Aromatic triazole foldamers induced by C-H...X (X = F, Cl) intramolecular hydrogen bonding

Article abstract of DOI:10.1021/jo500582c

Aryl-triazole oligomers based on isobutyl 4-fluorobenzoate and isobutyl 4-chlorobenzoate were designed and synthesized. Crystal structure and ¹H-¹H NOESY experiments demonstrate that the oligomers adopt stable helical conformation, which are induced by C⁵-H...X-C (X = F, Cl) intramolecular hydrogen bonding between triazole protons and halogen atoms. The stabilities of the folded conformations are confirmed by DFT calculations, which show that each C⁵-H...F-C planar interaction lowers the energy by ～3 kcal mol^-1 on average, and by ～1 kcal mol^-1 when C⁵-H...Cl-C bridges are formed. The hydrogen-bonding networks are disrupted in competitive hydrogen-bonding media such as DMSO, generating the unfolded oligomers.

Full text of DOI:10.1021/jo500582c

Article
pubs.acs.org/joc
Aromatic Triazole Foldamers Induced by C−H···X (X = F, Cl)
Intramolecular Hydrogen Bonding
Jie Shang,†,∥ Nolan M. Gallagher,§ Fusheng Bie,†,∥ Qiaolian Li,†,∥ Yanke Che,† Ying Wang,*,†,§
and Hua Jiang*,†,‡
†Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Photochemistry, Institute of Chemistry, Chinese
Academy of Sciences, Beijing 100190, China
‡College of Chemistry, Beijing Normal University, Beijing 100875, China
§Department of Chemistry, University of Nebraska, Lincoln, Nebraska 68588-0304, United States
∥University of Chinese Academy of Sciences, Beijing 100049, China
S
* Supporting Information
ABSTRACT: Aryl-triazole oligomers based on isobutyl 4-
fluorobenzoate and isobutyl 4-chlorobenzoate were designed
and synthesized. Crystal structure and 1H−1H NOESY
experiments demonstrate that the oligomers adopt stable
helical conformation, which are induced by C5−H···X−C (X =
F, Cl) intramolecular hydrogen bonding between triazole
protons and halogen atoms. The stabilities of the folded
conformations are confirmed by DFT calculations, which show
that each C5−H···F−C planar interaction lowers the energy by
∼3 kcal mol−1 on average, and by ∼1 kcal mol−1 when C5−
H···Cl−C bridges are formed. The hydrogen-bonding net-
works are disrupted in competitive hydrogen-bonding media
such as DMSO, generating the unfolded oligomers.
mide-based foldamers.13 Our previous works also demonstrated
that fluorine (or chlorine)-substituted oligo(quinoline-amide)s
INTRODUCTION
■
Hydrogen bonding has been widely used in the development of
are able to fold into single, double or quanta-helixes driven by
synthetic oligomers which adopt helical conformations, so-
the C−F(or Cl)···H−N hydrogen bonding between the
called foldamers, to mimic their natural counterparts such as
fluorines (or chlorines) and adjacent amide protons.14,15
proteins.1 Initial studies focused mainly on traditional strong
However, to date there have been no reports on foldamers
hydrogen bonds such as O−H···O, O−H···N, and N−H···O,
etc.,2 and the properties of foldamers utilizing these types of
hydrogen bonding is becoming increasingly understood. On the
contrary, the construction of foldamers based on weaker
hydrogen bridges, whose interaction energies are less than 16
kcal mol−1,3 is less studied. While fluoride and chloride ions are
well-known as very strong hydrogen-bond acceptors,4 cova-
lently bound halogen atoms, in contrast, were considered to
hardly ever form hydrogen bonds.5 In recent years, with
increasing importance of organic halogens in medicinal
chemistry and chemical biology,6 the properties of noncovalent
halogen interactions have become better understood,7,8 and the
fast progress achieved in this area indicates that the weak
interactions such as C−F···H−N (or O) or C−Cl···H−N (or
O) can play a crucial role in protein−ligand interaction,9
reactional stereoselectivity,10 and supramolecular assembly.11 In
particular, these types of hydrogen bonds have been used in the
construction of foldamers, in which halogen−hydrogen
bonding is the only driving force for folding.12 For example,
Li and co-workers reported that intramolecular C−F···H−N
hydrogen bonds can be utilized to construct 2-fluorobenza-
induced by C−F(or Cl)···H−C bridges, which is probably due
to the fact that, in most cases, this kind of bonding is too weak
to constrain the main strands of the oligomers.
It is well-known that the strength of a hydrogen bond will
increase as the hydrogen atom becomes more electron-
deficient. Accordingly, to improve the bonding strength of
C−F(or Cl)···H−C, polarization of the H−C bond via
substitution on the carbon with very strong electron-with-
drawing groups, such as F16 and CN,17 is often necessary. In
this aspect, the 1,2,3-triazole moiety is one of the recent
examples that has shown capability to serve as an excellent
hydrogen bond donor due to its high dipole moment (4.55 D
in comparison with 1.45−1.70 and 0.92−1.53 D for traditional
donors O−H and N−H, respectively) attributed to three sp2
hybridized nitrogen atoms. We and other groups previously
reported several types of halide-ion-controlled oligo(aryl-1,2,3-
triazole)s foldamers, in which the folding was driven by the
Received: March 25, 2014
Published: May 13, 2014
© 2014 American Chemical Society
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Scheme 1. Structure of Oligomers 1−4, Number of C5−H···F (or Cl) Bonds in Each Oligomer As Well As the Energy Gap
(ΔEF−L) between their Folded and Linear (completely unfolded) States Determined Computationally by Density Functional
Theory (DFT)
a
Scheme 2. Synthesis of Fluorine-Substituted Aryl-Triazole Oligomers 1−2
a
Reagents and conditions: a) KNO3/H2SO4; b) Fe, AcOH; c) HCl, NaNO2; NaN3; d) oxalyl chloride; i-BuOH, N-ethyldiisopropylamine; e) H2SO4
(90%), CrO3, I2; f) CuI, Pd(PPh3)4, (iPr)2NH, trimethylsilylacetylene; g) KF·2H2O; h) fuming HNO3, fuming H2SO4; (i) TFA, tert-butyl nitrite;
NaN3; j) CuSO4, L-sodium ascorbate; k) CuSO4, L-sodium ascorbate, tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine.
C5−H···X (X = F−, Cl− or Br−) bonding.18,19 More recently,
Hecht and Li found that the 1,2,3-triazole−fluorine H-bonding
interaction, C5−H···F−C, can induce rotational constraints of
short aryl-triazole backbones.20 The systems in the solid state
have been observed to possess a nearly planar geometry and
H···F distances of 2.3−2.9 Å, dependent on the side of fluorine
located (i.e., on the side of C4 or N1 of the triazole). If the
triazole has a fluorine acceptor interacting from both sides, the
hydrogen-bonding interaction was averaged, providing an
identical H···F distance of 2.45 Å.20b These findings provide
a hope to utilize this type of binding motif to develop new types
of foldamers. However, when one considers the increased steric
interactions and the other possible intrachain interactions such
as electrostatic or dipole repulsion originating from the
fluorines and triazoles present in the folded conformation of
oligomers incorporating multiple motifs, the folding of such
oligomers may not be thermodynamically favorable. Indeed, the
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foldability of longer oligomers incorporating halogen aryl-
triazole units until now has not been established yet.
In this contribution, we report the synthesis of the aromatic
triazole oligomers 1−4 (Scheme 1) based on isobutyl-4-
fluorobenzoate or isobutyl-4-chlorobenzoate and the character-
ization of their folded conformations. Also, to theoretically
confirm the foldability of the oligomers 1−4, their global
minimum energy conformations, as well as the energy levels for
various unfolded conformations were calculated using density
functional theory (DFT).
distance between the triazole protons and the neighboring
fluorine atoms is 2.3−2.4 Å (Table 1), indicating a nearly
Table 1. Parameters of the Crystal Structures of 1 and 4 As
Well As the Energy-Minimized Structures of 1−4 Calculated
a
at the DFT RB3LYP/6-31G(d,p) Level
RESULTS AND DISCUSSION
■
Synthesis. Synthetic routes for compounds 1 and 2 are
outlined in Scheme 2. Starting from 4-fluorobenzoic acid,
aromatic nitration with a mixture of potassium nitrate and
sulfuric acid or fuming nitric acid and fuming sulfuric acid
provided mono and dinitro-compound 5 and 13, respectively.
