Halogen Bond Asymmetry in Solution

Article abstract of DOI:10.1021/jacs.8b09467

Halogen bonding is the noncovalent interaction of halogen atoms in which they act as electron acceptors. Whereas three-center hydrogen bond complexes, [D···H···D]⁺ where D is an electron donor, exist in solution as rapidly equilibrating asymmetric species, the analogous halogen bonds, [D···X···D]⁺, have been observed so far only to adopt static and symmetric geometries. Herein, we investigate whether halogen bond asymmetry, i.e., a [D-X···D]⁺ bond geometry, in which one of the D-X bonds is shorter and stronger, could be induced by modulation of electronic or steric factors. We have also attempted to convert a static three-center halogen bond complex into a mixture of rapidly exchanging asymmetric isomers, [D···X-D]⁺ ? [D-X···D]⁺, corresponding to the preferred form of the analogous hydrogen bonded complexes. Using ¹⁵N NMR, IPE NMR, and DFT, we prove that a static, asymmetric geometry, [D-X···D]⁺, is obtained upon desymmetrization of the electron density of a complex. We demonstrate computationally that conversion into a dynamic mixture of asymmetric geometries, [D···X-D]⁺ r← [D-X···D]⁺, is achievable upon increasing the donor-donor distance. However, due to the high energetic gain upon formation of the three-center-four-electron halogen bond, the assessed complex strongly prefers to form a dimer with two static and symmetric three-center halogen bonds over a dynamic and asymmetric halogen bonded form. Our observations indicate a vastly different preference in the secondary bonding of H⁺ and X⁺. Understanding the consequences of electronic and steric influences on the strength and geometry of the three-center halogen bond provides useful knowledge on chemical bonding and for the development of improved halonium transfer agents.

Full text of DOI:10.1021/jacs.8b09467

Subscriber access provided by University of Sunderland
Article
Halogen Bond Asymmetry in Solution
Sofia Lindblad, Krenare Mehmeti, Alberte X. Veiga, Bijan
Nekoueishahraki, Jürgen Gräfenstein, and Máté Erdélyi
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b09467 • Publication Date (Web): 20 Sep 2018
Downloaded from http://pubs.acs.org on September 20, 2018
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the
course of their duties.

Page 1 of 13
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Halogen Bond Asymmetry in Solution
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Sofia Lindblad,†,║ Krenare Mehmeti,† Alberte X. Veiga,†,  Bijan Nekoueishahraki,† Jürgen Gräfen-
stein,† and Máté Erdélyi†,‡,║,
*
† Department of Chemistry and Molecular Biology, University of Gothenburg, SE-412 96 Gothenburg, Sweden
║Department of Chemistry – BMC, Uppsala University, SE-751 23 Uppsala, Sweden
‡ The Swedish NMR Centre, Medicinaregatan 5, SE-413 90 Gothenburg, Sweden
ABSTRACT: Halogen bonding is the noncovalent interaction of halogen atoms in which they act as electron acceptors. Whereas
three-center hydrogen bond complexes, [DHD]+ where D is an electron donor, exist in solution as rapidly equilibrating asym-
metric species, the analogous halogen bonds, [DXD]+, have been observed so far only to adopt static and symmetric geometries.
Herein, we investigate whether halogen bond asymmetry, i.e. a [DXD]+ bond geometry, in which one of the DX bonds is
shorter and stronger, could be induced by modulation of electronic or steric factors. We have also attempted to convert a static
three-center halogen bond complex into a mixture of rapidly exchanging asymmetric isomers, [DXD]+
[DXD]+, corre-
sponding to the preferred form of the analogous hydrogen bonded complexes. Using 15N NMR, IPENMR and DFT, we prove that a
static, asymmetric geometry, [DXD]+, is obtained upon desymmetrization of the electron density of a complex. We demonstrate
computationally that conversion into a dynamic mixture of asymmetric geometries, [DXD]+
[DXD]+, is achievable
upon increasing the donordonor distance. However, due to the high energetic gain upon formation of the three-center-four-
electron halogen bond, the assessed complex strongly prefers to form a dimer with two static and symmetric three-center halogen
bonds over a dynamic and asymmetric halogen bonded form. Our observations indicate a vastly different preference in the second-
ary bonding of H+ and X+. Understanding the consequences of electronic and steric influences on the strength and geometry of the
three-center halogen bond provides useful knowledge on chemical bonding, and for the development of improved halonium transfer
agents.
INTRODUCTION
ometry, demonstrated that the heavy halogens form static,
symmetric three-center arrangements, [DXD]+, where D is
an electron donor. This geometry possesses remarkably short
(RXB=0.65-0.69)26,30 and strong (up to 120 kJ/mol)13,25 halogen
bonds, and is formed with nitrogenous,23,31 sulphurous,32,33
selenious and tellurious34 halogen bond acceptors. Owing to its
extraordinary strength, the three-center halogen bond can be
used for stabilization of large supramolecular assemblies.35,36
Moreover, such complexes are synthetically applicable as
halonium transfer and oxidation agents.29,37-51 We have shown
that the three-center halogen bond has a partial covalent char-
acter that increases with the decrease in size of the
halogen(I),25,26 an observation recently confirmed by Fourmi-
gué et al.52 Halogen bond strength, however, increases with the
size of the halogen and thus with the increase in ionic charac-
ter (and the decrease in covalent character) of the bond.26
Halogen bonding (XB) is the attractive, noncovalent interac-
tion of an electron-poor region of a halogen with a Lewis
base.1,2 It resembles hydrogen bonding in strength and direc-
tionality, yet has different geometrical requirements due to the
larger van der Waals radii of halogen atoms (rwI 1.98 Å, rwBr
1.85 Å, rwCl 1.75 Å, rwF 1.47 Å whereas rwH 1.2 Å).3 Alt-
hough it has already been observed one and a half centuries
ago,4-6 the halogen bond phenomenon has for long been ne-
glected and remains considerably unexplored. However, recent
X-ray crystallographic work2 has inspired a resurgence of
interest and rationalizations based on the -hole7 and charge
transfer concepts.8 Halogen bonding has led to numerous
applications, including crystal engineering,9 material
sciences,10 structural biology,11 medicinal12 and solution13
chemistries as well as in organocatalysis.14
Following early investigations,4,5,15-18 a major leap enabling
the systematic experimental assessment of halogen bonding
was the introduction of perfluorinated halogen bond donors by
Resnati and co-workers.19 These promote the formation of a
large electrophilic area on a halogen, i.e. a -hole, and conse-
quently strong and thereby easy to detect halogen bonds.20,21
An alternative approach, introduced by us, is to increase bond
strength by the use of a positively charged halogen, formally a
halonium ion or halogen (I), X+, as halogen bond donors.6,22,23
In such complexes, X+ forms a halogen bond with two Lewis
bases simultaneously, each contributing with a lone pair of
electrons.23,24 Studies on the nature of the X+-centered halogen
bonds25,26 and the possible influence of solvent,27 counterion,28
electron density29 and the identity of the halogen26 on its ge-
The geometry of a three-centered halogen bond may be stat-
ic and centrosymmetric, [DXD]+, with the central halo-
gen(I) possessing two equally strong and equally long halogen
bonds. The motion of the halogen in such systems is described
by a single-well energy potential (Figure 1a). Alternatively,
the geometry may be asymmetric, [DXD]+, with one
stronger and shorter, DX, bond to one of the electron donors,
and a weaker and longer, DX, bond to the other donor (Fig-
ure 1b). The DX bond of this arrangement is expected to
have an increased, whereas the DX a decreased covalent
character, as compared to the bonds of the centrosymmetric
[DXD]+ geometry. If the Lewis basicity of the two electron
donors are comparable and the two asymmetric geometries,
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 13
1
2
3
4
ric double-well, where one of the minima is of lower energy
and of higher stability (Figure 1d).
5
6
7
8
The halogen motion in a three-center halogen bond is analo-
gous to the [LGCNu]+
[LGCNu]+
[LGCNu]+ process, where Nu denotes a nucleophile and
LG a leaving group in the transition state of, e.g. a SN2 reac-
tion.26,53,54 The energy profile of this reaction is the inverse of
that of halonium transfer, with the transition state being an
energy maximum. Owing to the different Lewis basicities of
the nucleophile and of the leaving group, it shows highest
analogy to the static asymmetric three-center halogen bond
system, whose energy profile is shown in Figure 1c.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Electrophilic halogenations involve the same general haloni-
um transfer process: (i) an initial weakening of a covalent
dihalogen bond; (ii) formation of a three-center complex con-
sisting of a nucleophile, the central halogen(I) center and a
leaving group (e.g. a halide ion); (iii) collapse of this interme-
diate upon formation of a covalent halogen-nucleophile bond
and leaving group elimination.
