molecules per unit cell. The receptor
interacts with the triflate anions through one moderate
HB and multiple anion–heteroarene contacts. The lack
of preorganisation of 3 in the solid state may arise from
the relaxed linearity requirements of HB as compared to
XB. Moderate HB is observed between an imidazolium C2
hydrogen (Hd) and one triflate (C–H⋯O ∠166.0954(12)°
and C–H⋯O distance of 2.25831(16) Å). The other triflate
molecule interacts via weak anion–heteroarene contacts
with the electron-deficient imidazolium rings (C2⋯O
3.1431(2) Å). Additionally, one of the triflate fluorines is
directed at a peripheral aryl C–H hydrogen (25).
flexibility of the meta-terphenyl scaffold allows for biden-
tate binding while taking advantage of the stringent direc-
tional requirements of XB. To create the XB receptor 1, the
imidazole C2 carbons of 6 were deprotonated with n-Buli
and the reaction was quenched with elemental iodine,
generating 4 in 58% yield. The monoiodinated scaffold 5,
which serves as a convenient control after alkylation, was
separated from 4 via flash column chromatography in 17%
yield. Scaffolds 4, 5 and 6 were then alkylated with methyl
triflate to produce the activated dicationic XB receptors 1
and 2, and the control HB receptor 3, respectively.
1
To investigate the strength of XB in solution, H NMR
titrations were performed with each receptor and tet-
ra-n-butylammonium (TBA) halides. Initial titrations were
run in 1:1 CD2Cl2:CDCl3. However, these conditions with
1 produced association constants that were beyond the
detection limit of the NMR spectrometer (>105 M−1) (26).
To address this limitation, subsequent titrations were per-
formed in CD3CN wetted with 1% D2O (v/v) at 289 K.2
Association constants were obtained by simultaneously
fitting the most responsive proton signals (1: Ha, Hb, and
Hc; 2:3 Ha, Hb, Hc, and Hd; 3: Ha, Hb, Hc, and Hd) to the step-
wise association model described below. The presence of
To grow suitable crystals for X-ray diffraction, a less sol-
uble non-tert-butyl analogue 1a (Figure 1) was employed.
Diffraction quality crystals of 1a were formed by slow evap-
oration of an acetone solution. Scaffold 1a crystallizes in
the P1̅ space group with two molecules per unit cell. 1a is
preorganised in the solid state with both iodines directed
to the same side of the molecule. 1a exhibits strong XB to
the triflate counter anions as indicated by the close I⋯O
contacts (2.825(2) Å and 2.810(2) Å, 79.3% and 78.9% of
the sums of the van der Waals radii, ΣrvdW, respectively)
(23) and near linear arrangement of C–I⋯O ∠ (169.73(1)°
Figure 2. (colour online) crystal structure of hB receptor 3, with a non-convergent conformation.

6
N. B. WAGelING eT Al.
Figure 3. (colour online) 1h Nmr spectra of XB receptor 1 (left) and hB receptor 3 (right) titrated withtBacl and tBaBr, respectively (both
titrations performed in 1% D2o in cD3cN).
Table 1. anion association constants in mixed solvents.
b
b
Host
Aniona
Solvent
K1
K2
1
cl–
Br–
i–
cD3cN 1% D2o
cD3cN 1% D2o
cD3cN 1% D2o
cD3cN
cD3cN 5% D2o
cD3cN 1% D2o
cD3cN 1% D2o
cD3cN 1% D2o
cD3cN 1% D2o
cD3cN
37,700
28,900
12,990
236,000
3410
5902
935
432
356
455
2 380
293
59.2
57.0
64.0
47.3
425
Br–
Br–
cl–
cl–
Br–
i–
2
3
759
624.3
11,000
229
Br–
Br–
cD3cN 5% D2o
18.4
Note: all mixed solvents are v/v. each titration was performed at 289 K to encourage intramolecular interactions, and discourage degradation of the receptor with
iodide.
aall anions used were tetrabutylammonium salts.
bcalculated based on imidazolium and methyl protons. errors estimated to be 10%.