Reduction of 5 with iron powder gave 6. Diazotization of 6 in
the presence of NaN3 provided 7, which was further converted
to the acid chloride by oxalyl chloride with DMF as a catalyst
and then reacted with iBuOH to generate monoazido-benzoic
ester 8. To prepare diazido-benzoic ester, compound 13 was at
first converted to the acid chloride with oxalyl chloride and
DMF then esterified to give 14. Although the same condition
was used for this reaction as that for preparation of 8, it was
observed that compound 13 was easier to convert to the
corresponding acid chloride in comparison with the case of 7,
which was probably due to the enhancement of electrophilicity
of the carbonyl group attributed to two nitro groups in
comparison with that for 7. Compound 14 was very easy to
hydrolyze so that the crude compound was directly reduced by
iron powder to generate 15. Due to the limited solubility of 15
and the instability of the diazo salt in water, diazotization of 15
using trifluoroacetic acid and tert-butyl nitrite in tetrahydrofur-
an, followed by dediazotization with the help of sodium azide,
provides diazido-benzoic ester 16. On the other hand,
iodination of 4-fluorobenzoic acid using iodine and chromium-
(VI) oxide in the acidic anhydrous medium gave 9, which was
further esterified to yield 10. Sonogashira coupling of 10 with
trimethylsilylacetylene, followed by removal of the TMS group
under basic condition, provides 12. Thus, through the “Click”
coupling of 8 and 16 with 12, respectively, aryl-triazole
oligomers 1 and 2 were prepared.
a
The angle and distance discussed in this table are illustrated in Figure
b
2. The dihedral angles between triazole and the adjacent benzene ring
in the strand listed in sequence. The range of H···X (X = F or Cl)
distances. The average H···X (X = F or Cl) distances. The bond
angles of the C5−H···X (X = F or Cl) hydrogen bonds listed in
sequence.
c
d
e
planar, folded conformation with a strong intramolecular C5−
H···F−C hydrogen-bonding network. The DFT optimization
also gives rise to a crescent structure of oligomer 1 (Figure 1,
right), with the predicted peripheral torsion angles a little bit
larger than the ones in the crystal structure (Table 1). Although
crystal structure geometry may not always represent the true
ground-state conformations for a monodisperse molecule due
to intermolecular interactions and solvation effects, the
optimized geometries still bear a close resemblance to the
single-crystal geometry in this case.
Figure 2. Model for elaboration the structural parameters.
1
The H NMR spectrum of 1 in CDCl3 showed one set of
Fluorine-substituted oligo(aryl-triazole)s foldamers.
The crystal structure of 1 (Figure 1, left) obtained by slowly
evaporating the solvent of mixture of dichloromethane and
ethanol showed a crescent coplanar arrangement of the whole
aryl-triazoles main strand. The dihedral angles between the
adjacent triazole and benzene ring are all less than 17°, and the
sharp signals with chemical shifts independent of the
concentration in the range of 0.3−10 mM, indicative of no
aggregation taking place (Figure S2, Supporting Information
[SI]). The signal of triazole protons Hb splits into a triplet
(Figure 3) with the coupling constant of 3.0 Hz. The splitting
of the Hb proton is due to the coupling from two neighboring
fluorine atoms, in agreement with the observation from Li, et al.
on the fluorine substituted 1,4-diaryl-1,2,3-triazoles.20 Since the
5JHF coupling, in most cases in nonstrained compounds, has a
1
magnitude of less than 0.5 Hz which is usually resolved in H
NMR spectrum, the remarkable coupling in this case should be
produced through the intramolecular triazole-proton-centered
hydrogen-bonding framework, C5−H···(F−C)2. This kind of
“through-space” coupling was also confirmed by the disappear-
ance of its triplet pattern upon dissolving into DMSO-d6
(Figure S1, SI). This disappearance was due to competition
with the better hydrogen-bond donor DMSO, leading to
collapse of the intramolecular hydrogen-bonding network of
Figure 1. Crystal structures of compound 1 (left) as well as its energy-
minimized geometry calculated at the DFT RB3LYP 6-31 G(d,p) level
(right) within the Gaussian 09 software package.21
1
the foldamer. In the H−1H NOESY spectrum of 1 in CDCl3,
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which showed triplets for both Hb and He with JHF = 2.8 and
3.0 Hz, respectively (Figure 3). The spin−spin coupling
constant of Hb is slightly smaller than that of He, which is
probably due to the fact that the central fluorine is more
sterically hindered because of the folding of 2, resulting in more
steric deshielding of the central fluorine.22 This affects the
coupling to the relative triazole protons. In the corresponding
2D NOESY spectrum of 2, the cross-peaks between the triazole
protons and the o-phenyl protons are completely absent
(Figure 4, left), providing additional evidence for the helical
conformation of 2. Unfortunately, compound 2 is not soluble in
1
DMSO. In 1:2 (v/v) CDCl3/DMSO-d6, the H NMR spectra
of 2 showed no splitting for the signals of triazoles protons Hb
and He due to the disruption of the hydrogen-bonding network
by DMSO (Figure 5). Furthermore, under such conditions, a
Figure 3. Partial 1H NMR spectra (400 MHz, 298 K) of oligomers 1−
4 in CDCl3. The inset plots on the top correspond to the signals of
triazoles on 1 and 2. [1] = [2] = [3] = [4] = 2 mM.
the correlation between the triazole proton and the adjacent o-
phenyl proton (Hb and Ha) was not observed (Figure S4, SI),
suggesting the dynamic rotation of the molecules through two
carbon−nitrogen linkages between the benzene rings and the
triazole were restricted by the intramolecular C5−H···F−C
bonding. The stability of the folded conformation of 1 is
supported by DFT results, which predicts oligomer 1 to possess
a folded conformation that is about ∼12 kcal mol−1 lower in
energy than the unfolded one (Figure S14, SI).
Figure 5. Partial 1H NMR spectra (400 MHz, 298 K) of compound 2
in CDCl3 (bottom) and CDCl3/DMSO-d6 = 1:2 (v/v) (top) at
ambient temperature. The inset plot in the middle corresponds to the
signals of triazoles on 2. [2] = 2 mM.
strong NOE correlation of Hb−Ha and comparatively weaker
correlations of Hb−Hc, He−Hd and He−Hf could be observed
(Figure 4, right), suggesting that oligomer 2 did not possess
folded conformation in DMSO. These observations once again
demonstrate that, in CDCl3, the folding of the oligomers was
driven by intramolecular C5−H···F−C bonding.
Since DFT describes the single-crystal geometries of 1
reasonably well, we then applied DFT to explore the ground-
state geometry of 2, for which a single crystal could not be
The folded conformation of 2 in CDCl3 was first confirmed
by 1H NMR spectroscopic analysis. Upon dilution from 14 mM
1
to 0.4 mM, the chemical shifts of triazole protons in the H
NMR spectra of 2 in CDCl3 displayed no significant changes
(Figure S3, SI), indicating that the intermolecular interactions
were weak in this range of concentration. In addition, the
splitting pattern of triazole protons could clearly be observed
Figure 4. Partial 1H−1H NOESY spectra (500 MHz, 298 K) of oligomer 2 (A) in CDCl3 ([2] = 14 mM) and (B) in 1:2 (v/v) CDCl3/DMSO-d6
([2] = 2 mM).
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obtained. The energy-minimized geometry as well as its
parameters of oligomer 2 are shown in Figure 6 and Table 1,
multiple unfolded minima which possess four C5−H···F
interactions, and lies ∼26 kcal mol−1 lower than that of the
completely unfolded one (Figure S14, SI). This is markedly
different from the system of oligo(phenyl triazole)s without
fluorines in which the energy level of the folded conformation
is +2.3 kcal mol−1 higher than the linear one (by MM2),23
illustrating the important role of fluorine hydrogen bonding in
stabilizing the folding of 2. Since the stability of the folded
conformation for a specified foldamer is determined by the
energy gap between its folded and unfolded states, the gap in
this case suggests that oligomer 2 has a strong preference to
exist in a helical conformation. We also examined two different
conformational minima of 2 which possess only four C5−H···F
interactions, one in which the edges are unfolded (anti−syn−
syn−anti20a,24), and another in which the core is unfolded (syn−
anti−anti−syn) (Figure S14, SI). The results show that these
conformations are nearly degenerate, with the former being
only 1.5 kcal mol−1 lower in energy, which is probably due to
the greater alleviation of steric strain in unfolding the edges or
increased conjugation in the case of anti−syn−syn−anti
conformer. Our DFT results suggest that each C5−H···F−C
planar interaction lowers the energy by ∼3 kcal mol−1 on
average, which was obtained by dividing ΔEF−L by the number
of C5−H···F (or Cl) bonds (Figure 1 and Figure S14 in the SI).
