Selective transition state stabilization via hyperconjugative and conjugative assistance: Stereoelectronic concept for copper-free click chemistry

Article abstract of DOI:10.1021/jo201434w

Dissection of stereoelectronic effects in the transition states (TSs) for noncatalyzed azide-alkyne cycloadditions suggests two approaches to selective transition state stabilization in this reaction. First, the formation of both 1,4- and 1,5-isomers is facilitated via hyperconjugative assistance to alkyne bending and C???N bond formation provided by antiperiplanar σ-acceptors at the propargylic carbons. In addition, the 1,5-TS can be stabilized via attractive C-H???F interactions. Although the two effects cannot stabilize the same transition state for the cycloaddition to α,α-difluorocyclooctyne (DIFO), they can act in a complementary, rather than competing, fashion in acyclic alkynes where B3LYP calculations predict up to ～1 million-fold rate increase relative to 2-butyne. This analysis of stereoelectronic effects is complemented by the distortion analysis, which provides another clear evidence of selective TS stabilization. Changes in electrostatic potential along the reaction path revealed that azide polarization may create unfavorable electrostatic interactions (i.e., for the 1,5-regioisomer formation from 1-fluoro-2-butyne and methyl azide). This observation suggests that more reactive azides can be designed via manipulation of charge distribution in the azide moiety. Combination of these effects with the other activation strategies should lead to the rational design of robust acyclic and cyclic alkyne reagents for fast and tunable "click chemistry". Further computational and experimental studies confirmed the generality of the above accelerating effects and compared them with the conjugative TS stabilization by π-acceptors.

Full text of DOI:10.1021/jo201434w

Article
pubs.acs.org/joc
Selective Transition State Stabilization via Hyperconjugative and
Conjugative Assistance: Stereoelectronic Concept for Copper-Free
Click Chemistry
Brian Gold, Nikolay E. Shevchenko, Natalie Bonus, Gregory B. Dudley, and Igor V. Alabugin*
Department of Chemistry and Biochemistry, Florida State University, Tallahassee, Florida, 32306-4390
S
* Supporting Information
ABSTRACT: Dissection of stereoelectronic effects in the transition
states (TSs) for noncatalyzed azide−alkyne cycloadditions suggests
two approaches to selective transition state stabilization in this
reaction. First, the formation of both 1,4- and 1,5-isomers is faci-
litated via hyperconjugative assistance to alkyne bending and C···N
bond formation provided by antiperiplanar σ-acceptors at the
propargylic carbons. In addition, the 1,5-TS can be stabilized via
attractive C−H···F interactions. Although the two effects cannot
stabilize the same transition state for the cycloaddition to α,α-
difluorocyclooctyne (DIFO), they can act in a complementary, rather than competing, fashion in acyclic alkynes where B3LYP
calculations predict up to ∼1 million-fold rate increase relative to 2-butyne. This analysis of stereoelectronic effects is
complemented by the distortion analysis, which provides another clear evidence of selective TS stabilization. Changes in
electrostatic potential along the reaction path revealed that azide polarization may create unfavorable electrostatic interactions
(i.e., for the 1,5-regioisomer formation from 1-fluoro-2-butyne and methyl azide). This observation suggests that more reactive
azides can be designed via manipulation of charge distribution in the azide moiety. Combination of these effects with the other
activation strategies should lead to the rational design of robust acyclic and cyclic alkyne reagents for fast and tunable “click
chemistry”. Further computational and experimental studies confirmed the generality of the above accelerating effects and
compared them with the conjugative TS stabilization by π-acceptors.
effort to “brush against the line between stability and reactivity
without crossing it”, Bertozzi reported that lactam-based
BARAC (Figure 1) provides a 10-fold increase in reactivity
INTRODUCTION
■
“Click chemistry”,1 organic coupling reactions that meet a series
of strict criteria for coupling efficiency, finds numerous
applications in fields ranging from drug design2 and chemical
biology3 to materials science,4 development of sensors,5 and
polymer chemistry.6 The copper-catalyzed azide−alkyne cyclo-
addition (CuAAC),7,8 a variant of the Huisgen9 1,3-dipolar
cycloaddition, has emerged as the prototypical example of a
“click reaction”.10 This process is fast, insensitive to changes in
solvent and/or pH, tolerant of a broad range of functionality
and produces no byproduct. However, it does require a catalyst,
namely, a copper salt, and the toxicity of copper salts limits in
vivo applications of CuAAC couplings.11 A click reaction that
satisfies all of the above criteria without the need for a catalyst
would be ideal.
