The Influence of Secondary Interactions on the [N?I?N]+ Halogen Bond

Article abstract of DOI:10.1002/chem.202102575

[Bis(pyridine)iodine(I)]⁺ complexes offer controlled access to halonium ions under mild conditions. The reactivity of such stabilized halonium ions is primarily determined by their three-center, four-electron [N?I?N]⁺ halogen bond. W

Full text of DOI:10.1002/chem.202102575

Accepted Article
Accepted Article
Title: The influence of secondary interactions on the [N-I-N]+ halogen
bond
Authors: Sofia Lindblad, Flóra Boróka Németh, Tamás Földes, Daniel
von der Heiden, Herh G. Vang, Zakarias L. Driscoll, Emily R.
Gonnering, Imre Pápai, Nathan Bowling, and Mate Erdelyi
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To be cited as: Chem. Eur. J. 10.1002/chem.202102575
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01/2020

10.1002/chem.202102575
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The Influence of Secondary Interactions on the [N-I-N]+ Halogen
Bond
Sofia Lindblad,[a] Flóra Boróka Németh,[b] Tamás Földes,[b] Daniel von der Heiden,[a] Herh G. Vang,[c]
Zakarias L. Driscoll,[c] Emily R. Gonnering,[c] Imre Pápai,*[b,d] Nathan Bowling,*[c] and Mate Erdelyi*[a]
[a]
[b]
[c]
[d]
S. Lindblad, Dr. D. von der Heiden, Prof. M. Erdelyi
Department of Chemistry – BMC
Uppsala University
SE-751 23 Uppsala, Sweden
E-mail: mate.erdelyi@kemi.uu.se
F. Boróka Németh, Dr. T. Földes, Prof. I. Pápai
Institute of Organic Chemistry
Research Center for Natural Sciences, Hungarian Academy of Sciences
Budapest, Hungary
E-mail: papai.imre@ttk.hu
H.G. Vang, Z.L. Driscoll, E.R. Gonnering, Prof. N. Bowling
Department of Chemistry
University of Wisconsin—Stevens Point
2001 Fourth Avenue, Stevens Point, Wisconsin 54481, United States
E-mail: nbowling@uwsp.edu
Prof. I. Pápai
Department of Chemistry
University J. Selyeho
94505 Komárno, Slovakia
Supporting information for this article is given via a link at the end of the document
Abstract: [Bis(pyridine)iodine(I)]+ complexes offer controlled access
to halonium ions under mild conditions. The reactivity of such
stabilized halonium ions is primarily determined by their three-center,
four-electron [N-I-N]+ halogen bond. We studied the importance of
chelation, strain, steric hindrance and electrostatic interaction for the
structure and reactivity of halogen bonded halonium ions by acquiring
their 15N NMR coordination shifts and measuring their iodenium
release rates, and interpreted the data with the support of DFT
computations. A bidentate ligand stabilizes the [N-I-N]+ halogen bond,
decreasing the halenium transfer rate. Strain weakens the bond and
accordingly increases the release rate. Remote modifications in the
backbone do not influence the stability as long as the effect is entirely
steric. Incorporating an electron-rich moiety close by the [N-I-N]+ motif
increases the iodenium release rate. The analysis of the iodine(I)
transfer mechanism highlights the impact of secondary interactions,
and may provide a handle on the induction of stereoselectivity in
electrophilic halogenations.
engineering,[5] material sciences,[6] organic synthesis,[7] and drug
design,[8] and has emerged as a complementary molecular tool to
the hydrogen bond. It lately developed into one of the quickest
growing areas of chemical research.
