Intramolecular halogen bonding supported by an aryldiyne linker

Article abstract of DOI:10.1021/jo501015x

Intramolecular halogen bonds between aryl halide donors and suitable acceptors, such as carbonyl or quinolinyl groups, held in proximity by 1,2-aryldiyne linkers, provide triangular structures in the solid state. Aryldiyne linkers provide a nearly ideal t

Full text of DOI:10.1021/jo501015x

Article
pubs.acs.org/joc
Intramolecular Halogen Bonding Supported by an Aryldiyne Linker
Danielle L. Widner,† Qianwei R. Knauf,† Mark T. Merucci,† Thomas R. Fritz,† Jon S. Sauer,†
Erin D. Speetzen,† Eric Bosch,‡ and Nathan P. Bowling*,†
†Department of Chemistry, University of Wisconsin-Stevens Point, 2001 Fourth Avenue, Stevens Point, Wisconsin 54481, United
States
‡Department of Chemistry, Missouri State University, 901 S. National Avenue, Springfield, Missouri 65897, United States
S
* Supporting Information
ABSTRACT: Intramolecular halogen bonds between aryl
halide donors and suitable acceptors, such as carbonyl or
quinolinyl groups, held in proximity by 1,2-aryldiyne linkers,
provide triangular structures in the solid state. Aryldiyne
linkers provide a nearly ideal template for intramolecular
halogen bonding as minor deviations from alkyne linearity can
accommodate a variety of halogen bonding interactions,
including O···Cl, O···Br, O···I, N···Br, and N···I. Halogen
bond lengths for these units, observed by single crystal X-ray
crystallography, range from 2.75 to 2.97 Å. Internal bond
angles of the semirigid bridge between halogen bond donor
and acceptor are responsive to changes in the identity of the
halogen, the identity of the acceptor, and the electronic
environment around the halogen, with the triangles retaining almost perfect co-planarity in even the most strained systems.
Consistency between experimental results and structures predicted by M06-2X/6-31G* calculations demonstrates the efficacy of
this computational method for modeling halogen-bonded structures of this type.
remote groups with a rigid linker to negate some of the
entropic cost of intramolecular halogen bonding.
INTRODUCTION
■
Halogen bonding is a well-studied intermolecular force that
involves the attraction of a Lewis base to an electropositive
region on a halogen.1−7 The strength of these attractions scale
with the polarizability of the electron-accepting halogen, with
strongest attractions to iodine and weak or no attractions to
fluorine. Halogen bonding can be an important contributor in
biological processes8−11 and materials design.12,13 The place-
ment and identity of halogens on molecules interacting with
proteins, for example, can be extremely important to drug
design.14−16 Likewise, careful incorporation of halogens onto
small molecules offers opportunities for controlled crystal
design17 and supramolecular construction.18−20 Additionally,
with the development of Lewis acid catalysts,21,22 anion
sensors,23,24 and anion transport systems,25 researchers have
started exploring the utility of this intermolecular force in
solution.26−28
An initial concern in the design of intramolecular halogen
bonding systems was the size of the non-alkyne side of the
triangle. System 1 (Figure 1), for instance, is nearly perfectly
triangular, as the non-alkyne side of the triangle has dimensions
nearly identical to the other two sides.29 When comparing this
to reported bimolecular halogen bonding systems 230 and 3,31
one challenge becomes obvious, namely, the size demands for
the third side of the triangle are significantly larger than one
would expect to be accommodated by a rigid linker.
The absence of intramolecular halogen bonds reported in the
literature speaks to the difficulties in designing such systems.
The strongest halogen bond attractions occur when the
electron donor is oriented directly opposite the carbon−
halogen bond (i.e., O(N)···X−C angle =180°). The entropic
cost of getting a remote oxygen or nitrogen lone pair to align
perfectly with a halogen in a flexible molecule would be too
high to account for the modest energetic gain of the halogen
bond. With this in mind, we envisioned connecting these
Figure 1. Comparison of spatial demands in noncovalent bridge of 1
with known bimolecular halogen bonding systems 2 and 3.
Received: May 9, 2014
Published: June 16, 2014
© 2014 American Chemical Society
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A second consideration in designing molecules with
intramolecular halogen bonds is incorporating groups that
yield the most stable “ring” structure. At first glance, the fact
that the largest halogen, iodine, is expected to provide the
strongest halogen bonds seems to present additional challenges.
Comparisons between 2 and 3 offer some relief in this pursuit
(Figure 1). Because halogen bonds become stronger as the van
der Waals radius for the halogen becomes larger, these factors
(bond strength vs van der Waals radius) cancel each other out
so that, with all other factors being equal, similar halogen bonds
are roughly the same length regardless of the halogen
involved.32 This can be seen when comparing the N···Br
distance of 2 (2.82 Å) to the N···I distance of 3 (2.81 Å)
(Figure 1). Consequently, only the length of the C−X bond
becomes important to the spatial demands of each halogen.
Another factor that must be considered in the design of
intramolecular halogen-bond-capable molecules is the elec-
tronic environment around the halogen bond donor (i.e.,
electron acceptor)33 and the halogen bond acceptor (i.e.,
electron donor). In comparisons of bimolecular systems 3 and
4,31 for instance, one can see that the presence of electron-
withdrawing groups near the halogen (3) significantly
strengthens/shortens the halogen bond (Figure 2). Similarly,
Figure 3. Different combinations of halogen bond donors and
acceptors allow for a systematic study of intramolecular halogen
bonding.
respectively, deprotection of the TMS-protected intermediate
alkyne, and PCC oxidation of the resulting propargylic alcohol
as the final step (Scheme 1).
Scheme 1. General Synthetic Sequence for Carbonyl-Based
Systems
Figure 2. Cumulative effects of electron-donating and -withdrawing
groups on the strength of halogen bonds.
introduction of an electron-donating group on the halogen
bond acceptor side (5) increases the strength of this
interaction.34 Though halogen bonds are sometimes weak
compared with their hydrogen bond counterparts, the
attractions can be substantial when there is appropriate
donor/acceptor pairing. For example, estimated interaction
energies for C6F5X-pyridine (X = I, Br, and Cl) pairs are −5.59,
−4.06, and −2.78 kcal/mol, respectively.32
RESULTS AND DISCUSSION
A similar reaction sequence was used to generate the
quinoline derivatives from 1735 (Scheme 2). Syntheses of all
carbonyl and quinoline compounds are relatively straightfor-
ward provided that one use a large excess of 1,2-
dibromotetrafluorobenzene or 1,2-diiodotetrafluorobenzene,
when needed. Sonogashira coupling with a stoichiometric
amount of these reagents leads to inseparable mixtures of
mono- and dicoupled products.
Proof of Concept with CO···Br Halogen Bonding. At
the outset of this project, we felt that bromoarenes offered the
greatest possibility of success as the bromine atom would not
be too spatially demanding but would provide relatively strong
halogen bonding. To our delight, separate experiments
involving single crystals of 14 (Figure 4) and 13 (Figure 5)
yielded co-planar, triangular structures.
■
Synthesis and Design. In this study, halogen bond donors
were designed with perfluorinated rings (A, C) or trifluor-
omethyl substituents (B, D) to maximize the electron-accepting
ability of the halogen (Figure 3). Pyridinyl and carbonyl groups
were initially targeted as halogen bond acceptor groups.