Inspired by the “explosive” reactivity of cyclooctyne (OCT)
toward organoazides,12 Bertozzi,13 Boons,14 and others15 are
developing strain-promoted azide−alkyne cycloadditions
(SPAAC) as a catalyst-free alternative to the CuAAC with
reactivity suitable for a variety of applications.16,17 For example,
Bertozzi and co-workers demonstrated that intracellular azide-
cyclooctyne coupling occurs within hours at room temper-
ature18 and enables in vivo biological imaging.19 Boons
introduced dibenzocyclooctyne (DIBO) reagents,12 where
further reactivity enhancements over cyclooctyne are achieved
as a result of an increase in ring strain (more sp2-centers). In an
Figure 1. Literature approaches to alkynes with increased reactivity in
noncatalyzed cycloaddition with azides.
over DIBO, leading to intracellular coupling within minutes.20
The drawback, however, is that the reagent (and its derivatives)
“should be stored as a solid at 0° C protected from light and
oxygen.”
Received: July 11, 2011
Published: November 11, 2011
© 2011 American Chemical Society
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Figure 2. Comparison of strategies for acceleration of copper-free click reactions.
This decrease in stability is typical for reagents activated via
reactant destabilization. The low stability of BARAC suggests
that this approach gets close to the limit for its practical utility.
In order to activate alkynes toward click chemistry without
sacrificing their stability or compromising functional group
tolerance, one has to decrease TS energy, either by minimizing
unfavorable interactions21 or by maximizing stabilizing effects
in the TS (Figure 2). Selective TS stabilization is particularly
attractive if the fine “line between stability and reactivity”20 in
the design of robust, yet reactive, alkynes is to be broadened. In
this context, an interesting observation by Bertozzi et al. was
that reactivity of OCT can be enhanced >50-fold by incorpo-
ration of electronegative fluorine atoms at the propargylic
position (cf. DIFO). Houk and co-workers have shown that the
∼2 kcal/mol decrease in the activation barrier for DIFO relative
to cyclooctyne is reproduced by DFT computations.22 This
decrease has been attributed to LUMO lowering, but more
specific orbital effects were not identified.
reactive and tunable alkyne substrates for click chemistry. In the
final part, we combine experiments and computations to com-
pare the importance of accelerating effects identified in this
work with conjugative assistance to cycloaddition imposed by a
π-acceptor. Because this study focuses on transition-state stabi-
lization rather than reactant destabilization, it offers a possibility
of selective acceleration of azide−alkyne cycloadditions without
compromising reactant stability.
COMPUTATIONAL DETAILS
■
The computational analysis of potential energy profiles for azide−
alkyne cycloadditions is performed at the B3LYP/6-31G(d) and
B3LYP/6-31G(d,p) levels of theory. For 1,3-dipolar cycloadditions,
B3LYP/6-31G(d) and B3LYP/6-31+G(d,p) have mean absolute
deviation of 1.5 and 2.6 kcal/mol, respectively, relative to the highly
accurate multicomponent CBS-QB3 method for activation barriers.27
Frequency calculations were performed to confirm each stationary
point as minima or first-order saddle points. Free energies of activation
and reaction have been calculated and are given in the Supporting
Information. Solvation corrections were performed on the gas phase
geometries at the B3LYP/6-31G(d) level of theory. A CPCM
dielectric continuum solvent model for acetonitrile and water with
UA0 radii was used before for related cycloadditions by Houk and co-
workers.34 This model does not explicitly include nonelectrostatic
contributions, cavitation, and dispersion energies and should be
considered as the first approximation of solvation effects.28
Since the donor ability of chemical bonds increases upon
their distortion, the interaction with a properly positioned
acceptor moiety should increase as bending increases, such as is
the case in the highly bent cycloaddition TS. The greater
distortion in the TS should lead to an increase in this stabiliz-
ing interaction, thus providing an approach to selective TS
stabilization.
Our previous research in stereoelectronic effects23 and alkyne
chemistry24,25 suggested to us that the accelerating effect of
vicinal fluorines may stem from the increase in hyper-
conjugative interaction between the alkyne π-system and vicinal
σ*C−F acceptors. This effect would be similar to the electronic
origin of torquoselectivity in electrocyclic reactions,26 where
hyperconjugative interactions provide selective stabilization to
the TS because of the increased donor and acceptor ability of
chemical bonds upon their distortion and breaking.
Electronic structures of reactants and transition states were analyzed
using NBO analysis. The NBO 4.029 program was used to evaluate
the energies of hyperconjugative interactions. The NBO analysis
transforms the canonical delocalized Hartree−Fock (HF) MOs or
corresponding natural orbitals of a correlated description into localized
orbitals that are closely tied to chemical bonding concepts. Filled
NBOs describe the hypothetical strictly localized Lewis structure. The
interactions between filled and vacant orbitals represent the deviation
of the molecule from the Lewis structure and can be used as a measure
of delocalization. This method gives energies of hyperconjugative
interactions both by deletion of the off-diagonal Fock matrix elements
between the interacting orbitals and from the second order
perturbation approach:
As a first step, we have investigated the possibility of selective
stabilization of bent alkynes via stereoelectronic hypercon-
jugative interactions with appropriately positioned σ-acceptors.