Halogen bonds stabilize reactive halenium ions.[9] In their
halogen bond complexes, the empty and accordingly highly
electrophilic p-orbital of a halogen(I) simultaneously receives
electron density from two Lewis bases,[10] and forms a remarkably
strong three-center, four-electron [N-X-N]+ bond.[11] For instance,
the three-center bond of the triiodide ion is of 180 kJ/mol
strength.[12] Three-center, four-electron halogen bond complexes
receive increasing attention,[9a, 10, 13] not least because they are
applicable as mild halonium transfer and oxidation agents in
7j-n]
synthesis,[7a-h,
as novel supramolecular synthons in the
assembly of complex architectures,[14] and as a key element in
halogen bonded frameworks.[15] Fundamental investigations
primarily included symmetry determination, where the effect of
varying the halogen,[13a, 13d] the solvent,[10] the counter ion,[13e] and
13c, 14d]
the electron density of the Lewis bases[13b,
have been
assessed. The [N-X-N]+ bond was shown to prefer a static,
symmetric geometry, which can be desymmetrized by using
Lewis bases of different electron density.[9b, 13c, 16] The symmetric
alteration of the electron density influences the halonium release
rate, with the electron-poor systems reacting quicker than the
electron-rich,[13a] but not their symmetry or geometry.[13b]
Herein we present a systematic investigation of the
influence of strain, steric and electronic effects on the three-
centered halogen bond using the model compounds 1-5, shown
in Figure 1. [Bis(pyridine)halogen(I)]+ (1) complexes are non-
Introduction
The halogen bond is the weak, attractive and directional
interaction of halogens with Lewis bases.[1] It has been studied as
early as the 1860s,[2] however, it has first received greater
attention
upon
Odd
Hassel’s
Nobel
prize-awarded
crystallographic studies a century later,[3] and has only recently
become widely acknowledged.[4] During the past decade it has
found applications in
a variety of fields including crystal
1
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Figure 1. Bis(pyridine)iodine(I) complexes studied for the assessment of the
impact of strain, steric hindrance and charge repulsion on the properties of the
[N-I-N]+ three-center bond.
chelating, and accordingly, the formation of their [N-X-N]+
complexes is associated with a larger entropic penalty. While they
are stable in dry solutions, they easily dissociate and in the
presence of other Lewis bases, they are involved in rapid
chemical exchange processes, complicating the interpretation of
their solution spectroscopic data.[16a] [(1,2-Bis(pyridine-2-
ylethynyl)benzene)halogen(I)]+ (2) complexes have been
developed for an accurate characterization of the three-center,
four-electron halogen bond complexes in solution as these are
entropically favorable, and thus their spectroscopic data is not
influenced by exchange processes. The 1,2-diethynylbenzene
backbone[17] enforces co-planarity of the pyridine Lewis bases
and a slightly longer (4.57 Å) than optimal (4.56 Å) inter-nitrogen
distance, marginally weakening the halogen bond.[13a]
Compounds 3-5 were designed to allow optimal inter-nitrogen
distance while posing different degrees of steric and electronic
effects, thereby allowing the evaluation of whether these influence
the reactivity of the halogen bonded halonium ion. We report our
findings from the systematic NMR spectroscopic, reaction kinetics,
and computational investigation of the influence of strain, steric
and electronic effects on the [N-I-N]+ bond geometry and strength.
An improved understanding of the influence of steric and
electronic effects on the three-center halogen bond is expected to
enable the rational modulation of the reactivity of
bis(pyridine)halogen(I)-type halonium transfer synthetic agents,
and facilitate their applications for instance in the design of
complex supramolecular systems,[14c, 14f, 14g, 18] and in halogen-
bonded organic frameworks.[15]
Scheme 1. The synthesis of 9-11. The synthetic routes to ligands 8-10.
Reagents and conditions: a) 3-ethynylpyridine, Pd(PPh3)4, CuI, NEt3, dry THF,
50 °C, 18 h, Ar (g); b) 1. trimethylsilylacetylene, Pd(PPh3)4, CuI, NEt3, THF,
100 °C, 24 h, Ar (g), 2. TBAF, THF, −89 °C, 2 h; c) 1,4-diiodobenzene,
Pd(PPh3)4, CuI, NEt3, THF, 75 °C, overnight, Ar (g); d) 1,4-dibromonaphthalene,
Pd(PPh3)4, CuI, NEt3, DMF, 95 °C, 20 h, Ar (g); e) 4,7-dibromo-
benzo[c][1,2,5]thiadiazole, Pd(PPh3)4, CuI, NEt3, DMF, 95 °C, 72 h, Ar (g).
tert-butyl-benzene was converted to 7 through Sonogashira
coupling with 3- ethynylpyridine. Subsequent Sonogashira
coupling with trimethylsilylacetylene, followed by TMS-
deprotection with TBAF, yielded 8, and a third Sonogashira
coupling gave 9, 10 and 11, respectively, upon varying the aryl
halide. 1,2-Bis(pyridine-2-ylethynyl)benzene (6) was synthesized
as reported.[13a] Complex 1[7c] is commercially available. The
iodine(I) complexes 1-5 were synthesized following a previously
established procedure.[13a, 13e] Hence, a ligand was mixed with
AgBF4 in CH2Cl2, under dry conditions, to form the corresponding
silver(I) complex. Upon addition of I2, AgI precipitated and the
iodine(I) complex was formed. Following filtration, the complex (1-
5) is precipitated upon addition of dry n-hexane.