Because the pyridinyl (X) systems yielded crystals that were
difficult to interpret by single crystal X-ray crystallography,
quinoline (Z) groups were installed to break up the
pseudosymmetry of the triangular compounds. A benzylic
ketone (Y) was chosen as the carbonyl moiety so that the
electronics of this system might be easily manipulated in future
studies by replacing the p-methoxy group.
All of the carbonyl systems were synthesized by a general
procedure involving Sonogashira coupling of 6, 7, and 8,
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Scheme 2. General Synthetic Sequence for Quinoline-Based
Systems
Figure 5. Crystal structure reveals that the perfluorinated ring of 13
significantly enhances the strength of the Br···O attraction compared
to a similar trifluoromethyl system.
triangle (from the ideal 4.0 Å) speaks to the versatility of the
1,2-aryldiyne linker as a template for intramolecular halogen
bonding.
Two other geometric parameters of interest are the CO···
Br angle around the oxygen and the C−Br···O bond angle
around the halogen. Our design strategy was to place the
electron-accepting halogen 120° from the carbonyl, presumably
aligned with an available lone pair. Computational models
predict that the ideal CO···Br angle gradually increases as the
halogen becomes more and more electropositive, with
electrostatic attraction of the halogen to the highest region of
electron density on the oxygen (∼127°)10,33,36 becoming the
dominant interaction. While our results seem to be consistent
with these predictions, with 14 displaying a CO···Br angle of
115.7° and 13 yielding a 121.4° angle, these angles do not
necessarily represent energetic minima for the halogen bonding
interaction as there are other geometric constraints within the
cyclic system.
Figure 4. X-ray crystal data from 14 reveals a co-planar structure with
minor deviations from ideal bond angles that accommodate intra-
molecular halogen bonding.
It is well established in studies of halogen bonding that the
ideal C−X···O(N) angle is 180°. This value stems from the
location of the electropositive region of the halogen (i.e., the
sigma hole) directly opposite the C−X bond. The observed C−
Br···O angles for 14 and 13 are 174.5° and 171.0°, respectively.
With the other variables that contribute to the overall geometry
of these molecules, it is difficult to draw meaningful conclusions
from these two data points. One possibility, though, is the
increase in sigma hole size that goes along with enhanced
electron-withdrawing effects on the halogen. Computational
models predict the growth of this electropositive region as
more electron-withdrawing groups act upon it. A larger sigma
hole could presumably better accommodate non-ideal halogen
bond angles, allowing the perfluorinated system to more
significantly deviate from 180°, alleviating angle strain in the
aryldiyne backbone.
Interestingly, despite the fact that the 4.79 Å span of the C−
Br···O unit in 14 and the 4.60 Å span of the C−Br···O unit in
13 are significantly larger than the ideal 4.0 Å distance, the
compounds are able to form halogen bonds while retaining
almost total co-planarity. The most striking difference between
these two structures is the significantly shorter halogen bond
interaction of 2.75 Å in 13 versus the 2.91 Å observed in 14.
This is likely a reflection of the enhanced electrostatic attraction
between bromine and oxygen due to the superior electron-
withdrawing capacity of the perfluorinated ring of 13 compared
to the trifluoromethyl group of 14.32,36
As a result of the third side of the triangle in 13 being
considerably shortened, angle strain is alleviated within the ring.
The largest bond angle distortions for 14 involve one of the
alkyne arms bending out of linearity to 174.6° and expansion of
one of the internal sp2 bond angles to 122.3°. With the
contraction of the C−Br···O span in 13, these same bond
angles relax to 177.7° and 121.7°, respectively. That these
relatively modest bond angle distortions can accommodate
such a significant increase in size on the third side of the
Expanding Possibilities for Intramolecular Halogen
Bonding. With our initial success in acquiring the two
bromoarenes (13 and 14) described above, we set out to
explore the limitations of our intramolecular halogen bonding
template. The first question to be answered was whether iodo-
and chloroarenes would yield similar triangular structures, or
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Table 1. Structures Analyzed by X-ray Crystallography
a
Table 2. Crystal Data for 13−16, 20, and 21
13
14
15
16
20
21
formula
FW (g mol−1
C24H11BrF4O2
487.24
C25H14BrF3O2
483.27
C24H11F4IO2
534.23
C25H14ClF3O2
438.81
C25H10BrF4N
480.25
C25H10F4IN
527.24
)
crystal system
space group
monoclinic
P21/c
monoclinic
P21/c
monoclinic
P21/c
triclinic
monoclinic
P21/c
triclinic
P-1
P-1
cell lengths (Å)
a 5.2823(5)
b 43.495(4)
c 9.5276(6)
α 90
a 9.8898(7)
b 26.9161(19)
c 7.5176(5)
α 90
a 10.5810(15)
b 25.437(4)
c 7.4819(11)
α 90
a 7.4366(4)
b 10.2527(5)
c 13.9827(7)
α 102.2720(10)
β 101.0770(10)
γ 102.5290(10)
984.72(9)
99(2)
a 11.1682(11)
b 7.7306(8)
c 21.808(2)
α 90
a 8.1996(3)
b 11.0966(5)
c 21.8061(9)
α 76.6170(10)
β 80.3790(10)
γ 88.7780(10)
1902.75(14)
99(2)
cell angles (deg)
β 119.975 (4)
γ 90
β 97.2660(10)
γ 90
β 101.720(2)
γ 90
β 101.726(2)
γ 90
cell volume (Å3)
1896.21
1985.1(2)
100(2)
1971.8(5)
99(2)
1843.5(3)
99(2)
temperature (K)
99(2)
final R indices [I > 2σ(I)]
R1 0.0894
wR2 0.1790
R1 0.1088
wR2 0.1853
1.272
R1 0.0476
wR2 0.1044
R1 0.0656
wR2 0.1110
1.076
R1 0.0312
wR2 0.0649
R1 0.0421
wR2 0.0689
1.066
R1 0.0327
wR2 0.0788
R1 0.0420
wR2 0.0835
1.035
R1 0.0258
wR2 0.0654
R1 0.0316
wR2 0.0678
1.027
R1 0.0194
wR2 0.0443
R1 0.0217
wR2 0.0455
1.074
final R indices (all data)
GOF
a
All crystalline compounds were colorless. Z:4 for all samples.
a
Table 3. Measurements from Crystal Structures of 13−16, 20, and 21
X···O(N)
distance (Å)
% summed van der
Waals radii
C−X···O(N)
C−X···O(N)
CO(N)···X
most strained C−CC most strained aryldiyne
angle (deg) angle (deg)
compd
distance (Å)
angle (deg)
angle (deg)
13
14
15
16
20
2.751(8)
2.909(2)
2.882(2)
2.966(1)
2.886(2)
2.856(2)
2.908(2)
82
86
82
91
85
81
82
4.60(1)
171.0(3)
121.4(5)
115.7(2)
120.5(2)
114.84(9)
117.6(1)
119.3(1)
117.1(1)
177.7(8)
174.6(3)
175.8(3)
175.9(2)
174.6(2)
174.7(2)
173.9(2)
121.7(7)
122.3(3)
121.6(3)
121.7(1)
122.6(2)
122.3(2)
122.8(2)
4.792(4)
4.934(4)
4.694(2)
4.749(2)
4.925(2)
174.5(1)
165.17(9)
175.62(6)
171.87(6)
168.96(6)
169.72(6)
b
21
4.983(3)
a
b
Measurement uncertainties are listed in parentheses. There are two unique molecules of 21 in the asymmetric unit; measurements are shown for
both.
was bromine, in fact, the perfect compromise of size and
halogen bonding ability. Single crystals of 15 and 16 provided
evidence that the 1,2-aryldiyne bridge is flexible enough to
accommodate chloro-, bromo-, and iodo-substituents, while
maintaining near perfect co-planarity.