perturbation after one equivalent of guest is added. Based
on the dicationic design of the molecule, it was hypoth-
esised that the most significant and plausible binding
modes would be 2:1, 1:1 and 1:2 receptor:guest associ-
ations. An exhaustive search of binding modes showed
that the data did not fit a stepwise 2:1 receptor:guest asso-
ciation model. The dicationic nature of the receptor and
the statistical results from fitting the binding isotherms
indicate that 1:1 and 1:2 receptor:guest associations are
the dominant species in solution. This, along with lack of
2:1 association in the solid state, led to the rejection of the
stepwise 2:1 association model. Strong XB in solution is
indicated by the halide induced upfield shifts (14b, 27) of
the imidazolium protons in 1 (Figure 3). In stark contrast,
the analogous imidazolium protons of 3 shifted downfield
throughout the titrations, as expected for HB. To further
Figure 4. (colour online) crystal Structure of 1∙2i– highlighting
strong XB to iodide.
highlight the spectroscopic difference between XB and HB
in solution, TBACl was titrated into monoiodinated recep-
two different binding events is supported by the signifi-
cant change in direction or the cessation of chemical shift
tor 2. The protons on the iodinated imidazolium initially
shifted upfield while the protons on the non-iodinated

SUPRAMOleCUlAR CHeMISTRY
7
imidazolium (HB) shifted downfield, suggestive of both
XB and HB, respectively, in solution (SI Figure S2).
packing motif of alternating conformations (see SI Figure
S3). While monodentate XB is observed in both solid state
crystal structures of the XB receptor, solution data suggests
bidentate interactions are the dominant binding mode in
solution.
In these competitive conditions, receptor 1 exhib-
ited significant association constants (Table 1). The
trend in halide binding follows the Hofmeister series (Cl–
K1 = 37,700 M−1; Br– K1 = 28,900 M−1; and I– K1 = 12,990 M−1),
with all values 24–40 times larger than the HB receptor 3.
The trend with 3 also followed the Hofmeister series, sug-
gesting that the difference in binding between 1 and 3 is
not due to size exclusion of the anion. Receptor 2, which
can only form one XB, showed an intermediate association
to chloride (K1 = 5902 M−1).
To explore solvent effects, receptors 1 and 3 were
additionally titrated with TBABr in neat CD3CN and 5%
D2O:CD3CN. The logarithms of the overall equilibrium
constants (log [K1K2]) of each titration were compared. HB
receptor 3 showed a 46% reduction in binding strength
from 0 to 5% D2O, while XB 1 showed only a 32% reduction
in binding strength.4 These data further demonstrate that
1 is less affected by water, highlighting the solvent resist-
ance of organic XB.
Both receptors 1 and 3 form bidentate interactions with
halides in solution as evidenced by comparing K1 and K2.
The K2 values for 1 are two orders of magnitude lower than
the corresponding K1 values, suggesting that for the 1:1
interaction, the receptor binds in a bidentate fashion. The
same trend is observed for 3. If monodentate binding were
dominant, it is likely for this system that the magnitude
of K2 would be similar to K1. Further support of bidentate
binding is found by comparing the chloride titrations of 1
and 2. The K1 values of 1 and 2 are an order of magnitude
apart, which can be partially explained by the ability of
1 to form a second XB. Bidentate XB is supported as the
dominant conformation in solution and is responsible for
the strong association of 1 with halides in competitive
organic/aqueous environments.
To further investigate the bidentate conformation,
DFT calculations were performed (28). energy minimi-
sations were executed at the B98 level of theory, using
the 6-31+G(d,p) basis set for non-halogen atoms and
lANl2DZ with effective core potential for all halogens.
The iodine atoms were further augmented with diffuse
functions of p-symmetry and polarisation functions of
d-symmetry. This basis set has been shown to correlate
well with experimental halogen bonding studies (14a).
Three conformations5 were studied for both 1 and 3: a
bidentate binding conformation, a monodentate binding
conformation and an unbound conformation. The starting
points for each calculation were informed by the crystal
structures of 1, 1a and 3 as well as from the rational design
of the compounds. each analysed structure was confirmed
as minima on the potential energy surfaces. Bidentate XB
to chloride resulted in the greatest stabilisation for 1 as
compared to the unbound mode (ΔG = –23.66 kcal mol−1)
followed by monodentate binding (ΔG = –9.19 kcal mol−1).