Structural analysis. DFT calculations were carried out for
structural analysis using the hybrid meta-GGA M06-2X functional
and the SMD18 solvation model. For geometry optimizations and
vibrational analysis, the Def2SVP basis set was employed, but
single-point energy calculations were performed with the more
extended Def2TZVPP basis set (for computational details, see
the Supporting Information). The DFT-predicted ground state
.
structures of complexes 1-5 are shown in Figure
2 (for
computational details, see the Supporting Information). In good
agreement with previous studies,[9b, 13b] the computed NI bond
distances show only a marginal variation along the series, and the
~180° N-I-N bond angle is in line with that observed by X-ray for
1[20] and 2.[11] The linear arrangement and short NI bond distance
are typical for three-center, four-electron halogen bonds.[9b] For
Results and Discussion
Synthesis. Ligand 9 was prepared following a published
procedure,[19] while ligands 10 and 11 were achieved through
modification of this route (Scheme 1). Hence, 1-bromo-2-iodo-4-
2
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2.271
2.272
2.275
2.275
2.271
179.5
176.8
180.0
2.271
1
2
3
Figure 3. The non-covalent interaction (NCI) plots of 3, and of the syn-
geometries of 4 and 5. The applied cutoff for reduced density gradient is set to
s
= 0.4 au. Green isosurfaces represent weak stabilizing non-covalent
interactions. The three-center, four-electron halogen bond is illustrated by blue
rings. Free energy differences between the syn and anti forms of 4 and 5 are
given in parenthesis (in kcal/mol).
2.270
2.274
15
Table 1. The 15N NMR Chemical Shift (
N
) and Coordination Shift
complex
177.9
15
15
177.0
(δ
N
) of 1-5 and of the Corresponding Free Ligands (
N
).
ligand
coord
2.275
2.266
15
15
15
Structure

N

N
 N
coord
complex
ligand
1
2
3
4
5
−175.1 [a]
−163.6
−173.6
−173.8
−173.8
−67.0 [a]
−64.5[b]
−65.5
−108.1
−99.1
4
5
−108.1
−108.0
−108.1
Figure 2. Structures of complexes 1-5 as obtained from DFT calculations.
Computed N-I bond lengths are in Å, N-I-N bond angles in degrees. Stabilizing
aryl-aryl interactions are highlighted by green arrows. As weakly coordinating
counterions have previously been shown not to influence the geometry of [N-I-
N]+ complexes,[13e] these were omitted in the computational models.
−65.8
−65.7
[a] Previously reported by us in ref. [13e], and [b] ref. [13a].
complexes 3-5, the N-I-N bond angle slightly deviates from 180°.
In contrast to complex 2,[13a] the optimized structures of 3-5
deviate from planarity. The distortion of the conjugated aromatic
system is already notable for complex 3, but becomes even more
significant for 4 and 5 (Figure 2), where the central bicyclic
aromatic groups interact with the adjacent pyridines.
Computations predict these syn conformers to be 1-2 kcal/mol
solution spectroscopic data. Based on their δ15Ncoord, 3-5 have
comparable electron density at their [N-I-N]+ bond as 1.
Halogen release rates. To indirectly characterize halogen
bond strength, similar to the previous investigation of related
systems,[13b] we measured the iodenium[7c] release rates of 1-5
using the halocyclization of 4-penten-1-ol in anhydrous 1,2-
dichloroethane as model reaction (Figure 4). The mechanism of
favored
over
those
with
the
naphthalene
and
22]
this reaction has been examined experimentally.[7j,
The
benzo[c][1,2,5]thiadiazole rings tilted away from the [N-I-N]+ bond
(anti arrangements), revealing these intramolecular aryl-aryl
contacts to be stabilizing (Figure S87, Supporting Information).