The second question to be answered was whether the
halogen bond acceptor (i.e., electron donor) is interchangeable.
Initial studies with pyridine were promising but provided
crystals that were difficult to interpret via X-ray crystallography.
Fortunately, elaboration of our simple pyridine strategy to
quinoline-based systems provided two samples (20 and 21)
that were suitable for X-ray characterization (see Tables 1 and
2).
Having generated a number of systems capable of intra-
molecular halogen bonding, the third question that arose was
whether the template being used was flexible enough to allow
for “natural” halogen bonding, or were the bond lengths and
angles observed overly constrained by the rigid linker. In order
to answer this question, we investigated the trends observed for
the new systems and compared those to observations and
predictions from prior studies of intermolecular halogen
bonding and our own computational predications.
Trends Observed for Intramolecular Halogen Bond-
ing. Halogen Bond Strength. As discussed above, larger
halogen atoms are expected to form stronger halogen bonds.
This trend cannot necessarily be correlated to bond lengths. A
large halogen with a strong attraction to an acceptor might
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a
Table 4. Computed Structures of 13−16, 20, and 21
X···O(N) distance % summed van der Waals C−X···O(N) distance C−X···O(N) angle
CO(N)···X angle
most strained C−CC angle
compd
(Å)
radii
(Å)
(deg)
(deg)
(deg)
13
14
15
16
20
21
2.86
2.89
2.90
2.89
2.89
2.96
85
86
83
88
85
84
4.72
4.76
4.96
4.61
4.75
5.03
172.1
173.1
166.3
173.6
172.2
168.6
116.9
115.9
118.9
118.2
117.3
115.4
177.0
176.7
176.3
177.7
175.4
174.4
a
Calculated using M06-2X functional and 6-31G* basis set. Small (28-electron) core Dirac−Fock (MDF) effective-core pseudo potential and
corresponding basis set used for iodine.
display a halogen bond length similar to that of a smaller
halogen with a weaker attraction to that acceptor. This is
evident in the first data column of Table 3, with all systems
except 13 displaying a halogen bond distance of roughly 2.9 Å.
A better indicator of halogen bond strength is how the length
of the halogen bond compares to the sum of the van der Waals
radii of the atoms involved. The second data column of Table 3
quantifies this as the percent of the summed van der Waals radii
(N = 1.55 Å, O = 1.52 Å, Cl = 1.75 Å, Br = 1.85 Å, I = 1.98
Å).37 Not surprisingly, the strongest halogen bonds (other than
13) come from iodo-systems 15 and 21, and the weakest come
from chloro-system 16. Interestingly, the perfluorinated-bromo-
quinoline system 20 is more comparable to the trifluoromethyl-
bromo-carbonyl system 14 than the other perfluorinated-
bromo compound 13. This observation is inconsistent with that
fact that the more basic quinoline is expected to be a better
acceptor than a carbonyl. One possible reason for elongation of
halogen bonds in quinoline systems 20 and 21 is steric
interactions between the neighboring fluorine atom of the
haloarene and a nearby hydrogen from the quinoline ring.
Similar secondary interactions of perfluorinated rings have been
invoked in explanations of anomalous intermolecular halogen
bond measurements.33
Halogen Bond Angle (C−X···O(N)). The dimensions of each
triangle likely result from a balance between minimizing angle
strain and maximizing halogen bond attractions. One
mechanism for angle strain relief may be deviation of the C−
X···O(N) angle from the optimal 180°. The degree to which
each halogen accommodates non-ideal angles is based upon the
size of the sigma hole. The largest sigma holes are expected to
be found on the largest halogen atoms and on those halogens
that have the strongest electron-withdrawing groups acting
upon them. Careful inspection of the fourth data column of
Table 3 reveals a clear trend that supports this expectation.
Specifically, in terms of halogen bonds that have the largest
deviations from linearity, the compounds rank iodo-systems >
perfluorinated-bromo-systems > trifluoromethyl-bromo-system
> chloro-system. The fact that this trend opposes predictions
that suggest the magnitude of the directionality of a halogen
bond correlates with the magnitude of the attraction32 may
indicate that this parameter (i.e., C−X···O(N) bond angle) is
dominated by relief of angle strain in our synthetic systems.
A consequence of these deviations from linearity may be
artificially elongated halogen bonds in the iodo-systems. For
example, one peculiarity in the halogen bond strengths noted in
Table 3 is the apparent equivalence in halogen bond strengths
between 13, a bromoarene, and 15, an iodoarene. It is well
established that the strongest halogen bonds form when the
acceptor is oriented 180° from the C−X bond. Halogen bonds
become weaker the more they deviate from this arrangement.
The two iodoarenes systems in this study, 15 and 21, stray the
most from this ideal bond angle. Consequently, the strengths of
these iodoarene halogen bonds are likely weaker, and therefore
longer, than optimal.
Angle around the Carbonyl (CO···X). Another location
where deviations from ideal angles may serve to balance the
negative effects of angle strain with the positive effects of the
halogen bond attraction is the carbonyl oxygen. While it is
difficult to fully understand how much of this measurement is
dictated by alleviation of angle strain, there is an interesting
correlation between the angles recorded in data column 5 of
Table 3 and predicted trends. Halogen bonding is thought to
be a result of a mixture of electrostatic attraction and
dispersion.38,39 The optimal geometry of a halogen bond can
depend on the relative contribution of each of these attractive
forces. Computational results suggest that as the electrostatic
contribution increases so does the bond angle around the
carbonyl, until the highest area of electron density is reached
around 127°.36 Analysis of the first four rows of data column
five in Table 3 reveals angles that are consistent with this trend.
Specifically, the molecules that contain the best electron
acceptors, 13 and 15, display the largest CO···X bond angles
(∼121°). The worst electron acceptors in 14 and 16 yield
much smaller CO···X angles (∼115°).
Flexible Nature of the 1,2-Aryldiyne Bridge. One of the
earliest concerns in the design of this project was the feasibility
of squeezing a C−X···O(N) unit, that we predicted to span
roughly 5 Å, into a “rigid” system that should only
accommodate 4 Å. Literature and past experience suggest
that alkyne linkers are surprisingly flexible. The current study
reflects this, with alkynyl geometries up to 6° away from linear
(data column 6, Table 4). Interestingly, the cumulative effect of
these fairly modest deviations is the ability to accommodate a
wide range of spatial demands. The triangular structures
maintain nearly perfect co-planarity in systems ranging from 4.6
to 5.0 Å (data column 3, Table 4) on the third side of the
triangle. This combination of flexibility and rigidity allows the
aryldiyne bridge to template a wide variety of intramolecular
halogen bonding interactions while minimizing the entropic
cost of bringing donors and acceptors into proximity.