This is consistent with the gap between the folded and
completely unfolded conformation of 1 (12.1 kcal mol−1, four
C5−H···F interactions), but less than the predicted energy
difference between the syn and anti conformations of the model
motif, (o-fluorophenyl) triazole20a (6.4 kcal mol−1 or 4.7 kcal
mol−1, depending on whether the phenyl is connected at the N1
or C4 of the triazole). The diminished gap in our case could
arise from the increased electrostatic repulsion of the additional
fluorine units as well as the bigger steric hindrance from the
longer oligomer strand, which slightly destabilizes the folded
conformations. However, the positive value of ΔEF−L indicates
Figure 6. Overhead (left) and side view (right) of lowest-energy
geometry of 2 (DFT RB3LYP 6-31 G (d,p)). Methyl groups were
substituted for long alky chains for computational efficiency.
respectively. The geometry is a global minimum (confirmed by
vibrational analysis as well as comparison with other unfolded
minima) in which the core region (i.e., the central fragment
containng a phenyl ring and two triazole units) maintains a
folded, nearly planar geometry. Closer to the termini of the
oligomer, one strand maintains a more planar geometry with
the dihedral angles between the adjacent rings of 6−24° while
the other is significantly more twisted (dihedral angles between
15−41°) to accommodate sterics (Figure 6, right; Table 1).
The C5−H···F−C hydrogen bond lengths range between 2.3
and 2.5 Å, consistent with the presence of a hydrogen-bonding
network.
Oligomer 2 exhibits a continual increase in energy as the
degree of unfolding increases. The energy level of the ground-
state conformation, which possesses eight C5−H···F inter-
actions is 11−13 kcal mol−1 lower in energy than that of the
a
Scheme 3. Synthesis of Chlorine-Substituted Aryl-Triazole Oligomers 3, 4
a
Reagents and conditions: a) H2SO4 (90%), CrO3, I2; b) oxalyl chloride, i-BuOH, N-ethyldiisopropylamine; c) CuI, Pd(PPh3)4, (i-Pr)2NH,
trimethylsilylacetylene; d) KF·2H2O; e) KNO3/H2SO4; f) Fe, AcOH; g) HCl, NaNO2; NaN3; h) N-ethyldiisopropylamine, t-BuCOCl; (i) Pd/C,
H2; j) CuSO4, L-sodium ascorbate.
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Figure 7. Partial 1H−1H NOESY spectra of oligomer 4 in (A) CDCl3 (600 MHz, 298 K; [4] = 8 mM) and (B) DMSO-d6 (500 MHz, 298 K; [4] = 4
mM).
that, in these oligomeric systems, the total effect of energetic
interactions which are favorable to folding, such as intra-
molecular C5−H···F−C bonding and dipole−dipole interac-
tions between the triazole and adjacent fluoro-benzene units,
outweigh those which are unfavorable to folding, such as the
electrostatic repulsion between fluorine lone pairs as well as
steric interactions of the folded oligomer strand.
substituted aryl-triazole oligomers. After having obtained the
compounds, we then performed 1H NMR and NOESY
experiments on oligomers 3 and 4. As expected, in the H
1
NMR spectra of 3 and 4 in CDCl3, the signal of triazoles are
singlets (Figure 3), which does not provide any information on
the H-bonding between the chlorines and the triazole protons.
However, in the corresponding NOESY spectra, no cross-peaks
between the triazole protons Hb and their neighboring aromatic
protons Ha and Hc could be observed for both 3 and 4 (Figure
7A and Figure S9 in the SI), which is the same as that in the
cases of fluorine-substituted oligomers, indicating 3 and 4 adopt
helical conformations in CDCl3. To illustrate the driving force
of the folding, 1H−1H NOESY experiment was performed on 4
in DMSO-d6, which shows that clear NOE cross-peaks of Ha−
Hb and Hb−He can be observed (Figure 7B), providing a proof
that the folding of oligo(aryl-triazole)s in CDCl3 is driven by
C5−H···Cl−C hydrogen bonding.
Although various methods for growing single crystal of 3
were failed, the single crystal of 4 was successfully obtained by
diffusion of n-heptane into the solution of 4 in dichlomethane.
The solid structure of 4 shows a helical conformation, where
the five rings are slightly twisted and tilted up and down in an
alternating sequence which provides slightly diminished
planarity compared to that of 1 (Figure 8). The difference in
geometry is probably due to the larger size of chlorine atoms
and longer C−Cl bond length, which increases electrostatic
repulsion for a planar geometry, as well as the weaker hydrogen
bonds formed with chlorine. The DFT geometry of 3 and 4 in
the lowest energy conformation show similar arrangement of
the main strands (Figure 8, Table 1 and Figure S14 in the SI).
In addition, oligomers 3 and 4 exhibit lower energy gaps
between their folded and unfolded conformations (about 5.5
and 4.8 kcal mol−1, respectively). From these DFT results, we
estimate that each C5−H···Cl interaction lowers the energy by
only ∼1 kcal mol−1 on average, in contrast to the C5−H···F
interaction which lowers the energy by ∼3 kcal mol−1. This
result indicates that chlorine-substituted oligo(aryl-triazole)s
foldamers are comparatively less stable due to the weaker C5−
H···Cl−C bridge. The DFT calculation predicted the distance
between the triazole protons and the neighboring chlorine
Because DFT predicted each C5−H···F−C planar interaction
to lower the energy by ∼3 kcal mol, to attempt to see unfolded
conformations we employed variable-temperature 1H NMR for
oligomers 1 and 2 in 1,1,2,2-tetrachloroethane-d2, a solvent that
has polarity similar to that of CDCl3 but with a higher boiling
point. (Figures S15, S16 in the SI). Besides a diminution of
signal intensity at higher temperatures, which was expected due
to lowered occupation of the lowest Zeeman energy level, the
signal of triazole protons for 1 and 2 do not show considerable
changes (Δδ = 0.04 and 0.03 ppm for triazole proton Hb in 1
and 2, respectively). Since the energy required to break one
hydrogen bond is on average only ∼3 kcal mol−1, there should
be only a little temperature dependence of the equilibrium
between folded and unfolded conformations (by the Van’t Hoff
equation), i.e., the relative concentrations of folded/unfolded
conformations are not drastically altered as temperature
increases. On the other hand, the cores of the oligomers likely
possess a higher barrier to rotation due to steric interactions,
and consequently conformations of the oligomers that involve
unfolding of the core may not be accessible even at higher
temperatures, providing a possible explanation of why the peaks
do not shift much as the temperature increases.
Chlorine-Substituted Oligo(aryl-triazole)s Foldamers.
To address the folding of oligo(aryl-triazole)s directed by C5−
H···Cl−C hydrogen bonds in solution, chlorine-substituted
aryl-triazole oligomers 3 and 4 were obtained by approaches
similar to that for compound 1 (Scheme 3). The structure of
oligomer 4 is very similar to that of structure 3, except the nitro
groups of 3 are substituted with N-tert-butylamide groups.
Since the localized dipoles of the nitro groups of 3 might affect
the crystal packing due to strong intermolecular interactions,
the substitution of N-tert-butylamides was designed to provide
us a better chance to obtain the crystal structure of chlorine-
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was stirred at ambient temperature overnight. To the mixture was
added crushed ice (500 g) with constant stirring. It took 2 h to melt all
the ice at room teperature, the mixture was filtered by a vacuum. The
solid was washed with cold water, then dried under vacuum at 50 °C
to yield product 5 (4.94 g, 67%) as a light -yellow solid, Rf = 0.3
(DCM/MeOH = 20/4). Mp = 125−127 °C (lit.,25b 119−120 °C); 1H
NMR (CD3COCD3, 400 MHz, 298 K), δ = 8.70 (dd, J = 2.0, 7.2 Hz,
1H), 8.44−8.40 (m, 1H), 7.67 (dd, J = 8.8, 10.8 Hz, 1H); 13C NMR
(CD3COCD3, 100 MHz, 298 K), δ = 165.0, 160.1, 157.4, 137.84,
137.74, 128.68, 128.64, 128.46, 128.44, 120.01, 119.79; HRMS (ESI-
FT-ICR) m/z: [M − H]− calcd for C7H3FNO4 184.0041; found
184.0046.
3-Amino-4-fluorobenzoic Acid (6). To compound 5 (2.10 g,
11.3 mmol) in the mixture of glacial acetic acid (40 mL) and methanol
(40 mL), was added iron powder (2.54 g, 45.3 mmol) at 60 °C, and
the mixture was heated to reflux for 4 h. When cooled down to
ambient temperature, the mixture was poured into water and extracted
with ethyl acetate (30 mL × 5). The combined organic layers were
washed with brine (150 mL × 4), dried over Na2SO4, and filtered.