This stabilization is found to be slightly higher for complex 4,
which is further corroborated by the non-covalent interaction
analysis of 3-5, shown in Figure 3.
decrease of the UV signal of 1-5 throughout the reaction was
followed, measuring pseudo-first-order rate constants for each
complex in the presence of a large excess of olefin. To obtain the
reaction rate constant (kobs), the data were fitted to the standard
exponential model A푡 = A∞ + (A0 − A∞)e−푘 푡 . Subsequently,
obs
the second-order rate constants (k2) were obtained by
determining the dependence of kobs on the concentration of 4-
penten-1-ol (Figure 5). The latter describes the overall rate of the
processes taking place ahead of the irreversible intramolecular
cyclisation of the halonium-substrate complex. We have shown
that k2 of this reaction is modulated by the electronic effect of the
pyridine substituents.[13b] As the m=0.14 and p=0.16 Hammett
constants of alkynes are comparable,[23] the backbones of 2-5 are
assumed to not be responsible for the differences observed in
their k2 (Figure 5). The highest iodenium release rate (k2 = 77.6
Nitrogen coordination shifts. The comparable 15N
coordination shifts (δ15Ncoord = δ15Ncomplex – δ15Nligand, Table 1)[13b,
13e, 21] of 1 and 3-5 compared with the slightly smaller δ15Ncoord of
2
suggests that 3–5 adapt non-strained geometries. This
interpretation is further corroborated by their comparable N-I-N
bond length and angle (Figure 2), and by the δ15Ncoord of
analogous systems.[13b] We wish to emphasize that 3–5 are the
first model systems that allow the investigation of the [N-I-N]+
three-center halogen bond without the influence of strain or
chemical exchange[9b, 16a] that complicate the interpretation of
3
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Figure 4. Figure The rate of halocyclization of 4-penten-1-ol in the presence of 1-5 was used to characterize their relative halenium release rate. A general, simplified
mechanism, established in previous studies,[7j, 22a, 22c, 22d] for the initial steps of the reaction is shown.
M-1s-1) was observed for 1, which is non-chelated and is known to
dissociate comparably easily,[16a] whereas 2-5 showed an order of
magnitude slower reactions. Based on the Hammett parameters
bond despite its bulkiness. The twice as high halenium release
rate of 5 (k2 = 2.3 M-1s-1) as compared to 3 and 4 suggests that
the benzo[c][1,2,5]thiadiazole ring of 5 may have a through-space
interaction with the bis(pyridine)iodine(I) moiety. This may be due
to the direct involvement of the benzo[c][1,2,5]thiadiazole in the
halenium transfer process or by aryl-aryl interaction with the
pyridines (Figure 2), lowering the energy of the transition state.
There may be an attractive Coulomb interaction between the
partially positively charged iodonium ion and the electron-rich
sulfur of the benzo[c][1,2,5]thiadiazole, influencing the halenium
release rate. Alternatively, the repulsion between the nonbonding
electron pairs of the sulfur and the filled p-orbitals of the iodine(I),
whose charge is transferred into the pyridines to a large extent,[9b,
(1, m(–H)=0.00; 2–5, m(–CCH)=0.14 and p(–CCH)=0.16),[23]
1
would be expected to have a slower reaction rate as compared to
2-5. Thus, the observed lower iodination rate (k2) of 2–5 is due to
chelation, and not to electronic effects. Chelation increases the
stability of the [N-I-N]+ complex by lowering the entropic driving
force of the halenium transfer process and the effective
concentration of the mono-coordinated halogen(I) species that
halogen bonds to and subsequently reacts with 4-penten-1-ol.
Hence, the ligand dissociation has a significant influence on the
reaction rate. Among the chelating ligands, 2 showed the quickest
halenium release rate (k2 = 4.3 M-1s-1) that is most likely due to its
non-optimal geometry resulting in substantial strain (Figure 2),
also detectable on its δ15Ncoord (Table 1). The comparable k2 of
3 and 4 (k2 = 1.4 and 1.2 M-1s-1) suggests that the naphthalene
ring of 4 does not considerably influence the [N–I–N]+ halogen
13d]
may increase the halenium release rate. The latter is in line
with the filled p-orbitals of an iodine that participates in a halogen
bond being able to act as Lewis base and hence as hydrogen
bond acceptor[24] or electron donor to silver(I).[18a] Electrostatic
repulsion between the bis(pyridine)iodine(I) moiety and the
polarized central aromatic systems would provide repulsion in an
analogous manner. The latter is supported by the electrostatic
potential maps (EPSs) computed for 3-5 (Figure S88, Supporting
Information), which indicate that the positive charge of iodine(I) is
distributed over the [bis(pyridine)iodine(I)] moiety, and the central
aromatic rings are indeed polarized as well. Even if it is not
possible to differentiate between the above possibilities, the fact
that the naphthalene of 4 does not influence k2 suggests that the
effect of the benzo[c][1,2,5]thiadiazole of 5 is unlikely to be
entirely steric. To gain further insight, we performed
computational coordinate scans mapping the potential energy of
3-5 as a function of the central aromatic ring system orientation.