Computed Predictions versus Experimental Results.
Computational models of the target compounds were studied
for two reasons. First, we wanted to find a method and basis set
that were suitable for study of these relatively large halogen
bonding systems. Comparing our calculated and experimental
results would allow an assessment of the chosen computational
method. Second, accompanying calculations might allow us to
take a closer look at each experimental data point to identify
solid-state structural features that may not be consistent with
gas-phase minima.
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The M06-2X functional with a 6-31G* basis set (for atoms
other than iodine) seems to be sufficient for modeling these
systems. Half of the predicted halogen bond lengths (14, 15,
and 20), for instance, are within 0.02 Å of their corresponding
experimental values. The largest deviations from experiment are
with 13 and 16, where the calculations overestimate and
underestimate, respectively, halogen bond lengths by approx-
imately 0.1 Å. In other words, the calculations underestimate
the strength of the halogen bond in the perfluoro-bromo-
carbonyl system, 13, and overestimate the strength of the
halogen bond in the trifluoromethyl-chloro-carbonyl system,
16.
Disagreements between computed and experimental results
are not necessarily an indictment of the computational method.
Measurements from crystal structures may relate to the lowest
energy conformations of the individual molecules, but the
effects of crystal packing cannot be ignored. This is most
apparent in a careful analysis of the torsions between the
alkyne-linked units of each molecule. Computationally, the
conjugated portions of the targeted structures are predicted to
be perfectly planar, with the largest calculated torsion at 0.5°.
Although all structures are nearly planar in the solid state,
torsions around the alkyne-linked units range from 0 to 7°,
which may partly explain the computational overestimation of
some halogen bond strengths.
likely diminish the co-planarity of the carbonyl regions, skewing
the observed geometries away from ideal.
CONCLUSIONS
■
A template for intramolecular halogen bonding has been
developed from 1,2-aryldiynes. The conjugated bridging unit
is rigid enough to negate some of the entropic cost that would
normally be associated with this type of remote intramolecular
attraction. At the same time, the aryldiyne unit is flexible
enough to accommodate a number of different halogen
bonding motifs, while maintaining near perfect planarity. The
versatility of the template provides an opportunity for
dissecting some of the most important parameters for this
attractive force.
Calculations using the M06-2X functional with a 6-31G*
basis set (for atoms other than iodine) provide satisfactory
halogen bonding predictions for these relatively large systems.
The most significant disagreements between the gas-phase
calculations and the experimental, solid-state structures likely
arise from packing anomalies in the crystalline samples.
EXPERIMENTAL SECTION
■
Crystallization. Compounds 13, 15, 16, and 20 were recrystallized
from absolute ethanol. In each case, approximately 4 mg of the target
compound was placed in a screw-cap vial and dissolved, with heating,
in 4 mL of boiling ethanol. The vial was sealed and allowed to cool to
room temperature and left undisturbed for several days. At this stage
the crystals were removed and analyzed. Compound 14 was
recrystallized in the same way from hexane solution. Compound 21
was recrystallized from acetonitrile by first dissolving 5 mg in 100 mL
of refluxing acetonitrile and allowing the resultant solution to stand
undisturbed for several days at which stage crystals suitable for X-ray
analysis had formed.
Slight deviations from planarity are likely due to crystal
packing effects. Packing in the trifluoro-bromo-carbonyl (14)
crystal provides an illustration of this (Figure 6). One stacking
X-ray Structure Determination. For each compound a single
crystal was mounted on a Kryoloop using viscous hydrocarbon oil.
Data was collected using a CCD diffractometer equipped with Mo Kα
radiation with λ = 0.71073 Å. Data collection at low temperature was
facilitated by use of a Kryoflex system with an accuracy of 1 K. Initial
data processing was carried out using the Apex II software suite.40
Structures were solved by direct methods using SHELXS-2013 and
refined against F2 using SHELXL-2013.41 In all structures, hydrogen
atoms were located in the difference maps but were placed in idealized
positions and refined with a riding model. The program X-Seed was
used as a graphical interface during refinement.42
Computational Methods. Gas-phase geometry optimizations of
the halogen-bonded molecules were performed with the Gaussian 09
suite of programs43 using M06-2X.44 The M06-2X functional was
chosen as it has been shown to give good results for halogen-bonded
systems.45 The 6-31G* basis set46 was used for all atoms except iodine,
for which the small (28-electron) core Dirac−Fock (MDF) effective-
core pseudo potential and the corresponding basis sets were used.47
All structures were verified to be local minima through vibrational
frequency analysis.
General Reaction Considerations. All starting materials and
reagents were either commercially available or readily synthesized
following literature procedures. Dry, air-free triethylamine was
acquired via distillation from CaH2 under a nitrogen atmosphere.
Dry, air-free THF was acquired by placing THF from a solvent
purification system (under N2) into a sealed flask containing activated
3 Å sieves. This flask was stored under a positive pressure of N2. All
Sonogashira reactions were performed using sealed, side-arm storage
tubes under an argon atmosphere. TMS-deprotection reactions were
performed with TBAF at −89 °C (liq N2/2-propanol), as these
conditions typically give higher yields, in a shorter period of time, than
standard K2CO3/MeOH deprotection reactions. The targeted
compounds have limited solubility in most solvents but are most
soluble in halohydrocarbon solvents (CH2Cl2 or CHCl3/CDCl3).
Figure 6. (a) View of packing of 14 along the c-axis shows the
antiparallel stacking of 4-methoxybenzoyl groups in neighboring layers.
(b) View of packing of 14 along the b-axis shows the qualitative co-
planarity of each layer with the exception of tetrahedral methoxy and
trifluoromethyl substituents.
feature that is common to most of the carbonyl systems studied
is the canceling of strong dipoles in the 4-methoxybenzoyl
groups. When these groups stack on top of each other, the
methoxy group of one molecule is placed in the proximity of
the carbonyl of a molecule in the neighboring layer (Figure 6a).
Through-space interactions of the methoxy hydrogens of one
layer with ketone groups of the next layer (distance = 2.71 Å)
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Even with these optimal solvents, creating concentrations that allowed
complete 13C NMR characterization was difficult (e.g., 20). In these
cases, 1H NMR, APCI-QTOF, and X-ray data were sufficient to
confirm the identity of the compounds.
and concentrated. This crude residue was loaded onto a flash column
(silica, 50% EtOAc/50% hexane) with a minimal amount of CH2Cl2.
The product was isolated as an orange-red oil (1.99 g, 0.759 mmol,
100% yield). 1H NMR (400 MHz, CDCl3): δ 7.60 (d, J = 8.7 Hz, 2H),
7.50 (m, 2H), 7.29 (m, 2H), 6.91 (d, J = 8.7 Hz, 2H), 5.68 (d, J = 5.4
Hz, 1H), 3.81 (s, 3H), 3.29 (s, 1H), 2.41 (d, J = 6.0 Hz, 1H) ppm. 13C
NMR (100 MHz, CDCl3) δ 159.7, 132.8, 132.6, 132.1, 128.5, 128.4,
128.3, 125.5, 124.8, 113.9, 93.0, 84.9, 82.2, 81.2, 64.8, 55.3 ppm. APCI-
Synthetic Procedures. 1-(4-Methoxyphenyl)prop-2-yn-1-ol (6).