In this part, we use DFT calculations in conjunction with
natural bond orbital (NBO) analysis for dissecting the key
electronic components responsible for the enhanced reactivity
of DIFO relative to cyclooctyne. In the second part, we test
conclusions derived from this analysis by analyzing stereo-
electronic effects of propargylic fluorines on alkyne bending
and reactivity in click cycloadditions. After identifying the most
efficient patterns, we illustrate how fully compatible accelerating
approaches can be combined toward the design of highly
2
2
F
⟨σ/F/σ*⟩
σ*
ij
E(2) = − n
= − n
σ
σ
ε
− ε
ΔE
(1)
σ
where <σ/F/σ*>, or Fij is the Fock matrix element between the i and
j NBO orbitals, εσ and εσ* are the energies of σ and σ* NBOs, and nσ
is the population of the donor σ orbital.30,31 Detailed descriptions of
the NBO calculations are available in the literature.32,33
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expect that the magnitude of hyperconjugative interaction with
an appropriately positioned σ-acceptor would increase as the
alkyne moiety deviates from linearity. Such an increase in
the stabilizing interaction should partially offset the energy cost
for distortion. Indeed, we have found that the energy penalty
for symmetric bending of 1-fluoro-2-butyne is lower than it is
for 2-butyne (Figure 4). The hyperconjugative origin of this
RESULTS AND DISCUSSION
■
OCT versus DIFO: Dissection of Hyperconjugative
Contributions to the Activation Barrier. The cyclo-
addition of α,α-difluorosubstituted cyclooctyne synthesized by
Bertozzi and co-workers has been previously investigated
computationally by Houk34 and Goddard,21 who found that
addition of fluorine substituents in the propargylic position
lowered the free energy of activation for 1,5-addition by
∼2 kcal/mol. Our calculated free energies of activation of 22.2 and
20.2 kcal/mol for the addition of methyl azide to cyclooctyne and
3,3-difluorocyclooctyne at the B3LYP/6-31G(d) level of theory
are in good agreement with the literature data.
Quantifying hyperconjugative effects via NBO analysis
revealed that hyperconjugative donation from the in-plane
alkyne π-system to the σ*C−F orbital directly leads to the TS
stabilization and explains the increased reactivity of DIFO
compared to OCT (Figure 3). This interaction increases by
Figure 4. (A) FMO orbital changes upon alkyne bending responsible
for the effect of acceptor substituents on the bending energy. (B)
Relaxed energy scans (kcal/mol) for the symmetric bending of
2-butyne and 1-fluoro-2-butyne at the B3LYP/6-31G(d,p) level of
theory. Cyclooctyne geometry is shown as a reference point for the
relevant range of geometries. See Supporting Information for the full
range of bending angles. (C) Average alkyne bending angles for three
representative transition states are included for comparison (OCT/
MeN3, DIFO/MeN3, app-1-fluoro-2-butyne/MeN3). Energies are
given in kcal/mol, angles in degrees.
Figure 3. Hyperconjugative interactions between σ*C−F acceptor and
the two π-systems in DIFO and two regioisomeric TSs for its
cycloaddition to methyl azide. The data are for NBO second order
perturbation energies in kcal/mol at the B3LYP/6-31G(d) level. ΔE⧧
values at the same level of theory are given at the bottom.
2.8 kcal/mol (from 4.3 to 7.1 kcal/mol, a ∼65% increase) when
the alkyne is distorted from the reactant to the TS geometry.
Intriguingly, the magnitude of this increase matches well with
the 2 kcal/mol decrease in the overall activation barrier.
These observations are especially interesting because the
exocyclic C−F bonds are not fully aligned with the breaking in-
effect is evident in its stereoelectronic features. The effect is
maximized when the σ*C−F acceptor is antiperiplanar (app) to
the in-plane π-system (e.g., 1.72 kcal/mol at the 150° C−CC
angle typical for the cycloaddition TS). For the syn-periplanar
arrangement the effect decreases slightly (1.64 kcal/mol). For
the gauche arrangement, the stabilizing effect is even smaller
(0.85 kcal/mol).
These observations are interesting because the effect of
alkyne bending on HOMO energies, a potential driving force
for intermolecular interactions with electrophiles, is believed to
be relatively small36 in comparison to the well-known enhance-
ment of electrophilicity associated with LUMO energy37
lowering in bent alkynes, e.g., benzyne.38 Nevertheless, it is
clear that the effect of the acceptor (∼2 kcal/mol) should be
experimentally significant.
plane π-bond (as illustrated by the greater energies of πout
→
σ*C−F interactions in Figure 3), and one could expect that the
TS-stabilizing effect to be enhanced once such alignment is
achieved. Basic stereoelectronic expectations suggest that the
π → σ*C−X interaction will be maximized for the antiperiplanar
orbital arrangement.35
Testing the Hyperconjugative Model: 2-Butyne
versus 1-Fluoro-2-butyne. In order to test the above
stereoelectronic expectations, we have investigated conforma-
tional effects on the distortion and reactivity of 1-fluoro-2-
butyne.