Solvents were rotary evaporated from the filtrate, and the residue was
dried under vacuum to give 6 (1.61 g, 91%) as a pale solid which was
used without further purification, Rf = 0.5 (DCM/MeOH = 20/4). Mp
= 188−190 °C (lit.,26 182−183 °C); 1H NMR (CD3SOCD3, 400
MHz, 298 K), δ = 12.66 (s, 1H), 7.40 (dd, J = 2.0, 9.2 Hz, 1H), 7.13−
7.09 (m, 1H), 7.05 (dd, J = 8.4, 10.8 Hz, 1H), 5.36 (s, 2H); 13C NMR
(CD3OD, 100 MHz, 298 K), δ = 169.6, 157.0, 154.5, 137.13, 137.0,
128.2, 120.85, 120.77, 119.46, 119.40, 115.88, 115.69. HRMS (ESI-
FT-ICR) m/z: [M − H]− calcd for C7H5FNO2 154.0304; found
154.0300.
Figure 8. Crystal structure of compound 4 (left) as well as its energy-
minimized geometry calculated at the DFT RB3LYP 6-31 G(d,p) level
(right).
atoms to be 2.7−2.9 Å for oligomer 3, and very similar lengths
were predicted for 4 (2.4−3.0 Å) (Table 1). Because the DFT-
optimized geometry of 4 closely resembles the single crystal
geometry, these results suggest that hydrogen bonding between
the amide and chlorine of 4 does not significantly affect the
C5−H···Cl bonds; thus 4 provides another analogue to
chlorine-substituted aryl-triazole oligomers.
1
Variable-temperature H NMR experiment was also applied
to oligomer 4 (Figure S17 in SI). Similar to fluoro-substituted
triazole oligomers 1−2, peaks representing triazole protons of
chloro-substituted oligomer 4 display no appreciable changes
up to 328 K, again indicating a little temperature dependence of
the equilibrium due to the relatively low gaps between
unfolded/folded conformations and possible barrier to rotation.
3-Azido-4-fluorobenzoic Acid (7). Compound 6 (1.55 g, 10.0
mmol) was dissolved in HCl (18%, 100 mL), and the solution was
allowed to cool to 0 °C with ice/salt bath. The solution of NaNO2
(1.04 g, 15.0 mmol) in H2O (5 mL) was added slowly. After stirring at
0−5 °C for 30 min, a solution of sodium azide (1.95 g, 30.0 mmol) in
H2O (10 mL) was added slowly. The mixture was stirred at room
temperature for another 2 h and then was extracted with ethyl acetate
(30 mL × 3). The combined organic layers were washed with brine
(100 mL × 2), dried over Na2SO4, and filtered. The solvents were
removed, and the residue was dried under vacuum to yield 7 (1.77 g,
97%) as a white solid which was used without further purification, Rf =
0.6 (DCM/MeOH = 20/4). Mp = 158−160 °C, (lit.,27 156−167 °C);
IR (KBr): 3432 (OH), 3071, 2964, 2656, 2531, 2132 (N3), 1707 (C
O), 1609, 1587, 1507, 1434, 1330, 1289, 1255, 1232, 1145, 1122,
1086, 1010, 916, 847, 764, 699, 628, 566, 512 cm−1; 1H NMR
(CD3SOCD3, 400 MHz, 298 K), δ = 13.31 (s, 1H), 7.78−7.72 (m,
2H), 7.44 (dd, J1 = 8.4 Hz, 10.8 Hz, 1H); 13C NMR (CD3COCD3,
100 MHz, 298 K), δ = 166.0, 159.4, 156.9, 129.29, 129.18, 128.89,
128.70, 128.61, 123.49, 123.47, 117.84, 117.64; HRMS (ESI-FT-ICR)
m/z: [M − H]− calcd for C7H3FN3O2 180.0209; found 180.0204.
Isobutyl 3-Azido-4-fluorobenzoate (8). To compound 7 (1.60
g, 8.84 mmol) suspended in DCM (30 mL, dry) under argon were
added oxalyl dichloride (1.70 mL, 20.0 mmol) and DMF (0.1 mL).
After stirring at room temperature for 4 h, the solvent and surplus
oxalyl dichloride were removed under vacuum to yield acid chloride.
The acid chloride was dried by vacuum for 2 h. To a solution of
isobutanol (0.92 mL, 10.0 mmol) in DCM (40 mL) containing N-
ethyldiisopropylamine (1.7 mL, 10.0 mmol), was added the solution of
acide chloride in DCM (40 mL) at 0 °C under Ar. The reaction was
warmed up to room temperature and stirred overnight. The solvents
were evaporated, and the product was purified by flash chromatog-
raphy (SiO2, DCM/PE: gradient 1/20 to 1/2) to provide 8 (1.02 g,
49%) as a brown oil, Rf = 0.5 (DCM/PE = 1/2). IR (KBr): 2965,
2877, 2123 (N3), 1724 (CO), 1604, 1506, 1469, 1420, 1376, 1310,
1274, 1143, 1109, 1087, 989, 947, 894, 834, 808, 762, 707, 652, 629,
CONCLUSIONS
■
In summary, we have shown that fluorine- and chlorine-
substituted oligo(phenyl-triazole)s can fold into helical
conformation which is directed by the intramolecular C5−
H···F−C or C5−H···Cl−C hydrogen-bonding bridges. DFT
calculations show that there are large energy gaps between their
folded and unfolded states, which determine their strong, well-
defined, conformational preferences. These results give a
broader insight into the roles of hydrogen bonding between
covalently bound halogen atoms and hydrogen attached to
carbon in the construction of biomolecules by nature.
EXPERIMENTAL SECTION
■
All starting materials and common solvents were commercially
available and used without further purification unless otherwise
noted. Anhydrous tetrahydrofuran (THF) was dried from sodium/
benzophenone and then distilled under inert atmosphere. Diisopropyl-
amine (iso-Pr2NH) and DCM were distilled over CaH2 under argon.
Routine NMR spectra were recorded with spectrometers at 400, 500,
or 600 MHz (1H NMR). Chemical shifts are reported in δ values
relative to the solvent (1H δ (CHCl3) = 7.26 ppm, δ (CH3SOCH3) =
2.50 ppm, δ (CH3COCH3) = 2.05 ppm, δ (CH3OH) = 3.31 ppm, δ
(CH3CN) = 1.94 ppm, 13C δ (CHCl3) = 77.16 ppm, δ (CH3SOCH3)
= 39.52 ppm, δ (CH3COCH3) = 29.84, 206.26 ppm, δ (CH3OH) =
49.00 ppm) peak. Exact mass spectra (EI, ESI, MALDI) were acquired
on GCT, FT-ICR spectrometer. IR spectra were recorded on FT-IR
spectrometer with thin KBr disk.
1
528 cm−1; H NMR (CDCl3, 400 MHz, 298 K), δ = 7.82−7.77 (m,
3-Nitro-4-fluorobenzoic Acid (5). It was prepared according to a
similar procedure described in the literature.25a To a solution of 4-
fluorobenzoic acid (5.6 g, 40.0 mmol) in concentrated H2SO4 (50 mL)
in an ice bath was added potassium nitrate (4.4 g, 44.0 mmol) in
portions within 30 min. The ice bath was removed and the mixture
2H), 7.15 (dd, J = 8.4, 10.4 Hz, 1H), 4.1 (d, J = 6.8 Hz, 2H), 2.09−
2.04 (m, 1H), 1.02 (d, J = 6.8 Hz, 6H); 13C NMR (CDCl3, 100 MHz,
298 K), δ = 165.04, 158.9, 156.4, 128.61, 128.50, 127.87, 127.83,
127.57, 127.49, 122.73, 122.71, 116.96, 116.76, 71.6, 28.0, 19.3;
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Article
HRMS (ESI-FT-ICR) m/z: [M + Na]+ calcd for C11H12FN3O2Na
260.0811; found 260.0812.
the temperature was kept below 25 °C during the process. Then the
solution was heated to 95 °C (reflux condenser attached). After 3 h,
the mixture was cooled to room temperature and poured into ice/
water, filtered by a vacuum, washed with cool water, and dried by
vacuum at 50 °C to yield 13 (11.95 g, 81%) as a white solid, Rf = 0.2
3,5-Diiodo-4-fluorobenzoic Acid (9). According to literature,28a
to finely powdered iodine (5.08 g, 20.0 mmol) suspended in H2SO4
(90%, 100 mL V/V) was added CrO3 (2.0 g, 20.0 mmol). The mixture
was stirred at about 30 °C for 30 min. To the solution was added 4-
fluorobenzoic acid (2.10 g, 15.0 mmol). The mixture was stirred at
25−30 °C for 24 h and then poured into ice/water and filtered by a
vacuum. The solid was washed with cool water and then dried by
vacuum at 50 °C to give crude 9 (3.65 g, 62%) as a white solid which
was used without further purification, Rf = 0.3 (DCM/MeOH = 20/3).