The [DXD]+, [DXD]+, and [DXD]+ species can
also be seen to represent varying stages of a halonium ion
transfer process from one halogen bond acceptor to another.
These stages possess a varying degree of covalency and vary-
ing DX bond lengths. Understanding whether a halogen
transfer in between two halogen bond acceptors follows a
single-well or double-well potential, whether it takes place at
all, and whether the symmetric transition geometry possesses
higher stability than the resonance stabilized equilibrating
mixture of asymmetric ones, is of fundamental interest and has
recently received an increasing attention.23,52,55-57
Figure 1. Energy potentials of halogen motion in a three-
center [DXD]+ halogen bond: (a) a symmetric single-well
energy potential describes the halogen motion when the DX
bonds are equal and the system is static and symmetric,
whereas (b) a symmetric double-well potential may reflect a
pair of asymmetric isomers, [DXD]+
[DXD]+, in
dynamic equilibrium, with each form having a shorter and
stronger DX and a longer and weaker DX bond when the
energy barrier between the minima is shallow. The system
becomes static and asymmetric if the energy barrier between
the two minima is high. Alternatively, if the electron density
of the two Lewis bases, D, are different, the halogen motion
may either follow (c) an asymmetric single-well potential, or
(d) an asymmetric double-well potential with a clear prefer-
ence for a shorter and stronger bond towards one of the elec-
tron donors. The potential energy variation is shown here as a
function of Δr, the displacement of X+ from the symmetrical
position.
To date, all reported X+-centered halogen bonds formed by
the coordination of two electron donors of comparable basicity
have been described as symmetric.23,34 Neither solvent polari-
ty,27 ion coordination58 nor symmetric alteration of the electron
density29 could desymmetrize the centrosymmetric [DXD]+
geometries of these systems. Asymmetric arrangements could,
so far, only be achieved by using two Lewis bases with vastly
different Lewis basicities.52,57 By contrast, analogous hydrogen
bond [D–H–D]+ complexes prefer asymmetric geometry.59,60
Herein, we evaluate whether the strongly favored symmetric
three-center halogen bond, [DXD]+, may be converted into
a static and asymmetric geometry (Figure 1c), [DXD]+, or
into a dynamic interconverting mixture of asymmetric com-
[DXD]+ and [DXD]+, are separated by a shallow energy
barrier, these may interconvert and the system will exist as a
dynamic mixture in which the halogen motion is described
with a symmetric double-well energy potential (Figure 1b).
Analogous to the term prototropy that describes tautomeric
exchange processes involving the transfer of a proton, such a
plexes, [DXD]+
[DXD]+ (Figure 1b). The former
low barrier [DXD]+
[DXD]+ interconversion may
ought to be achieved by asymmetrically adjusting the electron
density of the Lewis basic moieties, D, by introduction of
different electron-withdrawing versus donating substituents.
The latter, a dynamic asymmetric molecular system, is ex-
pected to be obtained upon enforcing a longer-than-optimal
donor-donor, here nitrogen-nitrogen, distance (2a). Based on
computational analyses, we designed, synthesized and investi-
gated compound 1a (Figure 2) as a candidate for a static
asymmetric halogen bonded system (Figure 1c) and compound
2a as a candidate for dynamic asymmetric (Figure 1b) system.
be designated as halotropy. If the two geometries, [DXD]+
and [DXD]+, are separated by a high-energy barrier, the
complex converts into a static, asymmetric geometry that has a
conventional covalent and a conventional halogen bond,
DX+D. The halogen of the latter has a classic -hole7 and,
accordingly, a covalent and secondary bond, whereas that of
the three-center-four electron [DXD]+ complex possesses a
p-hole, formed by the empty p-orbital of X+, as well as two
secondary bonds with a partial covalent character.23 If the
electron donors have slightly different Lewis basicities, the
complex may either become (c) static and asymmetric, with
the halogen showing a higher preference to one of the Lewis
bases and its motion between the electron donors being de-
scribed by an asymmetric single-well, or it is expected to form
(d) asymmetric geometries that are of different energy. In the
latter system, the halogen motion is described by an asymmet-
RESULTS AND DISCUSSION
Design. As a starting point for the design of asymmetrically
halogen bonded systems, we studied the [NIN]+ bond
energy dependence on the nitrogen-nitrogen distance, rNN, and
on the displacement of the iodine(I) Δr from a symmetric
geometry in [bis(pyridine)iodine]+, a model system (Figure 3,
computational details are given in the Supporting
ACS Paragon Plus Environment

Page 3 of 13
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
the system with a CH3 and a CF3 substituent, an asymmetric
single-well potential curve with the iodine shifted towards the
CH3-substituted pyridine by about 0.05 Å is obtained (Figure
4a, long-dashed line). In view of this, to obtain a halogen bond
showing a static asymmetric single-well potential, we de-
signed 1a. This backbone provides a sterically symmetric but
electronically asymmetric61 environment for the central halo-
gen of the three-center [NIN]+ bond. For analogs of 1, we
have shown that due to the flexibility of the acetylenes, the
backbone exerts only a weak strain on the [NIN]+ halogen
bond.25 For the hydrogen bond analogue 1b, which possesses a
CH3/CF3-substituted backbone and an [NHN]+ hydrogen
bond (Figure 2), the hydrogen motion is predicted to follow an
asymmetric double-well potential curve (Figure 1d), as shown
with short-dashed line in Figure 4a.
Figure 2. [(4-Methyl-2-((2-((4-(trifluoromethyl)pyridin-2-
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
yl)ethynyl)phenyl)ethynyl)pyridine)iodine]+ tetrafluoroborate
(1) and [(2,2'-(9,10-dimethoxyphenanthrene-3,6-diyl)dipyridi-
ne)iodine]+ tetrafluoroborate (2) were used as model systems
to study a static asymmetric and a dynamic asymmetric halo-
gen bond, respectively. Complex 1 allows optimal N-N dis-
tance for the formation of a three-center halogen bond and has
an asymmetric electron distribution. Complex 2 has a longer-
than-optimal distance between its nitrogens and has a symmet-
ric electron distribution. A mixture of 1 and its mono-
deuterated isotopologue 1-d was used in IPE NMR experi-
ments to differentiate between a static [NIN]+ and a dy-
namic [NIN]+
[NIN]+ system.
Information). The computed energy surface shows the global
energy minimum at rNN = 4.511 Å and Δr = 0, i.e. at a centro-
symmetric configuration, in agreement with the literature.22,25
Upon increasing the nitrogen-nitrogen distance, the symmetric
geometry remains most stable up to rNN = 4.880 Å, where a
bifucaration occurs, and at larger nitrogen-nitrogen distances
the asymmetric [NIN]+ geometry becomes energetically
most favorable. Upon a further increase of rNN, the energy
barrier between the asymmetric geometries increases, indicat-
ing them to be even more favored at large nitrogen-nitrogen
distances as compared to the corresponding symmetric geome-
try. It should, however, be noted that these asymmetric geome-
tries are of higher energy as compared to the symmetric geom-
etry at the global energy minimum (rNN = 4.511 Å, Δr = 0).
The energy surface shown in Figure 3 does not immediately
provide potential curves analogous to those shown in Figure 1,
as it does not account for strain energy and for geometric
constraints the backbone of 1 and 2 may impose on the
[NIN]+ bond. However, the potential curves can be qualita-
tively inferred from the energy surface. Hence, for a perfectly
flexible ligand, the strain energy vanishes and the potential
curve shown in blue in Figure 3, and accordingly the symmet-
ric single-well potential shown in Figure 1a, is predicted to
describe the halogen’s motion. A promising approach to ac-
complish a static asymmetric [N–IN]+ bond, Figure 1c, is to
add different para-substituents to the two pyridine moieties of
the complex. Model calculations were performed with various
combinations of para-substituted pyridine molecules, namely
CH3 and CF3 groups, which were chosen because of their
steric similarity yet highly different electronic properties, their
negligible Lewis basicity and our synthetic experience.29 For
systems with two equal substituents, the [NIN]+ bond is
stabilized (CH3) or destabilized (CF3), but the symmetric
shape of the potential curve remains unaltered. In contrast, for
Figure 3. The variation of electronic energy as a function of
the position of the iodine in an [NIN]+ halogen bond, upon
varying the N-N distance, rNN (Å), and the position of the
iodine as described by Δr, the elongation of the iodine from
the geometrical midpoint of the nitrogen-nitrogen distance.