Effect of Propargylic Acceptors on Alkyne Bending. If the
donor ability of alkynes increases upon its bending, one should
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Stereoelectronic Effects on Relative “Click” Reactivity. In
order to determine to what extent this effect operates in the
azide/alkyne cycloadditions, we have compared cycloaddition
activation energies for 2-butyne39 and 1-fluoro-2-butyne using
methyl azide as the parent 1,3-dipole.
Importantly, the accelerating effect of fluorines is not mani-
fested equally for the four stereo- and regioisomeric transition
states of the 1-fluoro-2-butyne cycloaddition with methyl azide
(Figure 5). In particular, the activation barriers are lowered
linearity observed at C4 suggest that this is the best place for
attaching a hyperconjugative σ-acceptor.
In contrast, the activation barrier for 1,4-cycloaddition of the
gauche conformer, where the C−F bond is misaligned with the
in-plane alkyne π-system, is lowered by only 0.65 kcal/mol
relative to the 2-butyne cycloaddition TS. In this context, the
very low calculated barrier for the 1.5-gauche case (3.3 kcal/mol
lowering relative to 2-butyne) looks surprising because this TS
cannot also benefit from the aforementioned hyperconjugative
assistance. This is not an isolated observation because the
analogously low 1,5-gauche TS energy has been reported earlier
by Houk and co-workers for the DIFO cycloaddition in the gas
phase.34 This effect can be traced to a stabilizing Me···F
interaction that can be considered as a weak C−H···X hydrogen
bond with a substantial electrostatic component. Because
electrostatic stabilization is strongly attenuated once solvation
effects are included in the calculation, the “hyperconjugation-
assisted” 1,4-app cycloaddition becomes the lowest calculated
energy reaction path in water and acetonitrile (2.7 kcal/mol
barrier decrease and ∼100-fold acceleration relative to 2-
butyne). Since solvation effects are important, we will generally
use the solvation-corrected data in our subsequent discussions.
Notably, the TS stabilization provided by a single fluorine
substituent in the acyclic 1,4-antiperiplanar TS is greater than
the TS stabilization provided by two fluorines in DIFO. This
computational observation is consistent with the stereo-
electronic nature of hyperconjugation and illustrates that the
cyclooctyne frame imposes unfavorable restrictions on reaching
the optimal orbital overlap with the C−F hyperconjugative
acceptors in the TS.
Distortion Analysis. In order to understand the origin of the
above accelerating effects better, we have turned to distortion
analysis. Houk and co-workers have used this concept
successfully toward a variety of cycloadditions.34 This analysis
dissects the activation barrier for cycloadditions into distortion
and interaction energies. Distortion describes the energy
penalty for adopting the TS geometry by the reactants, whereas
interaction energy reflects energy lowering due to covalent
and noncovalent interaction between the reactants. The data of
distortion analysis are summarized in Table 1.
The distortion analysis readily rationalizes the anomalously
low energy of the 1,5-gauche transition state where the
interaction energy is 0.9 kcal/mol (2.2 kcal/mol in the gas
phase) higher than for the 2-butyne TS. These numbers are
consistent with the selective TS stabilization by an H-bond type
C−H···F interaction corresponding to a relatively short (2.4 Å)
H···F contact. NBO analysis suggests that the covalent com-
ponent of this interaction is relatively small (hyperconjugative
nF → σ*C−H energy is 0.3 kcal/mol,40 the same order of
magnitude as the difference in the interaction energies for 1,4
and 1,5-gauche TS in water). The large part of stabilization is
due to the Coulombic attraction between the two centers
bearing significant charges (vide infra, “Electrostatics and Its
Cooperative and Anticooperative Effects on Hyperconjugative
Assistance”).
Distortion energies for the two cycloadditions where the
C−F bond is antiperiplanar to the breaking in-plane alkyne π-bond
are lower than for the analogous processes where the C−F bonds
are either gauche to the breaking bond or the acceptor σ*C−F
orbital is absent (2-butyne). The lower distortion energies reflect
the fact that their values include not only the destabilizing effects
of alkyne bending but other electronic effects associated with the
change of molecular geometry as well. TS-stabilization due to the
Figure 5. Geometries of the four transition states for the 1-fluoro-2-
butyne/methyl azide cycloaddition calculated at the B3LYP/6-31G(d)
level of theory (bottom) and numbering of atoms in the TS (top).
Changes in the activation barriers due to fluorine introduction are
shown in bold below the arrows. All energies are given in kcal/mol,
bond lengths in Å, angles in degrees.
relative to the 2-butyne barrier when the σ*C−F orbital is anti-
periplanar to the forming C−N bonds by 2.1 and 3.0 kcal/mol
(for the 1,5- and 1,4-isomers, respectively).