Mp = 264−266 °C (lit.28b 235−237 °C); 1H NMR (CD3SOCD3, 400
MHz, 298 K), δ = 13.47 (s, 1H), 8.27 (d, J = 5.6 Hz, 2H); 13C NMR
(CD3SOCD3, 100 MHz, 298 K), δ = 164.08, 163.83, 161.4, 140.35,
140.32, 130.31, 130.27, 82.33, 82.03; MS (ESI) m/z: [M − H]− calcd
for C7H2FI2O2 390.8; found 390.8.
(DCM/MeOH = 20/4). Mp 246−248 °C (lit.,29 238−240 °C); H
1
NMR (CD3CN, 400 MHz, 298 K), δ = 8.84 (d, J = 6.0 Hz, 2H); 13C
NMR (CD3COCD3, 100 MHz, 298 K), δ = 163.6, 154.2, 151.4, 140.1,
132.4, 128.23, 128.19; MS (ESI) m/z: [M − H]− calcd for
C7H2FN2O6 229.0; found 229.0.
Isobutyl 3,5-Diamino-4-fluorobenzoate (15). Compound 13
(2.30 g 10.0 mmol) was suspended in DCM (30 mL, dry) under Ar,
and oxalyl dichloride (1.70 mL, 20.0 mmol) and DMF (0.1 mL) were
added. The mixture was stirred for 2 h, at room temperatue. The
solvent and surplus oxalyl dichloride were removed under reduced
pressure to yield the acid chloride, which was dried under vacuum for
an additional 2 h. To a solution of isobutanol (0.92 mL, 10.0 mmol) in
DCM (20 mL) containing N-ethyldiisopropylamine (1.72 mL, 10.0
mmol) was added the solution of acide chloride in DCM (20 mL) at 0
°C under Ar. The mixture was stirred overnight. When the reaction
solution was exposed to air, the brown solution became dark brown
slowly. Solvents were removed under reduced pressure to give crude
product isobutyl 3,5-dinitro-4-fluorobenzoate (14). It is unstable and
was used for the next step at once without purification. Compound 14
was dissolved in glacial acetic acid (80 mL), and the solution was
heated. After the temperature rose to 90 °C, iron powder (5.6 g, 100.0
mmol) was added, and the mixture was heated to reflux for 5 h. When
the mixture was cooled to room temperature, it was filtered. The
filtrate was poured into water and extracted with ethyl acetate (30 mL
× 5). The combined organic fractions were washed with brine (100
mL × 5), dried over Na2SO4, and filtered. Solvents were removed
under reduced pressure, and the product was purified by flash
chromatography (SiO2, gradient DCM/PE to DCM/ethyl acetate =
gradient 1/1 to 10/1) to yield 15 (1.40 g, 61%) as a brown solid, Rf =
Isobutyl 3,5-Diiodo-4-fluorobenzoate (10). Compound 10 was
obtained by a procedure similar to that for compound 8 starting with
compound 9. Yield 89%, white solid, Rf = 0.6 (DCM/PE = 1/2). Mp =
1
61−63 °C; H NMR (CDCl3, 400 MHz, 298 K), δ = 8.38 (d, J = 5.6
Hz, 2H), 4.1 (d, J = 6.8 Hz, 2H), 2.13−2.03 (m, 1H), 1.01 (d, J = 6.8
Hz, 6H); 13C NMR (CDCl3, 100 MHz, 298 K), δ = 164.3, 163.1,
161.8, 141.13, 141.12, 129.71, 129.67, 80.47, 80.18, 71.9, 27.9, 19.3;
HRMS (EI-TOF) m/z: [M] calcd for C11H11FI2O2 447.8832; found
447.8837.
Isobutyl 3,5-Ditrimethylsilylethynyl-4-fluorobenzoate (11).
Compound 10 (6.0 g, 13.4 mmol), Pd(PPh3)4 (0.15 g, 0.13 mmol),
and CuI (52 mg, 0.27 mmol) were dissolved in dry THF (100 mL)
under Ar. To the solution were added diisopropylamine (10 mL) and
trimethylsilylacetylene (4.20 mL, 32.16 mmol). The mixture was
stirred at 55 °C overnight. It was filtered, the solvent was removed
under reduced pressure, and the residue was redissolved in DCM (100
mL). The solution was washed with saturated NH4Cl (50 mL × 2)
and brine (100 mL). The organic layer was dried over Na2SO4 and
concentrated under reduced pressure. The crude product was purified
by flash chromatography (SiO2, DCM/PE: gradient 1/20 to 1/2) to
provide 11 (4.57 g, 88%) as a slightly yellow solid, Rf = 0.5 (DCM/PE
= 1/2). Mp = 76−77 °C; IR (KBr): 3075, 2962, 2902, 2162 (CC),
1725 (CO), 1597, 1457, 1415, 1396, 1379, 1346, 1327, 1249, 1223,
1
0.2 (DCM/PE = 10/1). Mp = 72−73 °C; H NMR (CDCl3, 400
MHz, 298 K), δ = 6.91 (d, J = 8.0 Hz, 2H), 4.04 (d, J = 6.8 Hz, 2H),
3.75 (s, 4H), 2.09−1.99 (m, 1H), 1.0 (d, J = 6.4 Hz, 6H); 13C NMR
(CDCl3, 100 MHz, 298 K), δ = 166.5, 144.9, 142.5, 134.73, 134.62,
126.57, 126.54, 108.29, 108.26, 71.0, 27.9, 19.2; HRMS (ESI-FT-ICR)
m/z: [M + H]+ calcd for C11H16FN2O2 227.1196; found 227.1191.
Isobutyl 3,5-Diazido-4-fluorobenzoate (16). Compound 15
(0.45 g, 2.0 mmol) was dissolved in dry THF (30 mL) under Ar and
the solution was cooled to 0 °C with an ice/water bath. To the
solution were added tert-butyl nitrite (0.47 mL, 4.0 mmol) and TFA (4
mL). The mixture was stirred for 0.5 h at 0 °C. A solution of sodium
azide (0.52 g, 8.0 mmol) in H2O (6 mL) was added slowly. The
mixture was stirred at room temperature for 2 h and poured into
water. The crude product was extracted with DCM (20 mL × 3). The
combined organic layers were washed by brine (100 mL), dried over
Na2SO4, filtered, and concentrated in vacuo. The residue was purified
by flash chromatography (SiO2, DCM/PE: gradient 1/20 to 2/10) to
yield 16 (0.4 g, 72%) as a brown oil, Rf = 0.6 (DCM/PE = 2/1). IR
(KBr): 3058, 2966, 2877, 2125 (N3), 1726 (CO), 1611, 1499, 1469,
1427, 1397, 1378, 1357, 1272, 1150, 1100, 994, 948, 886, 800, 764,
679, 654 cm−1; 1H NMR (CDCl3, 400 MHz, 298 K), δ = 7.54 (d, J =
6.8 Hz, 2H), 4.12 (d, J = 6.4 Hz, 2H), 2.12−2.05 (m, 1H), 1.01(d, J =
6.8 Hz, 6H); 13C NMR (CDCl3, 100 MHz, 298 K), δ = 164.2, 150.7,
148.1, 129.94, 129.84, 127.67, 127.63, 118.0, 71.8, 27.9, 19.1; HRMS
(ESI-FT-ICR) m/z: [M + Na]+ calcd for C11H11FN6O2Na 301.0825;
found 301.0824.
1
1102, 1042, 1009, 994, 945, 909, 846, 764, 747, 704, 651 cm−1; H
NMR (CDCl3, 400 MHz, 298 K), δ = 8.05 (d, J = 6.4 Hz, 2H), 4.1 (d,
J = 6.8 Hz, 2H), 2.12−2.05 (m, 1H), 1.02 (d, J = 6.8 Hz, 6H), 0.26 (s,
18H); 13C NMR (CDCl3, 100 MHz, 298 K), δ = 167.2, 164.6, 135.1,
126.61, 126.57, 112.82, 112.65, 102.2, 96.2, 71.69, 28.0, 19.3, −0.1;
HRMS (ESI-FT-ICR) m/z: [M + H]+ calcd for C21H30FO2Si2
389.1768; found 389.1770.
Isobutyl 3,5-Diethynyl-4-fluorobenzoate (12). To compound
11 (4.50 g, 11.60 mmol) which was dissolved in THF (40 mL) and
methanol (40 mL) was added KF·2H2O (5.45 g, 58.0 mmol). It was
monitored by TLC, and after stirring at room temperature for 4 h, the
reaction mixture was concentrated under reduced presure. To the
residue was added water (100 mL), and the product was extracted with
DCM (50 mL × 3). The combined organic layers were dried over
Na2SO4 and concentrated under reduced pressure. Purification by flash
chromatography (SiO2, DCM/PE: gradient 1/20 to 1/1) to provide
12 (2.65 g, 93%) as a slightly brown solid, Rf = 0.4 (DCM/PE = 1/2).