Thus, at Δr = 0 the iodine is centered between the nitrogens,
whereas at Δr = 0.5 Å it is 1 Å closer to one of them. The blue
line shows the potential curve, corresponding to Figure 1a, for
variable rNN, whilst the red lines show the potential curves for
rNN kept fixed at 4.30 Å (solid), 4.88 Å (long-dashed) and 5.50
Å (short-dashed), respectively, shown both in the 3D plot and
projected on the rear border plane. The black line on the right
border plane shows the dissociation curve of the [NIN]+
bond model system. DFT calculations were performed using
the M06 exchange and correlation functional62 and a mixed-
level (double zeta/triple-zeta/augmented triple-zeta) basis set
(for details see the Supporting Information).
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 13
1
2
3
4
5
6
7
8
9
Synthesis. Complexes 1a and 1a-d were synthesized by
modification of reported protocols.25 Regioselective deuter-
ation of 3 to 3-d was accomplished by BuLi-Li-DMAE
(Scheme 1),63 followed by microwave-assisted Sonogashira
coupling64 yielding 4 (4-d). Subsequent fluoride-mediated
TMS-deprotection65 provided 5 (5-d), which was converted to
6 (6-d) by Sonogashira coupling with 1,2-diiodibenzene for a
short time, giving a mixture of mono- and di-coupled prod-
ucts. The latter could be separated by silica gel chromatog-
raphy. Another microwave-assisted Sonogashira coupling
followed by TMS-deprotection provided 8 (8-d). It should be
emphasized that all traces of residual Cu(I) used in the So-
nogashira coupling must be removed using EDTA to avoid in
situ Glaser coupling occurring simultaneously to the TMS
deprotection upon liberation of 8 (8-d). Aqueous extraction
and two-fold purification by silica gel chromatography were,
in our hands, insufficient to avoid this side reaction. Com-
pound 8 (8-d) was converted to 9 (9-d) via Sonogashira cou-
pling with 2-chloro-4-trifluoromethylpyridine. This bidentate
ligand was converted to its silver tetrafluoroborate complex,
which upon addition of I2 afforded the target compound 1a
(1a-d). This compound is stable in dichloromethane solution at
room temperature. Following a literature protocol,25 the analo-
gous hydrogen bonded [NHN]+ complex (1b), here used as
a reference for a comparable system in dynamic exchange,
was generated by the addition of one equivalent trifluoroacetic
acid to 9 (9-d). An alternative synthetic route through 2-((2-
ethynylphenyl)ethynyl)-4-(trifluoromethyl)pyridine, an analog
of 8 that could have provided a common precursor for 9 and 9-
d, has been evaluated, but was dismissed due to decomposition
in the Sonogashira coupling with 2-chloro-4-methylpyridine.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 4. The potential energy curves of [NIN]+ halogen
bonds: (a) Potential curves of complexes with flexible back-
bone, i.e. variable rNN: [bis(pyridine)iodine(I)] (solid line), 4-
methylpyridine – iodine(I) – trifluoromethylpyridine (long-
dashed line), and methylpyridine – hydrogen(I) – trifluoro-
methylpyridine (short-dashed line). (b) Potential curves for
systems with a rigid backbone, i.e. rNN kept fixed: rNN = 4.30
Å (solid line), 4.88 Å (long-dashed line), 5.50 Å (short-dashed
line). The energies are given relative to the ground-state ener-
gy of the respective system (see Supporting Information for
details).
Complex 2a was synthesized from commercially available
10 using the synthetic route shown in Scheme 2. (CH3O)2SO2-
mediated methylation followed by Negishi coupling with 2-
pyridylzinc bromide furnished the bidentate ligand 12, which
was converted to the Ag(I) complex 13 by addition of AgBF4
to its CD3CN solution. Compound 2a was prepared by addi-
tion of I2 to the above-mentioned solution in an NMR tube at -
40 C, followed by centrifugation at low temperature to sepa-
rate the silver iodide precipitate. As 2a decomposes above -40
C (to its protonated form), its solution was kept at low tem-
perature throughout its NMR investigation.
To achieve a three-center halogen bond complex showing a
symmetric double-well potential for the halogen motion be-
tween the Lewis bases, a donor-donor distance, rNN, beyond
4.880 Å has to be enforced. For such a system possessing a
fully rigid backbone, the potential curves shown in red in
The solution structure of 1a. The formation of an
[NIN]+ halogen bond in 1a was indicated by 15N NMR
coordination shifts, 15Ncoords (Table 1), of comparable mag-
nitude to those reported for related halogen bonded
systems.22,25,27,29,31 The 15Ncoord of the nitrogens of 1a are
~10 ppm larger versus smaller as compared to the systems
possessing two CH3 or two CF3 groups on their pyridine rings,
respectively. This suggests that the 15N of the nitrogens of 1a
differ not only on account of their different electron densities,
but also due to the formation of N–I bonds of different
strength and length. The observed 15Ncoords indicate that the
I+ is closer to the more electron-rich nitrogen of the 4-CH3
substituted pyridine ring as compared to that of the less elec-
tron-rich, 4-CF3 substituted pyridine. These experimental
findings are corroborated by theoretically predicted 15N NMR
chemical shifts (Table 1). Whereas the chemical shifts of the
ligands are predicted with high, ~5 ppm accuracy, those pre-
dicted for the complexes are all 31-37 ppm too negative. Con-
sequently, even though the calculated Δδ values are about 35
ppm too positive, which is not unexpected as the accurate
Figure 3 and extracted in Figure 4b are obtained. At rNN
<
4.880 Å, the halogen motion follows a symmetric single-well
potential (solid red lines in Figures 3 and 4b), which becomes
shallow at rNN = 4.880 Å (long-dashed red lines, Figure 4b).
For rNN > 4.880 Å, the halogen motion is described by a dou-
ble-well potential (short-dashed red lines, Figure 4b) with a
barrier that becomes wider and higher with increasing rNN
.
Thus, to obtain a rapidly interconverting [NIN]+
[NIN]+ system, a backbone enforcing a nitrogen-nitrogen
distance, rNN, not too far above 4.880 Å is necessary. In mo-
lecular systems with rNN >> 4.880 Å, the interconversion of
the [NIN]+
[NIN]+ becomes slow and its overall
stability decreases. As a candidate for such a dynamic system,
we designed the iodonium complex 2a of (2,2'-(9,10-
dimethoxyphenanthrene-3,6-diyl)dipyridine) which latter
compound has a more rigid backbone and a longer nitrogen-
nitrogen distance (predicted as 6.1 Å by DFT) as compared to
1a.
ACS Paragon Plus Environment

Page 5 of 13
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 1. General synthetic route of [(4-methyl-2-((2-((4-(trifluoromethyl)pyridin-2-yl)ethynyl)phenyl)ethynyl)pyri-dine)iodine]+
BF4 (1a) and its deuterated analog 1a-d. Reagents and Conditions: (a) 1. DMAE, n-BuLi, dry hexane, -78 C, N2; 2. MeOD, -78
C, 30 min, -78 – 25 C in 35 min; (b) TMS-acetylene, PdCl2(PPh3)2, CuI, PPh3, Et2NH, MW 120 C, 27 min; (c) MeOH, rt, 2.5 h;
(d) 1,2-diiodobenzene, Pd(PPh3)2Cl2, CuI, Et2NH, MW 120 C, 5 min; (e) Pd(PPh3)2Cl2, CuI, Et2NH, MW 120 C, 30 min; (f) KF,
MeOH, rt, 2.5 h; (g) PdCl2(PPh3)2, CuI, Et2NH, MW 100 C, 12 min; (h) 1. AgBF4, CH2Cl2, rt, 15 min; 2. I2, CH2Cl2, rt, 30 min.
-
Scheme 2. General synthetic route to [(2,2'-(9,10-dimethoxyphenanthrene-3,6-diyl)dipyridine)iodine(I)] tetrafluoroborate (2a).
Reagents and Conditions: (a) Bu4NBr, Na2S2O4, dimethyl sulfate, THF/H2O, 20 min; (b) Pd(PPh3)4, 2-pyridylzinc bromide, THF,
50 C, overnight; (c) AgBF4, CH2Cl2, 10 min; (d) I2, CD3CN, -40 C.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 13
1
2
3
4
5
Table 1. 15N Chemical Shift (ppm) of the I+ Complex 1, its
Table 2. The Temperature Coefficients (ppm K) of the
Structurally Closely Related Analogs, and of the Corre-
Isotope Shifts Observed for the CD2Cl2 Solutions of the
[NIN]+ Complex 1a, of the [NIN]+ Complex 1b, and
of the Free Bidentate Ligand 9, and the Sum of their Abso-
lute Value, Σ|obs|. a
sponding Nitrogen Bases.a
6
7
8
9
Δδ

compl

N
Structure
R/R’
15
15
15
N
N
coord
lig
Struc-
ture
C2
1obs
C3
2obs
C4
3obs
C5
4obs
C6
3obs
Σ
|obs|
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
-170.3
-138.6
-69.2
-70.4
-101.1
-68.2
a
1a
9
1b
-7.3
-6.5
+6.0
-9.9
-6.5
-10.2
+1.7
+5.8
-22.7
0
0
0
-3.4
-5.9
-10.3
22.3
24.7
49.2
CH3/CH3
aAll 13C{1H,2H} NMR experiments were run at 125.71 MHz for
the temperature interval -32 to 40 C.