In accord with published procedure,48 7.48 mL (18.7 mmol) n-BuLi
solution (2.5 M in hexane) was added dropwise to a chilled (−89 °C,
liq N2/2-propanol) solution of (trimethylsilyl)acetylene (2.83 mL,
20.0 mmol) in 30 mL THF under an atmosphere of argon. After 40
min at this temperature, 2.0 mL (16.4 mmol) p-anisaldehyde was
added dropwise via syringe. After the mixture warmed to room
temperature for 4 h, water was added to quench the reaction. The
aqueous layer was extracted twice with ethyl acetate. The combined
organic layers were dried with anhydrous Na2SO4, filtered, and
concentrated. Methanol (30 mL) and K2CO3 (until saturation) were
added to this crude residue. After stirring 18 h at room temperature,
methanol was removed under reduced pressure. The crude residue was
purified by flash chromatography (silica, 70% hexane/30% EtOAc) to
−
QTOF (m/z) calcd for C18H13O2 261.0921; found 261.0912.
2-((2-Bromophenyl)ethynyl)quinoline (18). Terminal alkyne 1735
(0.600 g, 3.92 mmol) was added to a storage tube under argon.
Pd(PPh3)4 (0.23 g, 0.20 mmol) and CuI (0.037 g, 0.20 mmol) were
added, followed by 20 mL dry, deoxygenated THF and 5 mL freshly
distilled NEt3. After 1-bromo-2-iodobenzene (0.503 mL, 3.92 mmol)
was added, and the tube was sealed and heated at 50 °C for 1 day.
Upon cooling to room temperature, the mixture was rinsed into a
separatory funnel with CH2Cl2. The organic phase was washed with
NH4Cl solution, dried with anhydrous Na2SO4, filtered, and
concentrated. The product was purified by flash chromatography
(silica, 1% EtOAc/99% toluene) to reveal an orange oil (0.641 g, 2.08
mmol, 53% yield). 1H NMR (400 MHz, CDCl3): δ 8.12 (d, J = 8.5 Hz,
1H), 8.06 (d, J = 8.4 Hz, 1H), 7.69 (m, 3H), 7.60 (m, 2H), 7.49 (m,
1H), 7.27 (td, J = 7.6, 1.2 Hz, 1H), 7.17 (td, J = 7.7, 1.7 Hz, 1H) ppm.
13C NMR (100 MHz, CDCl3) δ 148.1, 143.2, 136.1, 133.8, 132.4,
130.2, 130.0, 129.3, 127.5, 127.2, 127.13, 127.08, 126.0, 124.5, 124.3,
93.5, 88.2 ppm. APCI-QTOF (m/z) calcd for C17H10BrNH+
308.0075/310.0054; found 308.0073/310.0053.
1
yield 2.25 g (13.9 mmol, 84.2% yield) colorless oil. H NMR (400
MHz, CDCl3): δ 7.45 (d, J = 8.7 Hz, 2H), 6.89 (d, J = 8.7 Hz, 2H),
5.39 (s, 1H), 3.79 (s, 3H), 2.65 (d, J = 2.2 Hz, 1H), 2.51 (br s, 1H)
ppm. 13C NMR (100 MHz, CDCl3) δ 159.7, 132.4, 128.1, 114.0, 83.7,
74.6, 64.0, 55.3 ppm. APCI-QTOF (m/z) calcd for C10H10O2H+
163.0754; found 163.0747.
3-(2-Bromophenyl)-1-(4-methoxyphenyl)prop-2-yn-1-ol (7). Ter-
minal alkyne 6 (2.25 g, 13.9 mmol) was dissolved in 20 mL dry THF
and transferred to an air-free storage tube under Ar. Freshly distilled
triethylamine (10 mL) and 2-bromoiodobenzene (1.78 mL, 13.9
mmol) were added separately via syringe. Argon was bubbled through
this mixture for 15 min. CuI (0.132 g, 0.70 mmol) and Pd(PPh3)4
(0.80 g, 0.70 mmol) were added, and the tube was sealed and stirred at
room temperature for 20 h. The mixture was taken up in CH2Cl2. This
organic mixture was washed with NH4Cl solution, dried with
anhydrous Na2SO4, filtered, and concentrated. This crude residue
was purified by flash chromatography (silica, 10% EtOAc/90%
hexane) to yield 4.28 g orange oil (13.5 mmol, 97.1% yield). 1H
NMR (400 MHz, CDCl3): δ 7.58 (m, 3H), 7.48 (dd, J = 7.7, 1.5 Hz,
1H), 7.24 (td, J = 7.7, 1.1 Hz, 1H), 7.16 (td, J = 7.7, 1.7 Hz, 1H), 6.91
(m, 2H), 5.67 (d, J = 6.4 Hz, 1H), 3.80 (s, 3H), 2.53 (d, J = 6.4 Hz,
1H) ppm. 13C NMR (100 MHz, CDCl3) δ 159.7, 133.6, 132.6, 132.4,
129.7, 128.4, 127.0, 125.6, 124.7, 114.0, 93.5, 85.0, 64.8, 55.3 ppm.
2-((2-Ethynylphenyl)ethynyl)quinoline (19). Bromoarene 18
(0.641 g, 2.08 mmol) was dissolved in 20 mL dry THF and
transferred to a storage tube under Ar. Freshly distilled NEt3 (5 mL)
was added, and argon was bubbled through the mixture for 20 min.
Sequentially, Pd(PPh3)4 (0.116 g, 0.10 mmol), CuI (0.019 g, 0.10
mmol), and TMS-acetylene (0.424 mL, 3.0 mmol) were added. The
tube was sealed and heated at 90 °C for 24 h. Upon cooling to room
temperature, the mixture was rinsed into a separatory funnel with
CH2Cl2. The organic phase was washed with NH4Cl solution, dried
with anhydrous Na2SO4, filtered, and concentrated. The crude mixture
was purified via flash chromatography (silica, 1% EtOAc/99% toluene)
to reveal the TMS-protected intermediate as a dark red oil (0.473 g,
1
1.45 mmol, 70% yield). H NMR (400 MHz, CDCl3): δ 8.13 (d, J =
8.4, 1H), 8.12 (d, J = 8.3, 1H), 7.78 (d, J = 8.1 Hz, 1H), 7.72 (m, 1H),
7.65 (m, 2H), 7.53 (m, 2H), 7.31 (m, 2H), 0.29 (s, 9H) ppm. 13C
NMR (100 MHz, CDCl3) δ 148.2, 143.6, 135.9, 132.29, 132.26, 130.0,
129.4, 128.7, 128.2, 127.5, 127.1, 126.3, 124.9, 124.5, 103.2, 99.1, 93.0,
88.6, 0.0 ppm. APCI-QTOF (m/z) calcd for C22H19NSiH+ 326.1360;
found 326.1360. The TMS-protected alkyne (0.473 g, 1.45 mmol) was
dissolved in 30 mL THF and cooled to −89 °C (2-propanol/liq N2).