In each case, the C–I⋯Cl– distances and angles repre-
sented significant XB; the C–I⋯Cl– distances were less
than 80% of the ΣrvdW, and the angles were all above 169°.
The HB receptor 3 showed the same trend with biden-
tate binding being the most stable vs. the unbound state
(ΔG = –21.27 kcal mol−1) followed by monodentate bind-
ing (ΔG = –14.83 kcal mol−1). These computations add fur-
ther evidence in favour of bidentate binding for both the
XB and HB receptors described here.
4. Conclusions
Despite numerous attempts, 1∙2I– was the only hal-
ide salt for which X-ray quality crystals were obtained
(Figure 4). Small colourless plates developed upon slow
evaporation of a 1% D2O:CD3CN solution. The receptor
crystallises into the P21/c space group with 12 molecules
in the asymmetric unit cell. even though 1∙2I– contains
bulky tert-butyl groups, similarities to 1a are observed in
the solid state. Strong monodentate XB to both counter
anions is present (I⋯I– distances of 3.314 to 3.406 Å, 81
to 83% ΣrvdW, ∠ 170.72˚ to 177.97˚). Two distinct receptor
conformations are observed in the crystal. In one, iodide
counter anions are sandwiched between the imidazolium
rings of an adjacent scaffold, forming anion–heteroarene
contacts (C2⋯I–, 3.708(5) Å). The other conformation has
the iodoimidazoliums perpendicular to each other. These
two conformations form separate columns, of which single
planes orthogonal to the columns create a checkerboard
With experimental evidence of XB in two phases, and
computational data that supports favourable bidentate
binding in the gas phase, this research demonstrates the
advantages of XB donors over C–H HB donors on imida-
zolium hosts. Crystal structures displayed strong XB with
triflate and iodide counter anions with the XB donors
directed towards the same side of the molecule. Solution
studies demonstrated that in this system XB outcompetes
C–H HB for halide recognition. Furthermore, the greater
resistance of organic XB to aqueous solvents was high-
lighted from titrations in different solvent mixtures. The
growing need for anion receptors to function in competi-
tive situations underscores the importance of fully under-
standing these noncovalent interactions. This example of a
XB anion receptor is evidence that organic XB is a tractable
design principle that can be used to overcome competitive
environments.

8
N. B. WAGelING eT Al.
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Supplemental material
Spectral data (1H, 13C, and 19F NMR) of all new compounds,
titration data and the CIF information of 1a, 1∙2I– and 3.
This material is available online here: http://dx.doi.org/
10.1080/10610278.2015.1118101.
Notes
1. Of the experimental studies, only two have looked
at binding in partially aqueous solvent. To date, our
report is the only study that we know of that quantifies
the effect of water on the halide binding of these
haloimidazolium receptors.
2. 289
K was chosen to encourage intermolecular
interactions, and eliminate degradation of 1 with TBA+I–.
3. For asymmetric receptor 2, protons He, Hf, and Hg were
also followed. See general titration section of the SI.
4. The difference between the logarithms of the overall
association constants for the 0% D2O and the 5% D2O
systems was divided by the value for the 0% system,
and multiplied by 100 to give the per cent difference.
The values for the logarithms of the overall association
constant are the averages of the three titrations
performed in that solvent system. The error in each
titration is estimated at 10%.
5. The conformations used were at energetic minima.
Although this was not an exhaustive search of binding
conformations, the rational design of the compounds
(along with crystal structures of 1, 1a, and 3) was used
as starting points for the DFT calculations.
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Acknowledgements
We would like to acknowledge A. C. Sather for collecting pre-
liminary data for the crystal structure in Figure 1, the UM CBSD
X-ray core for all other crystal structures, and the CBSD NMR
core for support of the NMR spectrometers.
Funding
(19) Tobe, Y.; Utsumi, N.; Nagano, A.; Sonoda, M.; Naemura, K.
Tetrahedron 2001, 57, 8075–8083.
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This work was financially supported by the Center for Biomo-
lecular Structure and Dynamics CoBRe [grant number NIGMS
P20GM103546]; National Science Foundation (NSF)-MRI [grant
number CHe – 1337908]; Montana University System MReDI
[grant number 51030-MUSRI2015-02] and the University of
Montana (UM). Funding for N. W. was provided by the UM CBSD
Fellowship programme (NIGMS P20GM103546).
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