-183.1
-147.4
-71.8
-71.1
-111.3
-76.4
CH3
CF3
Accordingly, we have studied a mixture of compound 1a and
its isotopologue 1a-d in CD2Cl2 solution with the IPE tech-
nique using 13C {1H,2H} NMR detection, as described in detail
earlier.25,28,29 Similar to previous studies of halogen bonds,
isotopologue mixtures of the free ligand 9 (Scheme 1) and of
the analogous [NHN]+ hydrogen bonded complex 1b (Fig-
ure 2), were used as references for the static and dynamic
geometries, respectively (Table 2).25,27,28 The overall tempera-
ture dependence of the isotope effects, Σ|obs|, of 1a is compa-
rable to that of the static reference 9, and is significantly
smaller than that of the dynamic reference 1b. This indicates
that 1a is a static complex, which is supported by the tempera-
ture dependence of its individual isotope shifts being primarily
dependent on the distance of the observed nuclei from the
-145.1
-115.4
-53.7
-50.6
-91.4
-64.8
-156.7
-123.5
-53.4
-50.6
-103.3
-72.9
a
CF3/CF3
aThe 15N NMR chemical shifts of the reference compounds we
have previously reported.29 Values in italic style are DFT (M06)
predictions, see Supplementary Information for details.
prediction of 15N NMR chemical shifts remains a challenge,66
the trends in the calculated chemical shift are in agreement
with the experimental observations.
2
position of H-substitution. Further corroboration comes from
the T2 relaxation rate of H-2 (Figure 2), the proton closest to
the pyridine nitrogen of 1a (T2 = 1.7 ± 0.9 s), which is a com-
parable value to that of the static reference 9 (T2 = 1.4 ± 0.2 s)
and is significantly slower than that of the hydrogen bonded
complex 1b (T2 = 0.7 ± 0.6 s) involved in an [NHN]+
[NHN]+ dynamic exchange process.22,25 Overall, 15N NMR
chemical shifts in combination with isotopic perturbation and
relaxation NMR data reveal 1a to prefer a static and asymmet-
ric three-center halogen bond.
All NMR signals of 1a are sharp. This suggests that 1a has
either a single static geometry or is present in solution as a
rapidly interconverting dynamic mixture of isomers.23,25 To
differentiate between these structural alternatives, we applied
the isotopic perturbation of equilibrium (IPE) NMR tech-
nique,67,68 which can distinguish rapidly equilibrating mixtures
from static structures.22,25,28,29,59,60,67 IPE detects vibrational
energy changes upon selective isotope labeling, usually a
hydrogen-to-deuterium substitution, close to the molecular site
to be studied. For a mixture of isotopologues, two sets of
NMR signals are observed. One set belongs to the nondeuter-
ated compound, and the other to its deuterated analog. The
chemical shift difference between their signals is the isotope
effect, nobs. It is the sum of the intrinsic isotope shift, n0, and
Our experimental findings are supported by quantum-
chemical calculations [M06/mixed-level (double zeta/triple-
zeta/augmented triple-zeta) basis set, for details see the Sup-
porting Information] for 1a, 1b, and their close structural
analogs (Table 3). For 1a, the asymmetric single-well energy
potential (Figure 1c) is confirmed by the difference of 0.092 Å
between its two N–I bond distances. In contrast, the analogs
with two CH3 or two CF3 substituents show symmetric poten-
tial wells with two identical N–I bond distances each (Figure
1a) and N–I bond distances within 0.002 Å from that of the
unsubstituted complex. For symmetric CH3 substitution, the
[NIN]+ bond is predicted to be stabilized by 9.3 kJ mol–1 as
compared to the unsubstituted analog of 1a, [(1,2-bis(2-
pyridylethynyl)benzene)iodine(I)],25 whereas symmetric CF3
substitution causes a 30.0 kJ mol–1 destabilization. The three-
center bond of 1a is computed to be 9.7 kJ mol–1 less stable
than the unsubstituted reference. The stabilization energy of
1a is roughly half-way between those of the symmetric CH3
and CF3 substituted complexes, which can be comprehended
in the way that each of the N–I bonds in 1a has approximately
the equilibrium isotope shift, eq,13,67 where n denotes the
n
number of bonds between the detected nucleus and the posi-
tion of the isotopic substitution. The intrinsic isotope effect is
present in all isotopically substituted molecular systems and is
typically small, attenuating as n increases. In contrast, the
equilibrium isotope effect manifests only for dynamic molecu-
lar systems. Its magnitude is dependent on the equilibrium
constant of the exchange process. Accordingly, it is zero for
n
static molecular systems. The equilibrium isotope effect, eq,
is temperature dependent, as is the equilibrium constant, ac-
cording to the van’t Hoff equation.69 The magnitude of the
n
observed isotope effect, obs, does not allow differentiation
between a static [NIN]+ and a dynamic [NIN]+
[NIN]+ system, but its temperature dependence does.25
ACS Paragon Plus Environment

Page 7 of 13
Journal of the American Chemical Society
1
2
3
4
5
6
Table 3. Bond Distances (Å) and Relative Energies (kJ
mol–1) for 1a, 1b, and their Analogs.
Overall, NMR spectroscopy indicates 2a to be a dynamic
molecular system, with its nitrogen atoms involved in an ex-
change process. The specific dynamic process could not be
identified by NMR.
Structure
R
R’ State r(NX) r(N’X) ΔEb ΔEc
To rationalize the experimental findings, we have computa-
tionally investigated the potential-energy landscape for 2a and
2b (see Scheme 3). Electronic energies and Gibbs free ener-
gies are given relative to the [bis(pyridine)iodine(I)] 14a and
the [bis(pyridine)hydrogen(I)] 14b, respectively, as reference
(i.e., as stabilization energies relative to 14a,b). The electronic
energies have been decomposed into the halogen bond energy,
ΔEbond, the strain energy of the backbone, ΔEstrain, and where
applicable, the van der Waals energy between the monomers,
ΔEvdW (see Table 4; details of the computations are given in
7
8
9
X = I
H
H
GM
2.280
2.278
2.282
2.239
2.280
2.278
2.282 30.0
0
-9.4
CH3 CH3 GM
CF3 CF3 GM
CH3 CF3 GM
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2.331
9.7
1a
X = H
H
H
dGM 1.045
TS 1.309
CH3 CH3 dGM 1.043
TS 1.314
CF3 CF3 dGM 1.042
1.900
1.309
1.900
1.314
1.923 27.3
1.312
1.937
1.051
1.242
0
0
22.0
0
21.5
0
23.7
0
19.3
32.8
-9.5
TS
1.312
1.039
1.859
1.387
CH3 CF3 GM
-0.9
1b
LM
TS
aGM = global minimum, LM = local minimum, d = degenerate,
b
TS = transition state. Stabilisation energy relative to the corre-
sponding compound with R = R’ = H. bFor compounds with more
than one equilibrium structure, the energy of the present structure
relative to the ground-state energy.
the same strength as an N–I bond in the corresponding bond
distance for symmetric substituents. A combination of two N–
I bonds with different strengths as in 1a gives rise to an
asymmetric [NIN]+ bond. For 1b, however, an asymmetric
double-well (Figure 1d) is found. In the ground state, the pro-
ton is shifted towards the CH3-substituted pyridine. The sec-
ond (local) minimum, where the proton is close to the CF3-
substituted pyridine, is 19.3 kJ mol–1 above the ground state.
The transition state is shifted slightly towards the CF3-
substituted pyridine, and the barrier is 32.8 kJ mol–1 relative to
the global minimum, and thus (32.8 – 19.3) kJ mol–1 = 13.5 kJ
mol–1 relative to the local minimum. The barrier height is in
the same order of magnitude as that for the structural analogs
with two equal substituents (Table 3). Thus, DFT calculations
corroborate that 1a is a static, asymmetric complex, whereas
1b exists as a mixture of rapidly interconverting isomers in
solution.
Figure 5. The aromatic region of the 1H NMR spectrum of (a)
the I+ complex 2a, (b) the proton complex 2b, and (c) the free
ligand 12 acquired at -40 °C for CD3CN solution at 500 MHz
suggests 2a to be present in solution as a dynamic mixture.