Mp = 62−64 °C; IR (KBr): 3286 (C−H), 3075, 2959, 2909, 2874,
2119 (CC), 1890, 1819, 1723 (CO), 1684, 1606, 1587, 1459,
1415, 1378, 1344, 1321, 1322, 1298, 1248, 1208, 1168, 1103, 996, 952,
1
911, 891, 842 797, 766, 717, 702, 680, 651, 635 cm−1; H NMR
(CDCl3, 400 MHz, 298 K), δ = 8.14 (d, J = 6.0 Hz, 2H), 4.1 (d, J = 6.8
Hz, 2H), 3.37 (s, 2H), 2.13−2.03 (m, 1H), 1.02 (d, 6.8 Hz, 6H); 13C
NMR (CDCl3, 100 MHz, 298 K), δ = 167.7, 165.0, 164.3, 135.8,
126.92, 126.88, 111.87, 111.71, 84.22, 84.19, 75.4, 71.8, 28.0, 19.3;
HRMS (EI-TOF) m/z: [M] calcd for C15H13FO2 244.0900; found
244.0903.
3,5-Dinitro-4-fluorobenzoic Acid (13). It was prepared accord-
ing to the literature.29 4-Fluorobenzoic acid (9.0 g, 64.28 mmol) was
added to oleum (28% SO3, 60 mL) with stirring. To the solution was
added 90% nitric acid (60 mL) dropwise, using an addition funnel, and
Trimer 17. Compound 16 (0.22 g, 0.79 mmol) and compound 12
(2.0 g, 8.20 mmol) were dissolved in a mixture of toluene (20 mL) and
tert-butanol (20 mL) and then were degassed with argon. After 30 min,
to the solution were added in sequence CuSO4 (40.01 mg, 0.25 mmol)
dissolved in water (2 mL) and sodium ascorbate (99.32 mg, 0.50
mmol) dissolved in water (2 mL). The mixture was stirred for 2 days
at 90 °C with protection from light. The solvents were removed under
reduced pressure, and the residue was redissolved in DCM, washed
with saturated NH4Cl (50 mL) and brine (50 mL), respectively, and
then dried over Na2SO4. Solvents were removed under reduced
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Article
pressure, and the crude product was purified by flash chromatography
(SiO2, gradient DCM/PE to DCM/ethyl acetate = gradient 1/10 to
10/1) to yield 17 (0.33 g, 55%) as a pale solid, Rf = 0.4 (DCM/ethyl
acetate = 30/1). Mp = 117−119 °C; IR (KBr): 3263 (C−H), 3087,
2964, 2883, 2117 (CC), 1724 (CO), 1616, 1552, 1477, 1407,
1378, 1280, 1240, 1179, 1104, 1032, 989, 915, 819, 765, 694 cm−1; 1H
NMR (CDCl3, 400 MHz, 298 K), δ = 9.07 (dd, J = 2.4, 6.8 Hz, 2H),
8.81 (d, J = 6.8 Hz, 2H), 8.6 (t, J = 2.8 Hz, 2H), 8.22 (dd, J = 2.4 Hz,
6.8 Hz, 4H), 4.21 (d, J = 6.8 Hz, 2H), 4.16 (d, J = 6.8 Hz, 4H), 3.41 (s,
2H), 2,18−2.11 (m, 3H), 1.05 (d, J = 6.8 Hz, 18H); 13C NMR
(CDCl3, 100 MHz, 298 K), δ = 164.8, 163.5, 163.4, 160.9, 149.0,
146.4, 141.1, 135.4, 130.14, 130.09, 129.24, 129.20, 127.73, 127.70,
126.83, 126.73, 126.47, 124.20, 124.12, 124.07, 123.99, 118.64, 118.50,
112.11, 111.94, 84.13, 84.10, 75.8, 72.6, 71.8, 28.02, 27.98, 19.36,
19.30; HRMS (MALDI-FT-ICR) m/z: [M + H]+ calcd for
C41H38F3N6O6 767.2805; found 767.2772.
with compound 22. Yield 98%, yellow solid, Rf = 0.5 (DCM/PE = 1/
2). Mp = 95−96 °C; IR (KBr): 3083, 2969, 1721 (CO), 1611,
1546, 1469, 1359, 1307, 1188, 1136, 1065, 984, 933, 781, 752, 718
cm-1; H NMR (CDCl3, 400 MHz, 298 K), δ = 8.58 (s, 2H), 4.20 (d, J
= 6.8 Hz, 2H), 2.17−2.07 (m, 1H), 1.02 (d, J = 6.8 Hz, 6H); 13C
NMR (CDCl3, 100 MHz, 298 K), δ = 162.0, 149.8, 131.4, 128.21,
128.05, 124.7, 73.0, 27.9, 19.2.
Isobutyl 5-Nitro-3-amino-4-chlorobenzoate (24). To a
mixture of glacial acetic acid (30 mL) and methanol (30 mL) was
added compound 23 (4.0 g, 13.24 mmol). After the mixture was
heated to 70 °C, reduced iron powder (2.22 g, 39.73 mmol) was added
in six times. The reaction was monitored by TLC. When the starting
material vanished, the mixture was cooled to room temperature and
filtered. The filtrate was poured into water and extracted with ethyl
acetate (30 mL × 5). The combined organic fractions were washed
with brine (100 mL × 5), dried over Na2SO4, and filtered. Solvents
were removed under reduced pressure, and the residue was dried by
vacuum to give crude 24 (2.44 g, 67%) as a brown-black solid, which
was used without further purification. Pure 24 was recrystallized from
3,5-Diiodo-4-chlorobenzoic Acid (18). Compound 18 was
obtained by a similar procedure to compound 9 starting with 4-
chlorobenzoic acid. Yield 76%, white solid. It was used without further
purification, Rf = 0.2 (DCM/MeOH = 20/3). Mp > 300 °C (lit.,28a
1
DCM and PE, Rf = 0.5 (DCM/PE = 20/3). Mp = 88−89 °C; H
1
288−290 °C); H NMR (CD3SOCD3, 400 MHz, 298 K), δ = 13.59
NMR (CDCl3, 400 MHz, 298 K), δ = 7.79 (d, J = 1.6 Hz, 1H,), 7.6 (d,
J = 1.6 Hz, 1H), 4.56 (s, 2H), 4.11 (d, J = 6.8 Hz, 2H), 2.11−2.05 (m,
1H), 1.01 (d, J = 6.8 Hz, 6H); 13C NMR (CDCl3, 100 MHz, 298 K), δ
= 164.4, 149.2, 145.3, 130.1, 118.7, 114.57, 114.51, 72.0, 27.9, 19.2;
HRMS (ESI-FT-ICR) m/z: [M + H]+ calcd for C11H14ClN2O4
273.0642; found 273.0639.
(s, 1H), 8.35 (s, 2H); 13C NMR (CD3SOCD3, 100 MHz, 298 K), δ =
164.1, 145.1, 140.3, 131.8, 98.4; HRMS (ESI-FT-ICR) m/z: [M −
H]− calcd for C7H2ClI2O2 406.7833; found 406.7825.
Isobutyl 3,5-Diiodo-4-chlorobenzoate (19). Compound 19 was
obtained by a procedure similar to that for compound 8, starting with
compound 18. Yield 84%, yellow solid, Rf = 0.5 (DCM/PE = 2/5). Mp
= 131−132 °C; 1H NMR (CDCl3, 400 MHz, 298 K), δ = 8.46 (s, 2H),
4.1 (d, J = 6.8 Hz, 2H), 2.11−2.04 (m, 1H), 1.01 (d, J = 6.8 Hz, 6H);
13C NMR (CDCl3, 100 MHz, 298 K), δ = 163.2, 146.6, 141.1, 131.1,
96.5, 72.0, 27.9, 19.3; HRMS (ESI-FT-ICR) m/z: [M + Na]+ calcd for
C11H11ClI2O2Na 486.8435; found 486.8430.
Isobutyl 3,5-Ditrimethylsilylethynyl-4-chlorobenzoate (20).
Compound 20 was obtained by a procedure similar to that for
compound 11, starting with compound 19. Yield 76%, slightly yellow
solid, Rf = 0.6 (DCM/PE = 1/2). Mp = 74−76 °C; IR (KBr): 2962,
2900, 2159 (CC), 1723 (CO), 1637, 1568, 1544, 1468, 1403,
1378, 1344, 1321, 1248, 1229, 1124, 1063, 1002, 949, 907, 846, 764,
726, 702, 651 cm−1; 1H NMR (CDCl3, 400 MHz, 298 K), δ = 8.06 (s,
2H), 4.10 (d, J = 6.4 Hz, 2H), 2.13−2.03 (m, 1H), 1.01 (d, J = 6.8 Hz,
6H), 0.28 (s, 18H); 13C NMR (CDCl3, 100 MHz, 298 K), δ = 164.8,
142.5, 133.9, 128.8, 124.2, 102.0, 100.3, 71.7, 28.0, 19.3, −0.1; HRMS
(ESI-FT-ICR) m/z: [M + H]+ calcd for C21H30ClO2Si2 405.1473;
found 405.1474.