TBAF (1.45 mL 1 M solution in THF) was added dropwise, and the
mixture was stirred for 1 h. The mixture was rinsed into a separatory
funnel with ethyl acetate. This organic mixture was washed with H2O,
dried with an anhydrous Na2SO4, filtered, and concentrated. The
resulting residue was purified via flash chromatography (10% EtOAc/
90% toluene) to reveal 19 as a brown solid (0.358 g, 1.41 mmol, 97%
yield). 1H NMR (400 MHz, CDCl3): δ 8.12 (d, J = 8.5 Hz, 1H), 8.10
(d, J = 8.5 Hz, 1H), 7.76 (d, J = 8.2 Hz, 1H), 7.70 (m, 2H), 7.62 (d, J
= 8.4 Hz, 1H), 7.53 (m, 2H), 7.33 (m, 2H), 3.44 (s, 1H) ppm. 13C
NMR (100 MHz, CDCl3) δ 148.2, 143.5, 136.0, 132.6, 132.5, 130.0,
129.4, 128.8, 128.6, 127.5, 127.2, 125.3, 125.2, 124.7, 93.1, 88.3, 82.0,
81.7 ppm. APCI-QTOF (m/z) calcd for C19H11NH+ 254.0964; found
254.0968.
3-(2-((2-Bromo-3,4,5,6-tetrafluorophenyl)ethynyl)phenyl)-1-(4-
methoxyphenyl)prop-2-yn-1-one (13). Terminal alkyne 8 (0.214 g,
0.82 mmol) was rinsed into an air-free storage tube under Ar with
freshly distilled NEt3 (20 mL). Sequentially, Pd(PPh3)4 (44 mg, 0.038
mmol), CuI (3.9 mg, 0.020 mmol), and 1,2-dibromo-3,4,5,6-
tetrafluorobenzene (0.412 mL, 3.0 mmol) were added. The tube was
sealed and heated at 80 °C for 4 days. After cooling to room
temperature, the mixture was diluted with EtOAc and washed with
water. The organic phase was separated, dried with Na2SO4, filtered,
and concentrated. The crude residue was dissolved in a minimal
−
APCI-QTOF (m/z) calcd for C16H12BrO2 315.0021/317.0000;
found 315.0015/317.0040.
3-(2-Ethynylphenyl)-1-(4-methoxyphenyl)prop-2-yn-1-ol (8). Bro-
moarene 7 (4.28 g, 13.5 mmol) was dissolved in 10 mL dry THF and
transferred to an oven-dried storage tube under Ar. Another 10 mL
THF was added, followed by 10 mL freshly distilled NEt3. Argon was
bubbled through this mixture for 15 min. Pd(PPh3)4 (0.67 g, 0.58
mmol) and CuI (0.13 g, 0.68 mmol) were added, followed by 2.12 mL
(15.0 mmol) TMS-acetylene. The tube was sealed and heated at 80 °C
for 18 h. After cooling to room temperature, the mixture was rinsed
into a separatory funnel with CH2Cl2. This organic mixture was
washed with NH4Cl solution, dried with anhydrous Na2SO4, filtered,
and concentrated. The crude residue was purified via flash
chromatography (silica, 15% EtOAC/85% hexane) to yield the
TMS-protected intermediate as an orange-red oil (2.54 g, 7.59
1
mmol, 56.2% yield). H NMR (400 MHz, CDCl3): δ 7.58 (d, J = 8.7
Hz, 2H), 7.47 (m, 2H), 7.26 (m, 2H), 6.91 (d, J = 8.7 Hz, 2H), 5.68
(d, J = 6.2 Hz, 1H), 3.81 (s, 3H), 2.28 (d, J = 6.2 Hz, 1H) ppm. 13C
NMR (100 MHz, CDCl3) δ 159.8, 132.9, 132.4, 132.0, 128.4, 128.22,
128.21, 125.7, 125.3, 114.1, 103.4, 98.7, 92.9, 85.2, 64.9, 55.4, 0.05
ppm. APCI-QTOF (m/z) calcd for C21H22O2SiH+ 335.1462; found
335.1468. The TMS-protected intermediate (2.54 g, 7.59 mmol) was
dissolved in 40 mL THF. After cooling the mixture to −89 °C (2-
propanol/liq N2), 7.60 mL of a 1 M TBAF solution (in THF) was
added dropwise via syringe. After 1 h, NH4Cl solution was added to
the cold mixture. After warming to room temperature, the mixture was
rinsed into a separatory funnel with CH2Cl2. After separation of the
layers, the aqueous layer was again extracted with CH2Cl2. The
combined organic layers were dried with anhydrous Na2SO4, filtered,
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Article
amount of CHCl3 and loaded onto a flash column (silica, 20% EtOAc/
calcd for C25H14BrF3O2H+ 483.0208/485.0187; found 483.0215/
485.0197.
80% hexane). Isolation of the appropriate fractions yielded alcohol
1
intermediate 9 as a white solid (0.235 g, 0.48 mmol, 58.6% yield). H
1-(4-Methoxyphenyl)-3-(2-((2,3,4,5-tetrafluoro-6-iodophenyl)-
ethynyl)phenyl)prop-2-yn-1-one (15). Terminal alkyne 8 (0.093 g,
0.35 mmol) was rinsed into an argon-flushed storage tube with freshly
distilled NEt3 (30 mL). 1,2-Diiodotetrafluorobenzene (0.40 g, 1.00
mmol), Pd(PPh3)4 (13.2 mg, 0.011 mmol), and CuI (2.1 mg, 0.011
mmol) were added, and the tube was sealed under argon and heated at
90° for 20 h. After cooling to room temperature, the mixture was
rinsed into a flask with ethyl acetate. This organic mixture was dried
with anhydrous Na2SO4, filtered, and concentrated. The resulting
residue was purified by flash chromatography (silica, 5% EtOAc/95%
toluene) to reveal a white solid (0.11 g) that proved to be a mixture of
desired alcohol 11 and a small amount of reduced material (C−I →
C−H). This mixture was taken on to the oxidation step without
further purification. The impure alcohol was dissolved in 30 mL dry
CH2Cl2 and mixed with Celite (1.3 g) and PCC (0.054 g, 0.25 mmol).
After 24 h of stirring at room temperature, the mixture was filtered
through a pad of Celite. The filtrate was concentrated and purified by
sequential flash chromatography (silica, 1% EtOAc/99% toluene) and
prep TLC (silica, 5% EtOAc/95% toluene). The product was isolated
NMR (400 MHz, CDCl3): δ 7.60 (m, 1H), 7.54 (m, 3H), 7.36 (m,
2H), 6.83 (m, 2H), 5.69 (d, J = 6.2 Hz, 1H), 3.79 (s, 3H), 2.23 (d, J =
6.2 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3) extensive fluorine
coupling makes 13C signals of fluorinated ring impossible to accurately
interpret at achievable concentrations, δ 159.7, 132.7, 132.4, 132.3,
129.3, 128.4, 128.3, 125.3, 124.4, 113.9, 99.6 (coupled), 93.7, 84.5,
82.3 (coupled), 64.9, 55.3 ppm. 19F NMR (376.4 MHz, CDCl3) δ
−128.4 (ddd, J = 22.0, 9.4, 3.4 Hz), −132.0 (ddd, J = 21.1, 9.4, 3.4
Hz), −151.7 (m), −155.5 (m) ppm. APCI-QTOF (m/z) calcd for
C24H13BrF4O2H+ 489.0113/491.0093; found 489.0001/491.0081.