The signals of 2b are also broadened but to a lesser extent than
those of 2a, suggesting a faster rate of H+ exchange compared
to that of I+ in the corresponding halogen complex.
Table 4. Stabilization Energies (kJ mol–1) and their Com-
ponents for Different Conformers of 2a,b.a
Compound
2a-1
ΔEbond ΔEstrain ΔEvdW
ΔE
ΔG233
77.6
76.5
64.7
103.8
113.3
171.1
25.2
107.6
107.4
107.3
57.2
100.3
136.5
14.6
9.8
9.7
0.0
76.7
42.4
68.0
18.5
14.7
117.3
117.1
107.3
133.8
142.7
204.6
35.1
The solution structure of 2. Compound 13 was converted
to 2a (Scheme 2) under dry conditions at -40 °C in an NMR
tube using CD3CN as solvent. The tube was centrifuged at -40
°C and transferred into an NMR magnet with a pre-cooled (-40
2a-2
15a
2a-sym-1
2a-asy (TS)
2a-sym-2 (TS)
(2a)2-par
(2a)2-tw
1
°C) probe. The vastly broadened H NMR signals (Figure 5)
observed for 2a indicate it to be involved in a dynamic ex-
change process. This was confirmed by the rapid T2 relaxation
of the protons situated most proximately to its nitrogen donor
atoms (2a H-2: 0.0070 ±0.0009 s; H-12: 0.0030 ±0.0005 s, 12
H-2: 0.24 ±0.16 s; H-12: 0.29 ±0.03 s; for assignments see
Figure 4). The extensive line broadening prohibited the detec-
tion of 15N NMR chemical shifts and the measurement of
isotopic perturbation of equilibria for 2a. The 1H NMR signals
of the analogous proton complex 2b exhibit less extensive line
broadening than 2a. This is explained by a different rate of
exchange for the dynamic processes that 2a and 2b undergo.
2.0
-4.5
28.5
38.7
40.2
43.1
44.6
14.6
12.6
-0.1
0.0
5.2
4.1
43.0
44.6
-5.8
0.4
15.0
11.9
2.2
2b
15b
(2b)2-par
(2b)2-tw
-25.7
-16.3
-1.8
a Stabilization energies given with respect to the [N–X–N]+ bond
in 14a or 14b, respectively. For dimers, the values are given per
monomer. See the SI for computational details.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 8 of 13
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 3. Calculated electronic energies, (ΔE, kJ mol-1), Gibbs free energies (ΔG233, kJ mol-1) and bond distances (rNN and rNI, Å)
for a variety of possible geometries of 2a and 2b. Energies are given as stabilization energies relative to 14a or 14b, respectively,
i.e., positive energy values indicate that the respective compound is less stable than 14a or 14b, respectively. For dimeric structures,
energies are given per monomer. All species shown have a charge of +2 (dimers) or +1 (others). For the dimer structures, the meth-
oxy functionalities have been omitted to make the presentation of the bonding situation for these structures less crowded. Computa-
tional details are given in the Supporting Information.
the Supporting Information). The asymmetric geometry of 2a
(2a-asy, rNI = 2.142 Å and 3.212 Å, rNN = 5.240 Å, Scheme 3)
is predicted by DFT to be a transition state (TS) between a
symmetric structure (2a-sym-1, rNI = 2.366 Å and 2.373 Å, rNN
= 4.723 Å) and one that has a covalent N–I bond whilst lack-
ing an N…I halogen bond (2a-1, rNI = 2.091 Å and 5.878 Å,
ACS Paragon Plus Environment

Page 9 of 13
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
rNN = 6.468 Å). Accordingly, 2a-1 has comparable ΔEbond to
par and (2a)2-tw. The pyridine rings of these complexes are
rotated out of the plane of the phenanthrenes with two sets of
[N···I···N]+ bonds formed between the two 2a units. These are
oriented in a parallel or twisted fashion, respectively. The
[N···I···N]+ bonds of these dimers have similar geometries to
those in 14a and their backbones have low strain energies.
Accordingly, (2a)2-par is 52 kJ mol–1 and (2a)2-tw is 37 kJ
mol–1 lower in ΔG233 as compared to 2a-1, with energies being
given per monomer. Consequently, 2a is expected to exist
predominantly as (2a)2-par and, in second instance, as (2a)2-
tw. The most stable conformer, (2a)2-par remains 25 kJ mol–1
less stable than 14a, suggesting 2a to be rather unstable. This
is in excellent agreement with the experimentally observed
low stability of 2a, which we could only study experimentally
at -40 C. Rapid interconversion of the (2a)2-par and (2a)2-tw
geometries explains the NMR observed line broadening. For-
mation of larger oligomers, i.e. trimers or tetramers, is entrop-
ically disfavored and was therefore not studied here.
the reference compound 15a, whereas 2a-asy and 2a-sym-1
are considerably less stable, the difference in ΔG233 as com-
pared to 2a-1 being 36 kJ mol–1 and 26 kJ mol–1, respectively
(Table 4). As reflected by the 100.3 kJ mol–1 (ΔEbond) of 2a-
asy, its [N–IN]+ bond is considerably weaker than that of
14a, largely because of its nonplanarity. The geometry 2a-asy
has a ΔEbond 7 kJ mol–1 below those of 2a-1 and 15a, i.e. the
contribution of its N···I bond to the [N–I···N]+ interaction is
small. Owing to the bending of the phenanthrene rings of 2a-
sym-1 and 2a-asy, their strain energies are 67 kJ mol–1 and 33
kJ mol–1 above that of 2a-1, respectively, which makes them
less stable than 2a-1. We note that there is another conformer
with a symmetric [NIN]+ bond, 2a-sym-2, which is anoth-
er 67 kJ mol–1 (ΔG233) less stable as compared to 2a-sym-1
(Table 4), mainly due to the electrostatic and steric repulsion
between the I atom and the H atom in positions 12 and 12’
(Figure 2), which weakens the [NIN]+ bond. Geometry 2a-
sym-2 is a transition state between conformer 2a-2, which
resembles 2a-1 both in energy and bond properties, and its
mirror image.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The analogous hydrogen bonded complex 2b is predicted to
also prefer forming dimeric complexes (Scheme 3b), each
encompassing two asymmetric [N–HN]+ bonds with NH
bond lengths of 1.041 Å and 1.887 Å / 1.893 Å ((2b)2-par),
and 1.047 Å and 1.820 Å ((2b)2-tw), respectively. In contrast
to 2a, the twisted [(2b)2-tw] geometry possessing a shorter N–
N distance (2.853 Å versus 2.904 Å) has lower ΔG233, with a
difference of just 4 kJ mol–1 between the dimers. The dimers
of 2b, in contrast to 2a, are further stabilized by van der Waals
interaction between the two ligands, with ΔEvdW values of –26
and 16 kJ mol–1, respectively. The computed Gibbs free ener-
gy of these complexes is comparable to that of the analogous
[bis(pyridine)hydrogen(I)] complex 14b. This is in agreement
with the experimentally detected stability of 2b at room tem-
perature. The observation of a single set of NMR signals sug-
The geometries of 2a shown in Scheme 3 (2a-sym-1, 2a-
asy, and 2a-1, for example) reflect various stages of the disso-
ciation process of an [NIN]+ bond, as it is depicted by the
bold black line in the right border plane of Figure 3 for the
[NIN]+ bond of the analogous [bis(pyridine)-iodine(I)]
model system. At the same time, they demonstrate different
ways how stable complex structures can be formed in the
interplay between bond stability and backbone strain. Close to
the equilibrium distance, rNN = 4.511 Å, the dissociation curve
of the model complex shows a relatively narrow minimum of
ca 110 kJ mol-1 (Figure 3) belonging to a symmetric
[N···I···N]+ geometry. Consequently, in this region the result-
ing rNN value for the complex is only weakly influenced by the
strain from the backbone, and ligands with quite different
properties can form complexes with rNN values in this range,
such as e.g. 2a-sym-1 (rNN = 4.723 Å). Conversely, at rNN > 5
Å the asymmetric [N–I···N]+ bond geometry is more stable
than the symmetric alternative at the same rNN distance (short
dashed red line in Figure 3). The asymmetric [N–I···N]+ inter-
action at rNN > 5 Å is considerably weaker than the [NIN]+
bond at optimal rNN 4.511 Å; however, it is more stable than
the alternative symmetric [NIN]+ bond at the same rNN > 5
gests
a
rapid tautomeric exchange, [NHN]+
[NHN]+, within the hydrogen bonded complexes of 2b,
which is in agreement with the previous literature.59,60 Further
details of the computational investigation are given in the
Supporting Information.