Whereas the central benzene ring of 3 showed free rotation, the
naphthalene and benzo[c][1,2,5]thiadiazole rings of 4 and 5,
respectively, were hindered by the [N-I-N]+ bond (Figures S89-91,
Supporting Information).
0,35
0,30
0,25
0,20
0,15
0,10
0,05
0,00
Computed stabilities. DFT calculations were carried out to
gain further insight into the above reactivities. The relative
stabilities of iodine(I) complexes can be quantified by the
thermodynamics of the hypothetical isodesmic reactions shown in
Table 2. Although the phenyl(ethynyl)-substituted pyridine units of
the chelating ligands are slightly less basic than the unsubstituted
pyridine (see computed proton affinities in Table 2), the chelate
complexes 2-5 are predicted to be more stable than 1 (Giso > 0).
This is clearly due to the entropic loss associated with the
formation of the [bis(pyridine)iodine(I)] complex 1. The strained
0,00
0,03
0,05
0,08
[4-penten-1-ol] [M]
Figure 5. The second-order-rate constants (k2, M-1s-1) of 1-5 in iodocyclization
with 4-penten-1-ol in dry dicloroethane was obtained by fitting the observed
pseudo-first order rate constant (kobs) of each complex to the 4-penten-1-ol
concentration. The slopes of the corresponding graphs provided the k2 values
77.6 (R2 = 0.94) for 1, 4.3 (blue) for 2, 1.4 (green) for 3, 1.2 (violet) for 4, and
2.3 (yellow) for 5. The plot for 1 is not shown here for clarity and is given in the
Supporting Information (Figure S85).
4
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Table 2. Relative Stabilities of Complexes 1-5.
2.65
2.53
2.66
2.28
2.31
2.49
1-int1´ (12.1)
1-int1 (11.4)
2.49
2.89
2.16
2.21
Complex
Giso (kcal/mol) [a]
Proton affinity (kcal/mol) [b]
2.31
1-ts (17.0)
1-int2 (8.1)
1
2
3
4
5
0.0
3.9
4.7
4.6
4.6
-278.1
-275.1
-275.3
-275.3
-275.3
3.01
2.16
1.61
prod
+
1.56
1-int3 (–12.0)
[a] Relative stabilities are computed with respect to the [bis(pyridine)iodine(I)]
complex 1 as Giso values of isodesmic reactions. [b] Proton affinities of pyridine
and (phenyl)ethynyl-substituted pyridines corresponding to chelating ligands
(for details, see the Supporting Information).
1-H
Figure 7. Optimized structures of species identified computationally for the
reaction of complex 1 with 4-penten-1-ol. Relative stabilities are shown in
parentheses in kcal/mol, with respect to 1 + 4-penten-1-ol. Selected bond
distances are given in Å.
nature of complex 2 is corroborated by the calculated equilibria,
as this complex is found to be thermodynamically less favored
than 3-5. The latter systems are non-strained and have
comparable stabilities, indicating that the backbone modification
has only a minor impact on the ground state halogen bond
energies of iodine(I) chelate complexes. Overall, the computed
Giso data are in qualitative agreement with the experimentally
observed k2 trend 1 > 2 > 3-5.
The mechanism of halocyclization. Next, we investigated
the mechanism of iodocyclization upon the reaction of 1 with 4-
penten-1-ol (pent). The free energy profile corresponding to the
most feasible reaction pathway is shown in Figure 6, and the
optimized structures of the key states are illustrated in Figure 7.