A greater acceleration observed for the 1,4-isomer formation
results from the asynchronous nature of the TS. The incipient
N3···C4 distances are >0.1 Å shorter than the N1···C5
distances indicating that the N3−C4 bond formation is more
pronounced at this stage. This is fully consistent with the ∼5−7°
greater bending at the C4 alkyne carbon observed in most
cases (the unusual features of the 1,5-gauche TS will be
discussed later). Greater bending and greater deviations from
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Table 1. Activation, Reaction, Distortion, and Interaction Energies for 2-Butyne and 1-Fluoro-2-butyne Transition States at the
B3LYP/6-31G(d) level of theory
EDist (kcal/mol)
alkyne
azide
total
EInt, (kcal/mol)
ΔE⧧ (kcal/mol)
ΔERxn (kcal/mol)
2-butyne
10.12
10.11
9.25
19.78
20.14
19.41
19.75
18.52
18.57
18.43
18.75
18.52
18.85
29.90
30.26
28.66
29.25
28.75
28.67
27.17
27.68
28.68
28.91
−9.01
−7.66
−9.83
−8.41
−11.20
−8.52
−9.27
−7.77
−8.44
−7.71
20.89
22.62
18.83
20.84
17.55
20.15
17.90
19.91
20.24
21.20
−67.8
−70.4
−69.8
−71.2
−69.8
−71.2
−70.8
−72.3
−70.8
−72.3
ab
,
CPCM (H2O)
1,5-app gas phase
ab
,
CPCM (H2O)
1,5-gauche gas phase
ab
9.50
10.23
10.10
8.74
,
CPCM (H2O)
1,4-app gas phase
ab
,
CPCM (H2O)
1,4-gauche Gas phase
ab
8.93
10.16
10.06
,
CPCM (H2O)
a
b
B3LYP/6-31G(d) geometry. Radii = UA0.
hyperconjugative assistance is one of these effects (Figure 4),
which is displayed via the apparent lowering of the alkyne
distortion energy. The greater stabilization for the 1,4-app TS is
consistent with the greater bending at C4.
An additional manifestation of selective TS stabilization is the
increase of stabilizing interaction energy between the frag-
ments. This difference fully accounts for the considerable
deviations in the correlation of distortion energy with full
activation barriers in Figure 6, shown to be reliable for this class
of reactions on many occasions.34
Understanding the trends in interaction energy is, however,
complicated because the overall interaction energy is comprised
of covalent, steric and electrostatic components. Let us look at
the stabilizing components of the interaction energy more
carefully, hyperconjugation first, electrostatics next.
Natural Bond Orbital Dissection of Hyperconjugative
Effects. NBO analysis can quantify stereoelectronic interac-
tions in these systems. Even in the TS, the dominant NBO
Lewis structure corresponds to the separated dipole and alkyne
moieties, which makes comparison of hyperconjugative
interactions with the linear and bent alkynes possible.
The results are revealing. Although distortion (bending) of the
alkyne to the TS geometry does provide an increase in the π →
σ*C−F interaction (on the order of 1 kcal/mol , consistent with
the decrease in distortion energy and lowered bending energies
in Figure 6), the most dramatic enhancement of hypercon-
jugative assistance by the σ*C−F orbitals is observed in the full
TS where the azide is brought in direct proximity to the bent
alkyne (Table 2). In this situation, the effect of hyperconjugation is
Table 2. NBO Analysis of Hyperconjugative Interactions
Involved in the Methyl Azide Cycloaddition with 2-Butyne
a
and 1-Fluoro-2-butyne (FB)
π + π* → σ* energies (kcal/mol)
linear
alkyne
bent alkyne (TS
geometry)
full transition
state
2-butyne
3.27
8.96
8.96
8.96
8.96
2.99
8.86
9.99
9.39
9.56
3.75
8.84
1,4-gauche FB
1,4-app FB
1,5-gauche FB
1,5-app FB
14.43
10.40
15.54
a
Only donation from the in-plane π-system (both π and π*) is shown.
estimated to be significantly larger! Stereoelectronic properties
of these effects are illustrated by their dramatic enhancement
for the antiperiplanar arrangement between the donor
πin-system and acceptor σ*C−F orbitals.
When viewed through the prism of the distortion analysis,
this additional mechanism for TS stabilization should manifest
itself in a different way, as an increase in “interaction energy”
rather than a decrease in the “distortion energy”. Increase in this
interaction relative to the isolated alkyne is mostly due to an
increase in the population of donor π* orbital, which is empty
in the reactant but gains 0.2 electrons in the TS (Table 3).
Figure 6. Correlation of the full distortion energy and activation
energy for 2-butyne and 1-fluoro-2-butyne cycloadditions with methyl
azide (B3LYP/6-31G*). (Top) Gas phase data. (Bottom) Single point
solvation (water) correction. The energies below the straight line
deviate from the distortion plot as a result of selective TS stabilization.
(Gas phase: R2 = 0.48, if all five points are included. CPCM (water):
R2 = 0.85, if all five points are included.)