CONCLUSIONS
By asymmetric alteration of the electron density of the Lew-
is basic nitrogens within a three-center halogen bond, a static
and asymmetric solution geometry is obtained. The halogen
atom in this complex is positioned closer to the more electron-
rich nitrogen, and the system is best described by an asymmet-
ric single-well energy potential. The complex is slightly desta-
bilized compared to its symmetric and unsubstituted analog,
yet remains stable in solution at room temperature. The behav-
ior of the halogen bond is distinctly different from that of the
hydrogen bond in the analogous proton complex 1b; the latter
exists as a dynamic mixture of asymmetric geometries,
Å distance. Moreover, its energy depends only weakly on rNN
,
i.e., the [N–I···N]+ bond is easy to stretch. Thus the resulting
rNN of the complex is determined mainly by the overall ge-
ometry and rigidity of the backbone holding the two Lewis
basic sites. Thus, the rNN value in 2a-1 (6.468 Å) is close to
that in the free ligand 12 (6.100 Å), actually, rNN is slightly
longer in 2a-1 than in 12 because of electrostatic and steric
repulsions between the iodonium and the H atom in position
12. The intermediate geometry 2a-asy (rNN = 5.240 Å) is fa-
vored neither by a strong [NIN]+ bond nor by a low back-
bone strain and is thus the TS between 2a-sym1 and 2a-1.
[NHN]+
[NHN]+, with an asymmetric double-well
energy potential describing the motion of H+. This finding is
consistent with the previously reported asymmetry of hydro-
gen bonds in solution,59,60 as well as the distinctly different
behavior of three-center halogen and hydrogen bonds.22,23,29
Compound 2a possesses a longer than optimal rNN in combi-
nation with a comparably rigid backbone, which explains the
low stability of the 2a-asy geometry. The most stable ar-
rangements of 2a are predicted by DFT to be the dimers (2a)2-
Increasing the distance between the Lewis basic sites of a
bidentate ligand did not convert a static and symmetric three-
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 10 of 13
1
2
3
4
5
6
7
8
9
center halogen bond complex into a dynamic mixture of
bond strength is chosen to be characterized by binding energy,
asymmetric complexes. Complex 2a, which has a purposely
elongated N-N distance, prefers to avoid strain and forms
dimers encompassing two unstrained, symmetric three-center
[NIN]+ halogen bonds, instead of one strained asymmetric
[NIN]+ bond. The dimers interconvert between different 3D
geometries, are unstable and are therefore experimentally
detectable only at low temperature. The analogous hydrogen
bond complex 2b is stable in solution at room temperature and
exists as a rapidly interconverting mixture of dimers encom-
passing asymmetric [NHN]+ hydrogen bonds.
The three-center halogen bond, [DXD]+, is extraordinari-
ly strong and although it can be desymmetrized, its conversion
into an asymmetric [DXD]+ geometry with a distinct cova-
lent and a distinct secondary bond is highly challenging. The
difference between its behavior and that of the analogous
[DHD]+ hydrogen bond may be explained by the involve-
ment of two directional lobes of an electrophilic p-orbital on
X+ with the Lewis bases, as compared to the smaller and less
directional s-orbital on H+.
the three-center halogen bonds follow the same hierarchy as
classical halogen bond interactions. However, three-center
four electron halogen bonds are characteristically stronger
(100-150 kJ mol-1)26,29,31 than the classical halogen bonds
(typically < 50 kJ mol-1),70 and accordingly their formation is
associated with considerably larger spectroscopic changes (i.e.
Δδ15Ncoord ~100 ppm22,23,26,29,31,58 versus < 20 ppm71). The ex-
perimental investigations have been complemented by theoret-
ical studies. For instance, Cremer and co-workers72 have in-
vestigated the character of halogen bonds based on the bond
strength order (BSO), a measure for the strength of individual
bonds in a compound derived from its calculated vibration
spectrum. If, for a [D1–X–D2] moiety (D1 and D2 are the Lewis
bases interacting with the halogen X), the BSO values for [D1–
X] and [X–D2] are equal or nearly equal, the bond has a dis-
tinct three-center four-electron character, whereas substantial-
ly different BSO values for the two bonds indicate a classical
halogen bond.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The studied model systems provide valuable insights into the
fundamentals of chemical bonding, and will be of significance
for an improved understanding of the halogen transfer process
between two halogen bond acceptors as well as the three-
center-four-electron bond, whose nature and behavior remain
unresolved enigmas.54 The global energy minimum in the
bonding situation of 1 resembles the transition states of SN2
and halonium transfer reactions,53 We thus expect our results
to provide valuable insights for the development of future
halonium transfer agents.39,40,50
In a wider context, the current work raises the question
whether a distinction between halogen bonded systems pos-
sessing a “classical halogen bond” and those encompassing a
“three-center four-electron halogen bond” is useful, or even
possible, as both types of complexes involve three atomic
centers that are connected by four electrons. A classical halo-
gen bond is formed by the interaction of a Lewis base, D, with
a covalently bound halogen, DXD, through a -hole and
the resulting complex encompasses a conventional two-center
covalent, DX, and a classical two-center two-electron halo-
gen bond, DX. Even if the formation of the halogen bond
results in some lengthening and weakening of the DX cova-
lent bond, and in the shortening of the DX distance below
the sum of the van der Waals radii of the D and X atoms, the
two bonds clearly remain to have different. In contrast, the
halogen of a three-center halogen bond is not clearly covalent-
ly or weakly bonded to either of the Lewis bases, but is strong-
ly attracted to both, with its both DX bonds simultaneously
showing covalent and secondary characters. The latter com-
plexes have DX bond distances (here, r(N’I) = ~2.3 Å) in
between the sum of the van der Waals radii (rwI + rwN = 3.5
Å) and the sum of the covalent radii (rcI + rcN = 2.1 Å) of the
participating atoms with the halogen being roughly centered,
with < 10% difference between the DX distances. Both clas-
sical and three-center bonds have covalent and electrostatic
contributions, with the covalent character originating from
charge transfer and the electrostatic resulting from Coulomb
attraction and polarization. Dispersion has a smaller contribu-
tion, especially for strong interactions. With the decrease of
halogen size, the partial covalent character of the three-center
covalent bond increases25,26 whereas the halogen bond
strength, which is dominated by the electrostatic contribution,
decreases. Thus, despite a larger covalent contribution and a
larger reduction ratio23,30 of an N…Cl…N bond (0.61) as com-
pared to the analogous N…Br…N (0.63) and N…I…N (0.65)
bonds, the chlorine-centered halogen bond remains the weak-
est and the iodine-centered bond the strongest. Accordingly, if
ASSOCIATED CONTENT
Supporting Information. NMR and computational data, and
detailed information on the synthesis. (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
* mate.erdelyi@kemi.uu.se.
Present Addresses
 Concept Life Sciences, Discovery Park, Ramsgate Road, Sand-
wich, Kent, CT13 9ND, UK
Notes
The authors declare no competing financial interest.
Funding Sources
European Union Seventh Framework Programme (FP7/2007-
2013) grant agreement n˚ 259638. The Swedish Research Council
(2016-03602).
ACKNOWLEDGMENT
We thank Martin Uhrbom, Stefan Niebling and Daniel Sarabi
(University of Gothenburg) for their contributions to the computa-
tional work in the initial phase of this project. The research lead-
ing to these results has received funding from the European Re-
search Council under the European Union's Seventh Framework
Programme (FP7/2007-2013) / ERC grant agreement n° 259638.
ACS Paragon Plus Environment

Page 11 of 13
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Infinite Chain Formation Driven by Nitrogen…Iodine
We thank the Swedish Research Council (2016-03602) for finan-
Interactions, J. Am. Chem. Soc. 1998, 120, 8261.
(22) Carlsson, A.-C. C.; Gräfenstein, J.; Laurila, J. L.; Bergquist,
J.; Erdélyi, M. Symmetry of [N–X–N]+ Halogen Bonds in
Solution, Chem. Commun. 2012, 48, 1458.
(23) Hakkert, S. B.; Erdelyi, M. Halogen Bond Symmetry: The N-
X-N Bond, J. Phys. Org. Chem. 2015, 28, 226.
(24) Lin, G. H. Y.; Hope, H. Crystal-Structure of
Bis(Thiourea)Iodine(I) Iodide, Acta Crystall. B 1972, B 28,
643.
(25) Carlsson, A.-C. C.; Gräfenstein, J.; Budnjo, A.; Laurila, J. L.;
Bergquist, J.; Karim, A.; Kleinmaier, R.; Brath, U.; Erdelyi,
M. Symmetric Halogen Bonding Is Preferred in Solution, J.
Am. Chem. Soc. 2012, 134, 5706.