The reaction is initiated by the displacement of one of the
pyridines from complex 1. The dissociated state 1-dis (i.e. Py-I+ +
Py) is predicted to be 14.4 kcal/mol less stable with respect to the
reactants. Coordination of 4-penten-1-ol via its double bond is
thermodynamically favorable. The most stable form of this
intermediate (1-int1) lies at 11.4 kcal/mol on the free energy scale,
and the conformer with the OH group preorganized for ring
closure (1-int1) is only slightly less favored. The cyclization of 4-
penten-1-ol and the iodine(I) transfer takes place in a concerted
manner via transition state 1-ts, which is predicted to be at 17.0
kcal/mol, yielding intermediate 1-int2. The deprotonation of this
species by a pyridine is barrierless and highly exergonic. The
dissociation of the iodoether molecule from 1-int3 and the
formation of the hydrogen-bonded complex 1-H provides
additional stabilization for the product. This reaction pathway is in
line with the mechanism that has been previously proposed from
kinetic measurements (Figure 4). The reaction pathway involving
the association of the displaced pyridine with 4-penten-1-ol via an
O-HN hydrogen-bond prior to ring closure was found to be
kinetically less favored. The transition state of this hydrogen bond
assisted iodocyclization could be identified computationally to be
at 18.5 kcal/mol, and is thus slightly less favored than 1-ts (for
details, see the Supporting Information). Our computations reveal
that the 4-penten-1-ol iodocyclization induced by 2 has a similar
mechanism. The dissociated state of 2 corresponds to various
energetically close-lying asymmetric singly coordinated forms,
which are displayed in Figure 8. The relative stability of these
conformers range between 19.1 and 21.2 kcal/mol, and thus
these are significantly less stable than the symmetric ground state
complex. They all involve various intramolecular pyridine-pyridine
and iodine(I)-pyridine contacts. 4-Penten-1-ol iodocyclization
pathways associated with all four dissociated forms of 2 (Figure
8) were explored and here they are denoted as routes a, b, c and
d. We located an array of transition states along these pathways
lying within a fairly narrow (2 kcal/mol) energy range (see Table 3
20
1-int1' 1-ts (17.0)
+ Py
16.3
15
10
5
1-int ´ (12.1)
12.8
1
1-ts
+ Py
11.2
1-dis (14.5)
9.5
11.7
1-int (11.4)
11-int1
1-dis
1-int2
1-int2 (8.1)
+ Py
+ Py + S
+ Py
0.0
0
1 + S
1 + pent (0.0)
-5
-10
-15
-20
-25
–12.8
1-int3 (–12
1-int.30)
–24.8
1-H + T
1-H + prod (–24.6)
Figure 6. Free energy profile computed for the reaction of complex 1 with 4-
penten-1-ol (pent). Relative stabilities are shown in parentheses (in kcal/mol;
with respect to the energy of 1 + pent).
5
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Table 3. Relative Stability of Species Identified Computationally on Various
Pathways in the Reaction of Complex 2 with 4-Penten-1-ol.[a]
pathway
2-dis
19.1
19.3
19.3
21.2
2-int1
18.6
17.5
17.9
19.0
2-ts
2-int2
13.7
11.1
13.3
13.6
a
b
c
d
22.6
20.9
21.9
22.5
2-disa (19.1)
2-disb (19.3)
[a] Pathways a, b, c and d are denoted according to the related dissociated
states of complex 2 (2-disa, 2-disb, 2-disc, and 2-disd, see Figure 8). States 2-
int1 and 2-int2 refer to intermediates before and after transition states 2-ts.
Relative stabilities are given in kcal/mol with respect to 2 + 4-penten-1-ol.
4-penten-1-ol (Figures 6-7). The iodocyclization transition state is
preceded by a complex bearing an iodine(I) coordinated 4-
penten-1-ol (intermediate 2-int1b), and it is followed by a weakly
bound cyclic intermediate 2-int2b, which gets deprotonated in a
subsequent step. The deprotonation process has not been
examined in detail, yet our computational analysis suggests that
it may easily occur intramolecularly, i.e. via deprotonation by the
displaced pyridine of the ligand (Figure S99, Supporting
Information).
2-disc (19.3)
2-disd (21.2)
Figure 8. Dissociated forms of complex 2. Relative stabilities are
shown in parentheses (in kcal/mol; with respect to the symmetric
chelated form). Selected bond distances are given in Å. Green
dotted arrows indicate stabilizing non-covalent interactions.