Intermediate alcohol 9 (0.235 g, 0.48 mmol) was dissolved in 40
mL dry CH2Cl2. To this were added 3 Å molecular sieves (0.28 g),
Celite (0.2 g), and PCC (0.140 g, 0.65 mmol). After the mixture was
stirred at room temperature for 24 h, another portion of PCC (0.055
g, 0.26 mmol) was added, and the mixture was stirred for 3 days at
room temperature. The reaction mixture was filtered through a plug of
silica and the filtrate concentrated under reduced pressure. The crude
residue was dissolved in a minimal amount of CH2Cl2 and loaded onto
a flash column (silica, 25% EtOAc/75% hexane). The product was
isolated as an off-white solid (0.147 g, 0.30 mmol, 63% yield).
Additional purification can be achieved via prep TLC (silica, 30%
EtOAc/70% hexane) when necessary. 1H NMR (400 MHz, CDCl3): δ
8.21 (d, J = 8.9 Hz, 2H), 7.72 (m, 2H), 7.48 (m, 2H), 6.87 (d, J = 8.9
Hz, 2H), 3.87 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3) extensive
fluorine coupling makes 13C signals of fluorinated ring and neighboring
alkyne impossible to accurately interpret at achievable concentrations,
δ 176.4, 164.5, 133.6, 132.9, 132.2, 130.3, 130.2, 129.5, 125.30, 123.25,
113.7, 90.5, 89.7, 55.5 ppm. 19F NMR (376.4 MHz, CDCl3) δ −128.1,
(ddd, J = 21.8, 9.5, 1.1 Hz), −131.3 (ddd, J = 20.7, 9.4, 2.8 Hz),
−151.1 (m), −155.4 (m). APCI-QTOF (m/z) calcd for
C24H11BrF4O2H+ 486.9957/488.9936; found 486.9946/488.9930.
3-(2-((2-Bromo-5-(trifluoromethyl)phenyl)ethynyl)phenyl)-1-(4-
methoxyphenyl)prop-2-yn-1-one (14). Terminal alkyne 8 (0.200 g,
0.76 mmol) was dissolved in dry THF (6 mL) and transferred to a
storage tube under argon. 1-Bromo-2-iodo-4-(trifluoromethyl)benzene
(0.267 g, 0.76 mmol) was dissolved in a mixture of dry THF (4 mL)
and freshly distilled NEt3 (5 mL) and transferred to the same storage
tube. Argon was bubbled through this mixture for 15 min. Pd(PPh3)4
(46 mg, 0.040 mmol) and CuI (7.6 mg, 0.040 mmol) were added, and
the tube was sealed and heated at 40 °C for 3 days. After cooling to
room temperature, the mixture was rinsed into a separatory funnel
with CH2Cl2. The organic mixture was washed with NH4Cl solution,
and this aqueous phase was back-extracted with CH2Cl2. The
combined organic layers were dried with anhydrous Na2SO4, filtered,
and concentrated. The crude residue was purified via flash
chromatography (silica, 50% CH2Cl2, 50% hexane increased gradually
to 100% CH2Cl2) to reveal alcohol intermediate 10 as a colorless oil
1
as a white solid (0.054 g, 0.101 mmol, 29% yield over two steps). H
NMR (400 MHz, CDCl3): δ 8.20 (d, J = 8.8 Hz, 2H), 7.73 (m, 2H),
7.49 (m, 2H), 6.86 (d, J = 8.8 Hz, 2H), 3.87 (s, 3H) ppm. 13C NMR
(100 MHz, CDCl3) extensive fluorine coupling makes 13C signals of
fluorinated ring and neighboring alkyne impossible to accurately
interpret at achievable concentrations, δ 176.5, 164.6, 133.8, 133.0,
132.2, 130.3, 130.2, 129.4, 125.4, 123.1, 113.7, 90.5, 90.2, 55.5 ppm.
19F NMR (376.4 MHz, CDCl3) δ −113.5 (ddd, J = 22.9, 11.5, 3.8 Hz),
−129.7 (ddd, J = 20.7, 9.8, 3.8 Hz), −150.7 (m), −154.0 (td, J = 20.3,
3.8 Hz) ppm. APCI-QTOF (m/z) calcd for C24H11F4IO2H+ 534.9818;
found 534.9806.
3-(2-((2-Chloro-5-(trifluoromethyl)phenyl)ethynyl)phenyl)-1-(4-
methoxyphenyl)prop-2-yn-1-one (16). Terminal alkyne 8 (0.093 g,
0.35 mmol) was rinsed into an argon-flushed storage tube with freshly
distilled NEt3 (20 mL). Pd(PPh3)4 (23.1 mg, 0.020 mmol), CuI (3.8
mg, 0.020 mmol), and 1-chloro-2-iodo-4-(trifluoromethyl)benzene
(0.060 mL, 0.38 mmol) were added, and the tube was sealed and
heated at 80 °C for 20 h. After cooling to room temperature, the
mixture was rinsed into a separatory funnel with ethyl acetate. The
organic layer was washed with NH4Cl solution, dried with anhydrous
Na2SO4, filtered, and concentrated. The crude residue was purified via
flash chromatography using a solvent gradient (silica, 10% CHCl3/
90% hexane, increasing gradually to 75% CHCl3/25% hexane),
revealing alcohol intermediate 12 as a light brown oil (0.151 g, 0.34
mmol, 97% yield). 1H NMR (400 MHz, CDCl3): δ 7.79 (s, 1H), 7.58
(m, 1H), 7.55 (d, J = 8.8 Hz, 2H), 7.53 (m, 2H), 7.48 (dd, J = 8.5, 1.6
Hz), 7.33 (m, 2H), 6.79 (d, J = 8.7 Hz, 2H), 5.70 (d, J = 5.8 Hz, 1H),
3.75 (s, 3H), 2.33 (d, J = 6.0 Hz, 1H) ppm. 13C NMR (100 MHz,
CDCl3) δ 159.7, 139.5, 132.7, 132.2, 130.3, 129.9, 129.4, 129.1, 128.9,
128.4, 128.2, 125.8, 125.3, 124.9, 124.1, 124.0 (q, J = 270 Hz), 113.9,
94.7, 93.4, 88.5, 84.8, 64.9, 55.2 ppm. APCI-QTOF (m/z) calcd for
1
(0.261 g, 0.54 mmol, 70.6% yield). H NMR (400 MHz, CDCl3): δ
7.76 (d, J = 1.8 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.59 (m, 1H), 7.53
(m, 3H), 7.38 (dd, J = 8.4, 1.9 Hz, 1H), 7.32 (m, 2H), 6.78 (d, J = 8.7
Hz, 2H), 5.70 (d, J = 6.2 Hz, 1H), 3.74 (s, 3H), 2.43 (d, J = 6.2 Hz,
1H) ppm. 13C NMR (100 MHz, CDCl3) δ 159.7, 133.1, 132.7, 132.31,
132.28, 130.2 (q, J = 3.7 Hz), 130.0, 129.7, 129.3, 128.8, 128.4, 128.3,
126.3, 125.8 (q, J = 3.7 Hz), 125.2, 124.9, 123.4 (q, J = 271 Hz), 94.0,
93.4, 90.3, 84.9, 64.9, 55.2 ppm. APCI-QTOF (m/z) calcd for
C25H15BrF3O2− 483.0208/485.0187; found 483.0199/485.0225. Inter-
mediate alcohol 10 (0.198 g, 0.407 mmol) and PCC (0.088 g, 0.41
mmol) were dissolved in 30 mL CH2Cl2. After 22 h at room
temperature, the solvent was removed under reduced pressure. The
remaining residue was purified via flash chromatography (silica, 100%
CH2Cl2) to reveal the product as a white solid (0.168 g, 0.347 mmol,