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Table 3. NBO Analysis of In-Plane π/π* Energy and Population Involved in the Methyl Azide Cycloaddition with 2-Butyne and
a
the Four Conformers of 1-Fluoro-2-butyne
linear alkyne
bent alkyne (TS geometry)
πin π*in
full transition state
πin
π*in
πin
π*in
energy
pop
energy
pop
energy
pop
energy
pop
energy
pop
energy
pop
2-butyne
1,4-gauche
1,4-app
−6.95
−7.40
−7.40
−7.40
−7.40
1.965
1.945
1.945
1.945
1.945
4.27
3.80
3.80
3.80
3.80
0.055
0.046
0.046
0.046
0.046
−6.85
−7.35
−7.28
−7.37
−7.28
1.964
1.966
1.941
1.966
1.942
3.61
3.15
3.13
3.15
3.14
0.055
0.057
0.050
0.057
0.048
−6.95
−7.28
−7.23
−7.25
−7.27
1.727
1.750
1.731
1.753
1.719
3.37
2.98
3.06
3.00
3.07
0.193
0.210
0.196
0.216
0.203
1,5-gauche
1,5-app
a
Energies are given in eV, orbital population in electrons.
Because the above interaction is manifested to a greater degree in
the TS, this effect fits the classic definition of transition state
stabilization, the ideal scenario for selective reaction acceleration.
Such relatively high population of a formally antibonding
orbital in the NBO analysis is not surprising, considering the
delocalized nature of transition states. It is typical for strongly
Electrostatics and Its Cooperative and Anticooperative
Effects on Hyperconjugative Assistance. Electrostatic effects
on click reactivity were analyzed in two ways: (a) NBO charges
in the full TS and in the isolated alkyne distorted to the TS
geometry and (b) full ESP potentials of the four TS (Figure 8).
−
delocalized systems (e.g., benzene, 1,3-butadiene, HF2 ) where
a single Lewis structure is insufficient. Figure 7 (top) illustrates
Figure 7. (Top) Electronic basis for TS stabilization. The increase in
the alkyne π* population due to the C···N bond-forming interaction
complements the effect of propargylic acceptor on alkyne bending
(Figure 3). (Bottom) NBO plots for orbital interactions between the
propargylic σ-acceptors and the reacting in-plane alkyne π-bond in the
cycloadditions TS for the optimal antiperiplanar (left) and suboptimal
gauche (right) orbital arrangements.
orbital mixing for the highest in-plane occupied MO of the
azide and π*in‑plane of the alkyne, which transfers electron density
from the azide to the alkyne. Negative hyperconjugation with
the stereoelectronically aligned σ*C−F orbital enhances this
stabilizing interaction, which accounts for the second
component of selective TS stabilization described above.
Another way to understand the origin of the high π*-population
is provided by the curve crossing model of chemical reactivity
where a transition state is described as an avoided crossing
between ground and excited state configurations.41
Figure 8. (Left) NBO atomic charges at the B3LYP/6-31G(d) level of
theory (data in parentheses correspond to charges in the isolated
alkyne distorted to the TS geometry). (Right) Electrostatic potential
(ESP) surfaces. The ESP color coding and ESP surfaces for the alkyne
and azide reagents in their unperturbed geometries are shown below.
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Figure 9. Geometries of the transition states of the 1,1-difluoro-2-butyne (top) and 1,4-difluoro-2-butyne (bottom)/methyl azide cycloaddition
calculated at the B3LYP/6-31G(d) level of theory. All energies are given in kcal/mol, bond lengths in Å, angles in degrees.
Several observations are noteworthy. In particular, the N1
nitrogen of the azide bears significantly greater negative charge
in comparison to the N3 nitrogen. This azide polarization
creates unfavorable electrostatic interactions when the negative
part of the alkyne dipole is oriented toward N3 (i.e., the 1,5-
regiochemistry in the case of 1-fluoro-2-butyne). This observa-
tion suggests that more reactive azides can be designed via
manipulation of charge distribution in the azide moiety.
The alkyne is polarized toward the CH2F moiety. Interest-
ingly, the alkyne polarization decreases upon the approach of
azide along the 1,5-path but increases when azide approaches
along the 1,4-trajectory. This difference is due to the more
pronounced negative charge accumulation at the C2 carbon for
1,4-additions than for respective 1,5-additions (gauche vs gauche
and app vs app) and due to additional changes in alkyne
polarization, occurring as the azide approaches the bent alkyne.
For 1,4-additions, the alkyne carbon α-to the CFH2 group
becomes more negatively charged in the presence of the azide,
whereas for 1,5-additions, the same carbon becomes less
negatively charged in the azide’s proximity. Again, these
contrasting changes in polarization are consistent with the
greater antiperiplanar hyperconjugative assistance by the σ*C−F
acceptor observed for the 1,4-regioselectivity.
Cooperativity of Hyperconjugative Effects: Click
Reactivity of 1,4-Difluoro-2-butyne and 1,1-Difluoro-2-
butyne. An intriguing conclusion from the above analysis is
that propargylic fluorine atoms can accelerate both 1,4- and 1,5-
addition via different mechanisms: hyperconjugative assistance
for 1,4-addition and Me···F interaction for 1,5-addition. Since
the two mechanisms are independent from each other, it is
theoretically possible to combine them in a synergestic manner
for achieving an even larger reaction acceleration.