(26) Karim, A.; Reitti, M.; Carlsson, A.-C. C.; Gräfenstein, J.;
Erdelyi, M. The Nature of [N-Cl-N]+ and [N-F-N]+ Halogen
Bonds in Solution, Chem. Sci. 2014, 5, 3226.
(27) Carlsson, A.-C. C.; Uhrbom, M.; Karim, A.; Brath, U.;
Gräfenstein, J.; Erdelyi, M. Solvent Effects on Halogen Bond
Symmetry, CrystEngComm 2013, 15, 3087.
(28) Bedin, M.; Karim, A.; Reitti, M.; Carlsson, A.-C. C.; Topic,
F.; Cetina, M.; Pan, F. F.; Havel, V.; Al-Ameri, F.; Sindelar,
V.; Rissanen, K.; Gräfenstein, J.; Erdelyi, M. Counterion
Influence on the N-I-N Halogen Bond, Chem. Sci. 2015, 6,
3746.
(29) Carlsson, A.-C. C.; Mehmeti, K.; Uhrbom, M.; Karim, A.;
Bedin, M.; Puttreddy, R.; Kleinmaier, R.; Neverov, A. A.;
Nekoueishahraki, B.; Gräfenstein, J.; Erdelyi, M. Substituent
Effects on the [N–I–N]+ Halogen Bond, J. Am. Chem. Soc.
2016, 138, 9853.
(30) Troff, R. W.; Makela, T.; Topic, F.; Valkonen, A.;
Raatikainen, K.; Rissanen, K. Alternative Motifs for Halogen
Bonding, Eur. J. Org. Chem. 2013, 1617.
(31) Carlsson, A.-C. C.; Veiga, A. X.; Erdélyi, M. Halogen
Bonding in Solution. Top Curr. Chem. 2015, 359, 49.
(32) Koskinen, L.; Jaaskelainen, S.; Hirva, P.; Haukka, M.
Tunable Interaction Strength and Nature of the S…Br Halogen
Bonds in [(Thione)Br-2] Systems, Cryst. Growth Des. 2015,
15, 1160.
(33) Koskinen, L.; Hirva, P.; Hasu, A.; Jaaskelainen, S.;
Koivistoinen, J.; Pettersson, M.; Haukka, M. Modification of
the Supramolecular Structure of [(Thione)IY] (Y = Cl, Br)
Systems by Cooperation of Strong Halogen Bonds and
Hydrogen Bonds, CrystEngComm 2015, 17, 2718.
(34) Koskinen, L.; Hirva, P.; Kalenius, E.; Jaaskelainen, S.;
Rissanen, K.; Haukka, M. Halogen Bonds with Coordinative
Nature: Halogen Bonding in a S-I+-S Iodonium Complex,
CrystEngComm 2015, 17, 1231.
cial support. This study made use of the NMR Uppsa-
la infrastructure, which is funded by the Department of Chemistry
- BMC and the Disciplinary Domain of Medicine and Pharmacy.
REFERENCES
(1) Desiraju, G. R.; Ho, P. S.; Kloo, L.; Legon, A. C.; Marquardt,
R.; Metrangolo, P.; Politzer, P.; Resnati, G.; Rissanen, K.
Definition of the Halogen Bond (Iupac Recommendations
2013), Pure Appl. Chem. 2013, 85, 1711.
(2) Cavallo, G.; Metrangolo, P.; Milani, R.; Pilati, T.; Priimagi,
A.; Resnati, G.; Terraneo, G. The Halogen Bond, Chem. Rev.
2016, 116, 2478.
(3) Bondi, A. Van Der Waals Volumes and Radii, J. Phys. Chem.
1964, 68, 441.
(4) Collin, J. J. Sur L'iodide, Ann. Chem. 1814, 91, 251.
(5) Guthrie, E. XXVIII.—on the Iodide of Iodammonium, J.
Chem. Soc. 1863, 16, 239.
(6) Erdelyi, M. A Big Hello to Halogen Bonding, Nature Chem.
2014, 6, 762.
(7) Clark, T.; Hennemann, M.; Murray, J. S.; Politzer, P.
Halogen Bonding: The Sigma-Hole, J. Mol. Model. 2007, 13,
291.
(8) Wang, C. W.; Danovich, D.; Mo, Y. R.; Shaik, S. On the
Nature of the Halogen Bond, J. Chem. Theory Comput 2014,
10, 3726.
(9) Mukherjee, A.; Tothadi, S.; Desiraju, G. R. Halogen Bonds in
Crystal Engineering: Like Hydrogen Bonds yet Different,
Acc. Chem. Res. 2014, 47, 2514.
(10) Gilday, L. C.; Robinson, S. W.; Barendt, T. A.; Langton, M.
J.; Mullaney, B. R.; Beer, P. D. Halogen Bonding in
Supramolecular Chemistry, Chem. Rev. 2015, 115, 7118.
(11) Ho, P. S. Biomolecular Halogen Bonds, Top Curr Chem
2015, 358, 241.
(12) Wilcken, R.; Zimmermann, M. O.; Lange, A.; Joerger, A. C.;
Boeckler, F. M. Principles and Applications of Halogen
Bonding in Medicinal Chemistry and Chemical Biology, J.
Med. Chem. 2013, 56, 1363.
(13) Erdelyi, M. Halogen Bonding in Solution, Chem. Soc. Rev.
2012, 41, 3547.
(14) Bulfield, D.; Huber, S. M. Halogen Bonding in Organic
Synthesis and Organocatalysis, Chem. Eur. J. 2016, 22,
14434.
(15) Desiraju, G. R.; Parthasarathy, R. The Nature of Halogen ...
Halogen Interactions - Are Short Halogen Contacts Due to
Specific Attractive Forces or Due to Close Packing of
Nonspherical Atoms, J. Am. Chem. Soc. 1989, 111, 8725.
(16) Hassel, O. Structural Aspects of Interatomic Charge-Transfer
Bonding, Science 1970, 170, 497.
(17) Legon, A. C. Prereactive Complexes of Dihalogens XY with
Lewis Bases B in the Gas Phase: A Systematic Case for the
Halogen Analogue B - XY of the Hydrogen Bond B - HX,
Angew. Chem. Int. Edit. 1999, 38, 2687.
(18) Bertran, J. F.; Rodriguez, M. Detection of Halogen Bond
Formation by Correlation of Proton Solvent Shifts .1.
Haloforms in Normal-Electron Donor Solvents, Org. Magn.
Resonance 1979, 12, 92.
(19) Metrangolo, P.; Neukirch, H.; Pilati, T.; Resnati, G. Halogen
Bonding Based Recognition Processes: A World Parallel to
Hydrogen Bonding, Acc. Chem. Res. 2005, 38, 386.
(20) Metrangolo, P.; Resnati, G. Halogen Bonding: A Paradigm in
Supramolecular Chemistry, Chem. Eur. J. 2001, 7, 2511.
(21) Amico, V.; Meille, S. V.; Corradi, E.; Mesina, M. T.; Resnati,
G. Perfluorocarbon-Hydrocarbon Self-Assembling. 1D
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(35) Turunen, L.; Warzok, U.; Schalley, C. A.; Rissanen, K.
Nano-Sized I12l6 Molecular Capsules Based on the
[N…I+…N] Halogen Bond, Chem 2017, 3, 861.
(36) Turunen, L.; Warzok, U.; Puttreddy, R.; Beyeh, N. K.;
Schalley, C. A.; Rissanen, K. [NI+N] Halogen-Bonded
Dimeric
Capsules
from
Tetrakis(3-Pyridyl)Ethylene
Cavitands, Angew. Chem. Int. Edit. 2016, 55, 14033.
(37) Okitsu, T.; Yumitate, S.; Sato, K.; In, Y.; Wada, A.
Substituent Effect of Bis(Pyridines)Iodonium Complexes as
Iodinating
Reagents:
Control
of
the
Iodocyclization/Oxidation Process, Chem. Eur. J. 2013, 19,
4992.
(38) Barluenga, J. Recent Advances in Selective Organic
Synthesis Mediated by Transition Metal Complexes, Pure
Appl. Chem. 1999, 71, 1385.
(39) Barluenga, J.; González, J. M.; Campos, P. J.; Asensio, G.
I(Py)2BF4, a New Reagent in Organic Synthesis: General
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 12 of 13
1
2
3
4
5
6
7
8
9
(57) Puttreddy, R.; Jurcek, O.; Bhowmik, S.; Makela, T.;
Method for the 1, 2‐Iodofunctionalization of Olefins, Angew.
Chem. Int. Edit. 1985, 24, 319.