−
C25H15ClF3O2 439.0713; found 439.0708. Intermediate alcohol 12
(0.151 g, 0.34 mmol) was dissolved in 20 mL dry CH2Cl2. Celite (0.75
g), 3 Å sieves (1.0 g), and PCC (86 mg, 0.40 mmol) were added, and
the mixture was stirred for 1 day at room temperature. The entire
reaction mixture was loaded onto a silica gel column, and the
components were separated by gradually increasing the mobile phase
from 50% hexane/50% CHCl3 to 100% CHCl3. The product was
1
isolated as a white solid (0.111 g, 0.25 mmol, 74% yield). H NMR
(400 MHz, CDCl3): δ 8.24 (d, J = 8.9 Hz, 2H), 7.82 (d, J = 1.6 Hz,
1H), 7.77 (dd, J = 7.6, 1.2 Hz, 1H), 7.67 (dd, J = 7.7, 1.0 Hz, 1H), 7.55
(d, J = 8.5 Hz, 1H), 7.51 (dd, J = 7.0, 2.0 Hz, 1H), 7.47 (td, J = 7.6, 1.6
Hz, 1H), 7.43 (td, J = 7.6, 1.6 Hz, 1H), 6.75 (d, J = 8.9 Hz, 2H), 3.79
(s, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 176.4, 164.5, 140.0,
133.6, 132.6, 132.1, 130.3 (q, J = 3.8 Hz), 130.28, 130.24, 130.0, 129.3
(q, J = 33.4 Hz), 129.1, 126.2 (q, J = 3.6 Hz), 126.1, 123.7, 123.3 (q, J
= 271 Hz), 123.2, 113.7, 94.1, 90.5, 89.9, 89.5, 55.4 ppm. APCI-QTOF
(m/z) calcd for C25H14ClF3O2H+ 439.0713; found 439.0704.
1
85.2% yield). H NMR (400 MHz, CDCl3): δ 8.24 (d, J = 8.9 Hz,
2H), 7.79 (d, J = 1.9 Hz, 1H), 7.74 (m, 2H), 7.68 (d, J = 7.5 Hz, 1H),
7.45 (m, 3H), 6.75 (d, J = 8.9 Hz, 2H), 3.79 (s, 3H) ppm. 13C NMR
(100 MHz, CDCl3) δ 176.5, 164.5, 133.7, 133.2, 132.6, 132.1, 130.3,
130.1, 129.8, 129.1, 126.16, 126.13, 126.0, 123.3 (q, J = 271 Hz),
123.2, 113.8, 93.4, 91.3, 90.5, 90.0, 55.4 ppm. APCI-QTOF (m/z)
6276
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2-((2-((2-Bromo-3,4,5,6-tetrafluorophenyl)ethynyl)phenyl)-
ethynyl)quinoline (20). Terminal alkyne 19 (0.666 g, 2.63 mmol) was
dissolved in dry THF (20 mL) and transferred to a storage tube under
argon. After 5 mL NEt3 was added, argon was bubbled through the
mixture for 15 min. 1,2-Dibromotetrafluorobenzene (0.413 mL, 3.0
mmol), Pd(PPh3)4 (0.152 g, 0.13 mmol), and CuI (25 mg, 0.13
mmol) were added. The tube was sealed under argon and heated at 60
°C for 4 days. An off-white precipitate formed. After the mixture was
cooled in an ice bath, this precipitate was isolated via suction filtration
and rinsed with water, then hexane. Two crops of off-white solid were
REFERENCES
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1
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(400 MHz, CDCl3), very low solubility in NMR solvent: δ 8.16 (d, J =
8.6 Hz, 1H), 8.14 (d, J = 8.6 Hz, 1H), 7.83 (d, J = 8.2 Hz, 1H), 7.76
(m, 2H), 7.69 (m, 1H), 7.65 (d, J = 8.3 Hz, 1H), 7.58 (m, 1H), 7.43
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2-((2-((2,3,4,5-Tetrafluoro-6-iodophenyl)ethynyl)phenyl)ethynyl)-
quinoline (21). Terminal alkyne 19 (75 mg, 0.30 mmol) was rinsed
into an air-free storage tube under argon with NEt3 (20 mL). 1,2-
Diiodotetrafluorobenzene (0.40 g, 1.00 mmol), Pd(PPh3)4 (10.4 mg,
0.009 mmol), and CuI (1.7 mg, 0.009 mmol) were added, and the tube
was sealed under argon and heated at 80 °C for 22 h. After cooling to
room temperature, NH4Cl solution was added to the reaction tube.
The contents were rinsed into a separatory funnel with CHCl3. The
layers were separated, and the organic layer was dried with anhydrous
Na2SO4, filtered, and concentrated. Purification of this material via
flash chromatography (silica, 100% CHCl3) yielded the product as a
1
white solid (74.4 mg, 0.14 mmol, 47% yield). H NMR (400 MHz,
CDCl3), very low solubility in NMR solvent: δ 8.16 (d, J = 8.5 Hz,
1H), 8.13 (d, J = 8.6 Hz, 1H), 7.82 (d, J = 8.1 Hz, 1H), 7.76 (m, 2H),
7.70 (m, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.58 (m, 1H), 7.43 (m, 2H)
ppm. 13C NMR (100 MHz, CDCl3) extensive fluorine coupling makes
13C signals of fluorinated ring and neighboring alkyne impossible to
accurately interpret at achievable concentrations, δ 148.0, 143.4, 136.3,
133.5, 133.1, 130.3, 129.4, 129.2, 129.0, 127.6, 127.4, 127.2, 125.1,
124.8, 124.7, 93.5, 89.5 ppm. 19F NMR (376.4 MHz, CDCl3) δ −114.6
(ddd, J = 23.2, 10.2, 3.5 Hz), −130.9 (ddd, J = 20.6, 10.5, 3.9 Hz),
−151.5 (m), −154.8 (td, J = 19.9, 3.4 Hz) ppm. APCI-QTOF (m/z)
calcd for C25H10F4INH+ 527.9872; found 527.9875.
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ASSOCIATED CONTENT
■
S
* Supporting Information
X-ray data in CIF format and H/13C spectra for 6−16 and
1
18−21; Cartesian coordinates for calculated structures; and
ellipsoid representations of X-ray data. This material is available
free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*E-mail: nbowling@uwsp.edu.
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Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
The authors gratefully acknowledge that this material is based
upon work supported by the National Science Foundation
under grant CHE-1306284. The authors also acknowledge that
NMR characterization was based upon work supported by the
National Science Foundation under grant CHE-0957080.
HRMS characterization was based upon work supported by
the National Science Foundation under CBET-0958711. The
Missouri State University Provost Incentive Fund funded the
purchase of the X-ray diffractometer. Computational resources
were provided by the Midwest Undergraduate Computational
Chemistry Consortium (MU3C) through NSF-MRI CHE-
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