Isobutyl 5-Nitro-3-azido-4-chlorobenzoate (25). Compound
25 was obtained by a procedure to similar to that for compound 7,
starting with compound 24. Yield 90%, white solid, Rf = 0.6 (DCM/
PE = 1/2). Mp = 83−84 °C; IR (KBr): 3078, 2982, 2963, 2936, 2895,
2878, 2139 (N3), 2100, 1827, 1721 (CO), 1682, 1658, 1594, 1576,
1548, 1467, 1400, 1375, 1319, 1275, 1212, 1170, 1137, 1108, 1063,
1
992, 933, 918, 826, 890, 790, 768, 722, 704 cm−1; H NMR (CDCl3,
400 MHz, 298 K), δ = 8.15 (d, J = 1.6 Hz, 1H), 8.02(d, J = 1.6 Hz,
1H), 4.17 (d, J = 6.8 Hz, 2H), 2.17−2.07 (m, 1H), 1.02 (d, J = 6.8 Hz,
6H); 13C NMR (CDCl3, 100 MHz, 298 K): δ = 163.3, 149.9, 140.8,
130.7, 122.66, 122.20, 121.26, 72.5, 27.9, 19.2; HRMS (ESI-FT-ICR)
m/z: [M + Na]+ calcd for C11H11ClN4O4Na 321.0367; found
321.0363.
Isobutyl 5-Nitro-3-(tertbutylcarbonyl)amino-4-chloroben-
zoate (26). To a solution of compound 24 (0.59 g, 2.17 mmol)
and N-ethyldiisopropylamine (0.41 mL, 2.39 mmol) in dry DCM (20
mL) under N2 was added pivaloyl chloride (0.29 mL, 2.38 mmol)
dropwise at 0 °C. The mixture was stirred overnight at room
temperature. Solvent was removed under reduced pressure, and the
residue was purified by flash chromatography (SiO2, DCM/PE =
gradient 1/20 to 1/1) to provide 26 (0.73 g, 95%) of yellow solid, Rf =
Isobutyl 3,5-Diethynyl-4-chlorobenzoate (21). Compound 21
was obtained by a procedure similar to that for compound 12, starting
with compound 20. Yield 93%, slightly brown solid, Rf = 0.4 (DCM/
PE = 1/2). Mp = 76−77 °C; IR (KBr): 3291, 3253 (C−H), 3072,
2963, 2932, 2891, 2876, 2110 (CC), 1821, 1713 (CO), 1574,
1544, 1469, 1399, 1377, 1340, 1314, 1261, 1231, 1129, 1105, 1061,
1
0.6 (DCM/PE = 10/1). Mp = 99−100 °C;. H NMR (CDCl3 400
MHz, 298 K): δ = 9.3 (d, J = 1.6 Hz, 1H), 8.2 (d, J = 1.6 Hz, 2H), 4.15
(d, J = 6.8 Hz, 2H), 2.15−2.08 (m, 1H), 1.38 (s, 9H), 1.02 (d, J = 6.8
Hz, 6H); 13C NMR (CDCl3 100 MHz, 298 K): δ = 176.9, 163.9,
148.4, 137.2, 130.8, 125.1, 120.4, 119.4, 72.2, 40.6, 27.93, 27.58, 19.2.
HRMS (ESI-FT-ICR) m/z: [M + H]+ calcd for C16H22ClN2O5
357.1217; found 357.1211.
1
994, 946, 910, 804, 766, 704, 676, 644, 613 cm−1; H NMR (CDCl3,
400 MHz, 298 K), δ = 8.15 (s, 2H), 4.11 (d, J = 6.8 Hz, 2H), 3.45 (s,
2H), 2.12−2.05 (m, 1H), 1.02 (d, J = 6.8 Hz, 6H); 13C NMR (CDCl3,
100 MHz, 298 K), δ = 164.5, 142.7, 134.7, 129.1, 123.4, 84.0, 79.2,
71.8, 27.9, 19.3; HRMS (ESI-FT-ICR) m/z: [M + H]+ calcd for
C15H14ClO2 261.0682; found 261.0676.
Isobutyl 5-Amino-3-(tert-butylcarbonyl)amino-4-chloroben-
zoate (27). To the solution of 26 (1.0 g, 2.81 mmol) in ethyl acetate
(50 mL) was added Pd/C (0.1 g, 10%). The mixture was stirred
overnight in hydrogen atmosphere at room temperature. It was filtered
through Celite. The solvent was removed under reduced pressure and
the residue was dried to yield 27 (0.90 g, 98%) as a yellow solid, Rf =
0.3 (DCM/ethyl acetate =30/1). Mp = 123−125 °C; 1H NMR
(CDCl3 400 MHz, 298 K): δ = 8.43 (d, J = 1.6 Hz, 1H), 7.94 (s, 1H),
7.24 (d, J = 1.6 Hz, 1H), 4.16(s, 2H), 4.08 (d, J = 6.8 Hz, 2H), 2.11−
2.05 (m, 1H), 1.36 (s, 9H), 1.01 (d, J = 6.8 Hz, 6H); 13C NMR
(CDCl3 100 MHz, 298 K): δ = 176.6, 166.2, 143.1, 135.4, 130.2,
113.0, 112.05, 112.01, 71.4, 40.4, 28.0, 27.74, 19.4; HRMS (ESI-FT-
ICR) m/z: [M + H]+ calcd for C16H24ClN2O3 327.1475; found
327.1468.
3,5-Dinitro-4-chlorobenzoic Acid (22). According to the
literature30a 4-chlorobenzoic acid (5.0 g, 32.05 mmol) was dissolved
in concentrated H2SO4 (50 mL). To the solution was added KNO3
(8.1 g, 80.2 mmol) in batches, and the temperature was kept below 40
°C during the process. The mixture was heated to 140 °C and stirred
for 5 h (reflux condenser attached). It was cooled to room temperature
and poured into ice/water, filtered, washed with cool water, and dried
by vacuum to yield 22 (7.2 g, 91%) as a white solid, Rf = 0.5 (DCM/
MeOH = 20/5). Mp = 165−167 °C (lit.,30b 161−163 °C); H NMR
1
(CD3SOCD3, 400 MHz, 298 K), δ = 14.27 (b, 1H), 8.77 (s, 2H); 13
C
NMR (CD3COCD3, 100 MHz, 298 K), δ = 163.6, 150.5, 132.8, 129.4,
124.3.
Isobutyl 3,5-Dinitro-4-chlorobenzoate (23). Compound 23
was obtained by a procedure similar to that for compound 8, starting
Isobutyl 5Azido-3-(tert-butylcarbonyl)amino-4-chloroben-
zoate (28). Compound 28 was obtained by a procedure similar to
5142
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The Journal of Organic Chemistry
Article
that for compound 7, starting with compound 27. Yield 95%, white
solid, Rf = 0.3 (DCM/PE = 2/1). Mp = 143−145 °C; IR (KBr): 3118,
2969, 2874, 2118 (N3), 1713 (CO), 1673, 1589, 1536, 1469, 1430,
1399, 1381, 1350, 1302, 1266, 1244, 1195, 1161, 1123, 1050, 1002,
gradient 1/1 to 10/1) to yield 3 (136.2 mg, 79%) as a white solid, Rf =
0.4 (DCM/ethyl acetate = 30/1). Mp = 192−194 °C; 1H NMR
(CDCl3, 400 MHz, 298 K), δ = 8.94 (s, 2H), 8.67 (s, 2H), 8.62 (d, J =
1.2 Hz, 2H), 8.58 (d, J = 1.2 Hz, 2H), 4.22−4.20 (m, 6H), 2.22−2.11
(m, 3H), 1.07 (d, J = 4.4 Hz, 6H), 1.06 (d, J = 4.4 Hz, 12H); 13C
NMR (CDCl3, 150 MHz, 298 K), δ = 165.1, 162.6, 149.6, 144.1,
136.9, 133.4, 131.51, 131.45, 130.37, 126.9, 125.8, 72.8, 71.8, 27.98,
27.88, 19.33, 19.19; HRMS (ESI-FT-ICR) m/z: [M + H]+ calcd for
C37H36Cl3N8O10 857.1620; found 857.1606.