Indeed, the calculated 1,4-difluorobutyne cycloaddition barrier
where the TS combines the two accelerating effects is 5.4 kcal/mol
(6.6 kcal/mol in the gas phase) lower in energy than the 2-butyne
TS. The 2.7 and 3.0 kcal stabilization relative to the 1,4-app and
1,5-gauche TS for 1-fluorobutyne reveals remarkable additivity of
the two effects (5.4 vs 3.0 + 2.7 kcal/mol).
In contrast, two fluorine atoms placed at the same
propargylic carbon of 1,1-difluorobutyne cannot engage in
hyperconjugative assistance and Me···F interaction at the same
time, and a lower increase in reactivity is observed in com-
parison to that of the monofluorinated substrates. The lowest
energy TS for this alkyne results from two Me···F interactions
in the 1,5-cycloaddition geometry. The combined 3.8 kcal/mol
stabilization from the two interactions indicates partial
saturation of this effect: the second Me···F interaction is
∼50% weaker (1.4 vs 2.4 kcal/mol, Figure 9).
Overall, the cooperativity effects are interesting and complex.
Although their full discussion extends beyond the scope of this
paper, we have summarized the effect of the second fluorine on
the cycloaddition barriers in Figure 10.
Remarkably, the two 1,5-gauche interactions and one 1,4-app
interaction in the 1,1,4-trifluoro-2-butyne cycloaddition TS
shown in Figure 11 are sufficient to achieve the same
acceleration as the full fluorination of both propargylic posi-
tions. The calculated gas phase cycloaddition barriers for both
cases are essentially identical: ∼12.5 kcal/mol. The 8.4 kcal/mol
barrier decrease in comparison to that of the 2-butyne cyclo-
addition, indicates that ∼1 million-fold acceleration may be
possible! Solvation effects suggest that although this accelerating
effect will be larger in nonpolar solvents than in water,
such acceleration should be substantial in polar environments
as well.
The “economic” use of fluorine effects via strategically
accurate positioning of the C−F bonds is interesting from the
practical perspective because the remaining positions at the
propargylic carbons can be used for attaching other substituents
(Figure 12). The combined effect of the three F-substituents
eliminates ∼80% of the barrier difference between 2-butyne and
cyclooctyne without introducing any strain destabilization in the
reactant! Unfortunately, unlike the acyclic analogues, DIFO
itself cannot benefit from the two effects identified in this paper
at the same time because cyclic restraints render the optimal
antiperiplanar position of a C−F bond impossible. Instead,
DIFO relies on two effects, but only one at a time: (a) C−H···F
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Figure 10. Contrasting effects of the second fluorine substituent on the cycloaddition barriers of difluorosubstituted 2-butynes with methyl azide at
B3LYP/6-31G(d) level of theory. Activation energy changes are shown next to the arrows (top value: gas phase; bottom value: with solvation
correction). The two interactions chosen for the further cooperative TS stabilization are shown with the bold arrows.
Figure 11. Geometries of the transition states of the 1,1,4-trifluoro-2-
butyne (left) and perfluorobut-2-yne (right)/methyl azide cycloaddition
calculated at the B3LYP/6-31G(d) level of theory. All energies are given
in kcal/mol, bond lengths in Å, angles in degrees.
interactions in the 1,5-TS or (b) imperfect hyperconjugative
assistance from the two gauche C−F bonds in the 1,4-TS. We
will provide possible ways to overcome this limitation in our
subsequent papers.
These accelerating effects should not be limited to fluorines.
One can readily incorporate other H-bond acceptors near C5
and other σ-acceptors near C4 (Figure 12, bottom. See also the
next section).
Figure 12. Favorable placement of fluorine substituents for optimal
Competing Stabilizing Interactions: σ- versus π-
activation via cooperative effects and further possible variations in the
Acceptors. In order to get further insights in the nature of
design of reactive alkynes with suitable activation patterns.
TS stabilization in 1,3-dipolar cycloadditions, we have also
compared relative acceleration provided by the σ*C−F acceptors
carbonyl (Figure 13) or the analogous interaction with the
with that of a typical carbonyl acceptor: π*CO of an ester.
carbonyl σ*C−O). The transition state geometries for the 1,4-
In the cycloadditions of 2-butynoates, several accelerating
isomer formation clearly indicate that the preferred assistance
effects are possible, although not simultaneously. The Me···O
to the C−N bond formation is provided by the π*C−O orbital,
interaction between the ester moiety and a propargylic C−H in
in full agreement with the higher acceptor ability of π-bonds vs
the 1,5-TS has a close analogue in the Me···F electrostatic
σ-bonds and the greater importance of conjugation42 versus
hyperconjugation. These preferences are consistent with the
NBO energies for the stabilizing interactions in Figure 13.