(40) Barluenga, J.; González‐Bobes, F.; Murguía, M. C.;
Ananthoju, S. R.; González, J. M. Bis (Pyridine) Iodonium
Tetrafluoroborate (IPy2BF4): A Versatile Oxidizing Reagent,
Chem. Eur. J. 2004, 10, 4206.
(41) Lown, J. W.; Joshua, A. V. Electrophilic Additions of
Iodonium Nitrate to Unsaturated Substrates, Can. J. Chem.
1977, 55, 122.
(42) Simonot, B.; Rousseau, G. Oxygen Effect in the Iodo
Lactonization of Unsaturated Carboxylic Acids Leading to 7-
to 12-Membered Ring Lactones, J. Org. Chem. 1994, 59,
5912.
(43) Brunei, Y.; Rousseau, G. Iodination of Phenols and Anilines
with Bis (Sym-Collidine) Iodine (I) Hexafluorophosphate,
Tetrahedron Lett. 1995, 36, 8217.
(44) Brunel, Y.; Rousseau, G. An Easy Preparation of
Iodoacetylenes, Tetrahedron Lett. 1995, 36, 2619.
(45) Homsi, F.; Rousseau, G. 4-Endo-T Rig Cyclization Processes
Using Bis (Collidine) Bromine (I) Hexafluorophosphate as
Reagent: Preparation of 2-Oxetanones, 2-Azetidinones, and
Oxetanes, J. Org. Chem. 1999, 64, 81.
(46) Rousseau, G.; Robin, S. Halogenation of Pyridinols Using
Bis (Sym-Collidine) Iodine(I) and Bis(Sym-Collidine)
Bromine(I) Hexafluorophosphate, Tetrahedron Lett. 1997,
38, 2467.
(47) Rousseau, G.; Robin, S. Bis(Sym-Collidine)Bromine(I)
Hexafluorophosphate as Oxidant, Tetrahedron Lett. 2000, 41,
8881.
Rissanen, K. Very Strong N--X+…O--N+ Halogen Bonds,
Chem. Commun. 2016, 52, 2338.
(58) Bedin, M.; Karim, A.; Reitti, M.; Carlsson, A.-C. C.; Cetina,
M.; Pan, F.; Havel, V.; Al-Ameri, F.; Sindelar, V.; Rissanen,
K.; Gräfenstein, J.; Erdelyi, M. Counterion Influence on the
Nin Halogen Bond, Chem. Sci. 2015, 6, 3746.
(59) Perrin, C. L. Are Short, Low-Barrier Hydrogen Bonds
Unusually Strong?, Acc. Chem. Res. 2010, 43, 1550.
(60) Perrin, C. L. Symmetry of Hydrogen Bonds in Solution, Pure
Appl. Chem. 2009, 81, 571.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(61) Ebrahimi, A.; Razmazma, H.; Delarami, H. S. The Nature of
Halogen Bonds in [N…X…N]+ Complexes: A Theoretical
Study, Phys. Chem. Res. 2016, 4, 1.
(62) Zhao, Y.; Truhlar, D. G. The M06 Suite of Density
Functionals
for
Main
Group
Thermochemistry,
Thermochemical Kinetics, Noncovalent Interactions, Excited
States, and Transition Elements: Two New Functionals and
Systematic Testing of Four M06-Class Functionals and 12
Other Functionals, Theor. Chem. Acc. 2008, 120, 215.
(63) Gros, P.; Choppin, S.; Mathieu, J.; Fort, Y. Lithiation of 2-
Heterosubstituted Pyridines with Buli-Lidmae: Evidence for
Regiospecificity at C-6, J. Org. Chem. 2002, 67, 234.
(64) Erdelyi, M.; Gogoll, A. Rapid Homogeneous-Phase
Sonogashira Coupling Reactions Using Controlled
Microwave Heating, J. Org. Chem. 2001, 66, 4165.
(65) Erdelyi, M.; Langer, V.; Karlen, A.; Gogoll, A. Insight into
Beta-Hairpin Stability: A Structural and Thermodynamic
Study of Diastereomeric Beta-Hairpin Mimetics, New J.
Chem. 2002, 26, 834.
(66) Gregusova, A.; Perera, S. A.; Bartlett, R. J. Accuracy of
Computed N-15 Nuclear Magnetic Resonance Chemical
Shifts, J. Chem. Theory Comput. 2010, 6, 1228.
(48) Andre, V.; Lahrache, H.; Robin, S.; Rousseau, G. Reaction of
Unsaturated Phosphonate Monoesters with Bromo-and Iodo
(Bis-Collidine) Hexafluorophosphates, Tetrahedron 2007, 63,
10059.
(67) Siehl, H. U. Isotope Effects on NMR-Spectra of Equilibrating
Systems, Adv. Phys. Org. Chem. 1987, 23, 63.
(68) Saunders, M.; Telkowski, L.; Kates, M. R. Isotopic
Perturbation of Degeneracy - C-13 Nuclear Magnetic-
(49) Neverov, A. A.; Brown, R. Mechanistic Evaluation of the
Transfer of Br+ from Bis (Sym-Collidine) Bromonium
Triflate to Acceptor Alkenes, J. Org. Chem. 1998, 63, 5977.
(50) Barluenga, J.; Vázquez-Villa, H.; Ballesteros, A.; Gonzàlez,
J. M. Cyclization of Carbonyl Groups onto Alkynes Upon
Reaction with IPy2BF4 and Their Trapping with
Nucleophiles: A Versatile Trigger for Assembling Oxygen
Heterocycles, J. Am. Chem. Soc. 2003, 125, 9028.
(51) Fujioka, H.; Nakahara, K.; Hirose, H.; Hirano, K.; Oki, T.;
Kita, Y. Intramolecular Iodoetherification of Ene or Diene
Ketals: Facile Synthesis of Spiroketals, Chem. Commun.
2011, 47, 1060.
(52) Aubert, E.; Espinosa, E.; Nicolas, I.; Jeannin, O.; Fourmigue,
M. Toward a Reverse Hierarchy of Halogen Bonding
between Bromine and Iodine, Faraday Discuss. 2017, 203,
389.
(53) Firestone, R. A. Application of Linnett Electronic Theory to
Organic Chemistry.4. SN2 Transition State, J. Org. Chem.
1971, 36, 702.
Resonance
Spectra
of
Dimethylcyclopentyl
and
Dimethylnorbornyl Cations, J. Am. Chem. Soc. 1977, 99,
8070.
(69) van't Hoff, J. H. Z. Die Rolle Des Osmotischen Druckes in
Der Analogie Zwischen LöSungen Und Gasen, Z. Phys.
Chem. 1887, 1, 783.
(70) Duarte, D. J. R.; Angelina, E. L.; Peruchena, N. M. On the
Strength of the Halogen Bonds: Mutual Penetration, Atomic
Quadrupole Moment and Laplacian Distribution of the
Charge Density Analyses, Comput. Theor. Chem. 2012, 998,
164.
(71) Castro-Fernandez, S.; Lahoz, I. R.; Llamas-Saiz, A. L.;
Alonso-Gomez, J. L.; Cid, M. M.; Navarro-Vazquez, A.
Preparation and Characterization of
Shape-Persistent Chiral Alleno-Acetylenic
Complex, Org. Lett. 2014, 16, 1136.
a
Halogen-Bonded
Inclusion
(54) Landrum, G. A.; Goldberg, N.; Hoffmann, R. Bonding in the
Trihalides (X3 ), Mixed Trihalides (X2I-) and Hydrogen
-
(72) Oliveira, V.; Kraka, E.; Cremer, D. The Intrinsic Strength of
the Halogen Bond: Electrostatic and Covalent Contributions
Described by Coupled Cluster Theory, Phys. Chem. Chem.
Phys. 2016, 18, 33031.
Bihalides (X2H-). The Connection between Hypervalent,
Electron-Rich Three-Center, Donor-Acceptor and Strong
Hydrogen Bonding, J. Chem. Soc. Dalton 1997, 3605.
(55) Makhotkina, O.; Lieffrig, J.; Jeannin, O.; Fourmigue, M.;
Aubert, E.; Espinosa, E. Cocrystal or Salt: Solid State-
Controlled Iodine Shift in Crystalline Halogen-Bonded
Systems, Cryst. Growth Des. 2015, 15, 3464.
(56) Raatikainen, K.; Rissanen, K. Interaction between Amines
and N-Haloimides: A New Motif for Unprecedentedly Short
Br…N and I…N Halogen Bonds, CrystEngComm 2011, 13,
6972.
ACS Paragon Plus Environment

Page 13 of 13
Journal of the American Chemical Society
1
2
3
4
5
6
Table of Contents artwork
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13
ACS Paragon Plus Environment