1
977, 901, 869, 762, 733, 647 cm−1; H NMR (CDCl3, 400 MHz, 298
K), δ = 8.88 (d, J = 1.6 Hz, 1H), 8.08 (s, 1H), 7.63 (d, J = 1.6, 1H Hz),
4.12 (d, J = 6.8 Hz, 2H), 2.15−2.08 (m, 1H), 1.36 (s, 9H), 1.01 (d, J =
6.8 Hz, 6H); 13C NMR (CDCl3 100 MHz, 298 K): δ = 176.8, 165.2,
138.1, 136.7, 130.7, 118.00, 117.83, 114.9, 71.8, 40.5, 28.00, 27.66,
19.3. HRMS (ESI-FT-ICR) m/z: [M + H]+ calcd for C16H22ClN4O3
353.1380; found 353.1372.
Trimer 4. Compound 21 (0.13 g, 0.5 mmol) and compound 28
(0.43 g, 1.22 mmol) were dissolved in toluene (10 mL) and tert-
butanol (10 mL) and degassed with argon. After 30 min, CuSO4 (16.1
mg, 0.1 mmol) dissolved in water (1 mL) and sodium ascorbate (39.8
mg, 0.2 mmol) dissolved in water (1 mL) were added to the solution.
The mixture was stirred overnight at 90 °C, protected from light.
Solvents were removed under reduced pressure, and the residue was
dissolved in DCM. The solution was washed with saturated NH4Cl
(50 mL) and brine (50 mL × 2), respectively, and dried over Na2SO4.
Solvents were evaporated, and the product was purified by flash
chromatography (SiO2, gradient DCM/PE to DCM/ethyl acetate =
gradient 1/1 to 10/1) to yield 4 (0.37 g, 77%) as a white solid, Rf = 0.4
Trimer 1. Compound 8 (0.35 g, 1.47 mmol) and compound 12
(0.12 g, 0.49 mmol) were dissolved in the mixture of toluene (10 mL)
and tert-butanol (10 mL) and then were degassed with argon. After 30
min, to the solution were added in sequence CuSO4 (23 mg, 0.14
mmol) dissolved in water (1 mL) and sodium ascorbate (59 mg, 0.29
mmol) dissolved in water (1 mL). The mixture was stirred at 90 °C
overnight with protection from light. Solvents were removed under
reduced pressure, and the residue was redissolved in DCM, washed
with saturated NH4Cl (50 mL) and brine (50 mL × 2), dried over
Na2SO4, and concentrated under reduced pressure. The crude was
purified by flash chromatography (SiO2, gradient DCM/PE to DCM/
ethyl acetate = gradient 1/1 to 10/1) to yield 1 (0.29 g, 83%) as a
white solid, Rf = 0.6 (DCM/ethyl acetate = 30/1). Mp = 169−170 °C;
1H NMR (CDCl3, 400 MHz, 298 K), δ = 9.07 (d, J = 6.8, 2H), 8.74
(dd, J = 2.0 Hz, 7.2 Hz, 2H), 8.58 (t, J = 3.0 Hz, 2H), 8.22−8.18 (m,
2H), 7.44 (dd, J = 8.8 Hz, 10.3 Hz, 2H), 4.20 (d, J = 6.8 Hz, 2H), 4.16
(d, J = 6.8 Hz, 4H), 2.20−2.07 (m, 3H), 1.07 (d, J = 6.8 Hz, 6H), 1.04
(d, J = 6.8 Hz, 12H); 13C NMR (CDCl3, 150 MHz, 298 K), δ = 165.2,
164.4, 159.0, 157.3, 156.9, 155.2, 141.0, 131.95, 131.90, 129.47,
128.35, 128.12, 126.6, 125.19, 125.12, 123.9, 119.09, 118.99, 117.46,
117.32, 71.80, 71.60, 53.4, 30.9, 27.91, 27.87, 19.30, 19.18; HRMS
(ESI-FT-ICR) m/z: [M + H]+ calcd for C37H38F3N6O6 719.2805;
found 719.2819.
Pentamer 2. Compound 8 (0.27 g, 1.14 mmol), compound 17
(0.3 g, 0.39 mmol), and tris(benzyltriazolylmethyl)amine (34.03 mg,
0.06 mmol) were dissolved in the mixture of toluene (15 mL) and tert-
butanol (15 mL) and then were degassed with argon. After 30 min, to
the solution were added CuSO4 (18.92 mg, 0.12 mmol) dissolved in
water (1 mL) and sodium ascorbate (46.61 mg, 0.24 mmol) dissolved
in water (1 mL). The mixture was stirred at 90 °C for 5 days with
protection from light. The solvents were removed in vacuo, and the
residue was redissolved in DCM, washed with saturated NH4Cl (50
mL) and brine (50 mL), respectively, and dried over Na2SO4. Solvents
were evaporated, and the crude was purified by flash chromatography
(SiO2, gradient DCM/PE to DCM/ethyl acetate = gradient 1/1 to 10/
3) to yield 2 (0.25 g, 52%) as a white solid, Rf = 0.2 (DCM/ethyl
acetate = 20/1). Mp = 229−231 °C; 1H NMR (CDCl3, 400 MHz, 298
K), δ = 9.08−9.07 (m, 4H), 8.83 (d, J = 6.4 Hz, 2H), 8.74 (dd, J = 2.0
Hz, 7.2 Hz, 2H), 8.66 (t, J = 2.8 Hz, 2H), 8.57 (t, J = 3.0 Hz, 2H),
8.20−8.16 (m, 2H), 7.42 (dd, J = 8.8 Hz, 10.4 Hz), 4.24 (d, J = 6.4 Hz,
2H), 4.22 (d, J = 6.8 Hz, 4H), 4.16 (d, J = 6.8 Hz, 4H), 2.22−2.09 (m,
5H), 1.09−1.02 (m, 30H); 13C NMR (CDCl3, 125 MHz, 298 K), δ =
165.3, 164.5, 163.4, 159.3, 157.3, 157.1, 155.1, 148.9, 146.8, 141.6,
141.1, 132.09, 132.02, 129.89, 129.63, 129.25, 128.52, 128.49, 128.38,
126.87, 126.79, 126.65, 126.47, 125.27, 125.18, 124.06, 123.96, 119.31,
119.20, 118.86, 118.75, 117.59, 117.42, 72.6, 71.95, 71.80, 28.05,
27.98, 27.05, 19.42, 19.30;. HRMS (MALDI-FT-ICR) m/z: [M +
Na]+ calcd for C63H61F5N12O10Na 1263.4451; found 1263.4438.
Trimer 3. Compound 21 (52.8 mg, 0.20 mmol) and compound 25
(149.3 mg, 0.50 mmol) were dissolved in toluene (10 mL) and tert-
butanol (10 mL) and degassed with argon. After 30 min, CuSO4 (9.4
mg, 0.06 mmol) dissolved in water (1 mL) and sodium ascorbate (24.1
mg, 0.12 mmol) dissolved in water (1 mL) were added to the solution.
The mixture was stirred overnight at 35 °C, protected from light.
Solvents were removed under reduced pressure, and the residue was
dissolved in DCM. The solution was washed with saturated NH4Cl
(50 mL) and brine (50 mL × 2), respectively, and dried over Na2SO4.
Solvents were evaporated, and the product was purified by flash
chromatography (SiO2, gradient DCM/PE to DCM/ethyl acetate =
1
(DCM/ethyl acetate = 30/4). Mp = 213−214 °C; H NMR (CDCl3,
400 MHz, 298 K), δ = 9.27 (d, J = 2.0 Hz, 2H), 8.93 (s, 2H), 8.51 (s,
2H), 8.14 (s, 2H), 8.06 (s, J = 2.0 Hz, 2H), 4.20 (d, J = 6.8 Hz, 2H),
4.16 (s, J = 6.8 Hz, 4H), 2.22−2.08 (m, 3H), 1.39 (s, 18H), 1.05 (d, J
= 6.8 Hz, 6H), 1.02 (d, J = 6.8 Hz, 12H); 13C NMR (CDCl3, 150
MHz, 298 K), δ = 176.9, 165.4, 164.5, 143.9, 136.8, 135.0, 133.5,
131.40, 131.00, 130.73, 130.28, 125.7, 123.70, 123.42, 123.12, 72.07,
71.80, 40.6, 28.02, 27.96, 27.65, 19.39, 19.30; HRMS (ESI-FT-ICR)
m/z: [M + H]+ calcd for C47H56Cl3N8O8 965.3287; found 965.3255.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H NMR, 13C NMR, and 2D NMR spectra and X-ray
crystallographic data as well as computational details. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Authors
*hjiang@iccas.ac.cn (H.J.)
*windsyn@iccas.ac.cn (Y.W.)
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(21125205 and 21332008) for financial support. We also thank
the Holland Computing Center at the University of Nebraska-
Lincoln, for computational resources.
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