The free energy data computed for the two reactions (for
complexes
1 and 2; Figures 6 and 10) imply that the
iodocyclization transition states represent the rate-determining
states. This is likely for the reaction of 1 with 4-penten-1-ol,
because 1-ts lies well above the 1-dis state. It is less evident for
the corresponding reaction of 2, where the relative stability of the
dissociated states is more comparable to those of the
iodocyclization transition states, for instance, 2-disb lies only 1.6
kcal/mol below 2-tsb. Considering the uncertainty of the present
methodology for free energy predictions, particularly in
comparison of states with different molecularity, no firm
conclusion can be drawn for the rate-determining state.
Nevertheless, calculations predict significantly higher barrier for
the reaction with the chelated complex 2, which can be clearly
associated with the relative stabilities of complexes 1 and 2. The
2.60
2.22
2.28
2.28
2.57
2.27
2-tsa (22.6)
2-tsb (20.9)
2.60
2.54
2.27
2.24
2.25
2.30
2-tsc (21.9)
2-tsd (22.5)
2-tsb (20.9)
2-disb (19.3)
Figure 9. Transition states computed on various pathways in the
reaction 2 + pent. Relative stabilities are shown in parentheses
(in kcal/mol; with respect to reactant state). Selected bond
distances are given in Å. Stabilizing non-covalent interactions
between the substrate and the displaced pyridine are highlighted
by green dotted arrows.
20
1-int1'
+ Py
16.3
15
10
5
12.8
2-int1b (17.5)
1-ts
+ Py
11.2
9.5
11.7
1-int1
+ Py
1-dis
2-int2b (11.1)
1-int2
+ Py
+ Py + S
0.0
0
and Figure 9). The most favored reaction pathways are
associated with the 2-disb and 2-disc forms of the dissociated
state, wherein the coordination of 4-penten-1-ol is sterically
hindered. Coordination to these complexes requires structural
rearrangement; however, the cost of this structural change is
counterbalanced, and even exceeded, by the stabilization arising
from noncovalent substrate-pyridine interactions. In complexes 2-
disa and 2-disd, the iodine(I) is readily accessible, but the related
intermediates and transition states do not benefit from stabilizing
intermolecular contacts. The overall free energy profile of the
most favored reaction pathway, shown in Figure 10, and also all
other pathways, show close resemblance to that of reaction 1 with
1 + S
2 + pent (0.0)
-5
-10
-15
-20
-25
-30
–12.8
1-int3
–24.8
2-H + prod (–21.9)
1-H + T
Figure 10. Free energy profile computed for the reaction of
complex 2 with 4-penten-1-ol. Relative stabilities are shown in
parentheses (in kcal/mol; with respect to 2 + pent).
6
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10.1002/chem.202102575
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destabilizing and accordingly increases the iodenium release rate,
as demonstrated by the higher reactivity of 2 as compared to 3-5
(Figure 4). Steric crowding in itself does not influence halogen
bond stability, which is reflected by the comparable halenium
release rates of 3 versus 4 (Figure 4). The iodenium release rates
of complexes 3–5 suggest that electronic effects, here modelled
by the thiadiazole – iodonium interaction of 5, may have an
influence on halonium ion reactivity, stronger than steric crowding,
2.53
2.29
2.28
which in turn are comparable in
4 (naphthalene) and 5
3-ts (21.1)
(benzo[c][1,2,5]thiadiazole). Computations on the DFT level
suggest that the mechanism of iodenium transfer in
halocyclization with 4-penten-1-ol is analogous for the chelated
(2-5) and non-chelated (1) bis(pyridine)iodine(I) reagents. It
involves the initial dissociation of the [N-I-N]+ complex (N+-I + N),
coordination of the alkene to the -hole of the transient N-
pyridinium ion, followed by a concerted halocyclisation and
iodenium transfer that constitutes the transition state of the
process. The subsequent dissociation and proton transfer steps
are barrierless. The improved understanding of this mechanism is
expected to support, for instance, the development of robust and
general methods for asymmetric halogenation of olefins, which is
a long-sought goal of synthetic organic chemistry.[26] Moreover,
understanding the influence of strain, steric and electronic effects
along with that of chelation on the three-center halogen bond of
halonium ions will also enable the development of more complex
supramolecular assemblies[14a-c, 14f] and halogen-bonded organic
frameworks (XOFs).[15] It may in addition provide helpful
knowledge for the development of structurally closely related
organometallic reagents[27] and systems held together by other
types of three-center, four-electron bonds, such as tetrel,
pnictogen and chalcogen bonds.[11] The bis(pyridine)iodine(I)
complex has lately been proposed to be involved in a spectacular
cation-cation interaction,[18a, 28] for which the influence of steric
and electronic effects, strain, crystal packing forces and
hydrophobic stacking are yet by far not well understood. The
presented study of novel model systems that neither suffer from
ligand scrambling or strain ought to support their further studies.
Figure 11. Transition state computed for the reaction of complex
3 with pent. Relative stability is given in parentheses (in kcal/mol;
with respect to 3 + pent). Selected bond distances are given in Å.
free energy difference between 1-ts and 2-tsb (3.9 kcal/mol) is
virtually identical to that obtained for the relative stabilities of the
complexes (Table 2).
The increased size and the flexibility of 3-5 prevented us
from extensively exploring the mechanistic details of their
iodocyclization; however, our computations indicate similar
mechanistic features for their reactions, and similar reactivities to
2. One representative transition state computed for the
iodocyclization using 3 is shown in Figure 11. The transition state
3-ts is predicted to be at 21.1 kcal/mol in free energy. The
corresponding dissociated state 3-dis is computed to be 19.8
kcal/mol less stable with respect to the symmetric chelated form
of 3. Due to the uncertainties of the applied computational
approach, one cannot expect to be able to reproduce the
differences in the experimental reaction rates of 3-5. However, our
computational analysis suggests that the difference in the
reactivity of complexes 4 and 5 might be related to the
intramolecular aryl-aryl interactions discussed above. It indicates
that the relative stabilities of the transition state of the
iodocyclization reactions of 4 and 5 are barely influenced by the
orientation of the naphthalene and benzo[c][1,2,5]thiadiazole
rings (Figure S101, Supporting Information). However, the syn-
orientation of compound 4 is more stabilized (2.1 kcal/mol) as
compared to that of 5 (1.1 kcal/mol, Figure 3) by intramolecular
aryl-aryl interaction, resulting in slightly higher barrier for the
iodocylization reaction with 4. Whereas this energy difference is
minor, it is in line with the experimentally observed 5 > 4 reactivity
trend (Figure 5).
Acknowledgements
We thank Leif Hammarström, Tianfei Liu and Alexei Neverov for
helpful discussions regarding the kinetic measurements. This
project made use of the NMR Uppsala infrastructure, which is
Conclusion
funded by the Department of Chemistry – BMC and the
Disciplinary Domain of Medicine and Pharmacy. We thank the
Swedish Research Council (2016-03602, 2020-03431) and
FORMAS (2017-01173) for financial support. The UWSP group
would like to acknowledge research funding (CHE 1903581 and
CHE 1606558) and instrument funding (NMR: CHE 0957080)
from the National Science Foundation and research funding from
the Henry Dreyfus Teacher-Scholar Awards Program. This work
was also supported by the European Regional Development Fund
via the "Support of research and development capacities in the
area of nanochemical and supramolecular systems" project
(code: 313011T583).
We evaluated the influence of chelation, ligand strain,
charge repulsion and steric hindrance on the [N-I-N]+ halogen
bond. The 15N NMR coordination shifts (Table 1) indicate that in
contrast to complex 2, the backbones of 3-5 adapt non-strained
geometries. This is of significance as 2 has originally been
introduced[13a] to evade ligand scrambling that is unavoidable for
the halogen bond complexes of halonium ions with monodentate
Lewis bases, such as 1.[25] Whether symmetric or asymmetric,
ligand scrambling cannot be neglected at the interpretation of the
solution spectroscopic data without risking the misinterpretation
of their bonding situation.[16] Chelation has a stabilizing effect,
which is reflected by the lower iodenium[7c] release rates of 2-5 as
compared to 1 (Figure 5), and is corroborated by the computed
stabilities (Table 2). Within a chelated complex, strain is
Keywords: halogen bond • iodonium ion • iodenium ion • NMR
spectroscopy • density functional calculations
7
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Entry for the Table of Contents
Halogen bond-stabilized halonium ions are mild halenium transfer agents. The dependence of their reactivity on chelation, strain,
steric hindrance and electrostatic interaction has been evaluated using NMR, DFT and kinetics experiments. The mechanistic
analysis of the transfer is expected to provide a handle in the induction of stereoselectivity in electrophilic halogenations.
9
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