interaction mentioned above (1,5-gauche-TS). Similar to the
trend observed in 1-fluoro-2-butyne, the Me···X interaction
provides more stabilization in the gas phase, but when solvation
Comparison of the two regioisomeric transition states reveals
a more complex and interesting picture. The 90° rotation of the
ester moiety in the transition state for the 1,5-isomer turns off
the conjugative πin → π*CO stabilization and trades it for the
combination of two effects outlined in the earlier section of this
corrections are taken into consideration, the conjugative
interaction provides a greater TS stabilization. The delocalizing
assistance by an ester can be manifested as conjugation or
hyperconjugation (i.e, either as a π → π*C−O interaction
between the breaking π bond of the alkyne and the π* of the
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Figure 13. Changes in the magnitude of key alkyne/π-acceptor inter-
actions leading to transition state stabilization in the methyl 2-butynoate/
methyl azide cycloaddition. All NBO energies are in kcal/mol.
paper: the C−H···O interaction and the σ*C−O hyper-
conjugative assistance. The lower energy of the 1,5-TS indicates
that together hyperconjugation plus C−H···O interaction can
be more effective than the πin → π*CO conjugative assistance,
especially in this system, where steric repulsion between the
two groups further destabilizes the 1,4-TS.
In the fluorinated ester, the stabilizing effects can operate
simultaneously. The electrostatic Me···X interaction can occur
with either F or O, while the electronic assistance, either as the
hyperconjugative π → σ*C−F interaction seen in fluorobutyne
or as the conjugative π → π*C−O interaction, is possible in each
regioisomer. In both the gas phase and in solution, the
combination of Me···F interaction and π → π*C−O assistance
provide the greatest stabilization (Figure 14).
Finally, we have also analyzed the effect of 2-pyridinyl
substituent at the alkyne moiety. Similar to the ester group, this
substituent can accelerate cycloadditions via three effects:
hyperconjugative assistance (via σ*C−N), conjugative assistance
(via aromatic π-system), and C−H···N interaction (via the lone
pair of the pyridine nitrogen) following the general design
outlined in Figure 12. Comparisons with the fluorinated ester
are interesting: the ester → pyridine replacement at the fifth
position increases the barrier by 1.4 kcal/mol, whereas the
same change at the fourth position has a much larger effect
(3.7 kcal/mol). As the result, the preferred position of the CF3
group should change in the cycloadditions of the two alkynes.
Experimental Studies. A number of alkynes can be
designed to manifest the synergy between the two effects
discussed above as long as they contain a σ- or π-acceptor at
one of the propargylic carbons and a heteroatom with a lone
pair at the other propargylic position as outlined in Figure 12.
In order to test the accuracy of computational methods and
gain further insight into the nature and magnitude of the accele-
rating effects discussed in the previous section, we have deter-
mined the rates of cycloaddition for three systems outlined in
the previous section. p-Fluorobenzyl azide was chosen as a
model substrate for convenience, as the kinetics can be
Figure 14. Geometries and energies of the cycloaddition transition
states of methyl 2-butynoate (top), methyl 4,4,4-trifluoro-2-butynoate
(middle), and (3,3,3-trifluoroprop-1-ynyl)pyridine (bottom) with methyl
azide calculated at the B3LYP/6-31G* level of theory. All energies are
given in kcal/mol, bond lengths in Å, angles in degrees.
σ*C−F and (b) and electronic differences between CF3 and CH3
discussed in the previous section. The pyridine moiety in
alkyne 3 can provide either a σ*C−N hyperconjugative acceptor
or nitrogen lone pair depending on the electronic demand in
the cycloaddition TS. The CF3-substituted substrates were
prepared via vacuum pyrolysis of appropriately substituted
phosphorus ylides (Figure 16).43 Ethyl 2-butynoate is
commercially available.
In each case, the cycloadditions proceeded smoothly to
provide a mixture of two regioisomers. After chromatographic
separation, the structures of the isomers were determined with
2D NMR techniques. In particular, the regiochemistry of
cycloaddition is confirmed via the long-range HMBC correlations
between benzylic hydrogens and the adjacent triazole carbon.
Although copper-free azide−alkyne cycloadditions of both
ethyl 2-butynoate and ethyl 4,4,4-trifluoro-2-butynoate were
reported earlier,44 the kinetic comparison of their reactivity has
not been conducted prior to this work. The differences in
reactivity are dramatic (Figure 17). The cycloaddition of the
fluorinated ester proceeds within hours at the room temper-
ature and 0.5 M concentration of the reagents. The ∼10−4 rate
1
monitered via both H and 19F NMR spectroscopy. Com-
parison of calculated barriers suggested that reactivity of the
three alkynes should follow the order methyl 4,4,4-trifluoro-2-
butynoate > 2-(3,3,3-trifluoroprop-1-ynyl)pyridine > methyl
2-butynoate with the fluorinated ester being the most reactive
(Figure 15).
The comparison of ethyl 2-butynoate 1 and ethyl 4,4,4-
trifluoro-2-butynoate 2 allows us to get experimental infor-
mation on the relative importance of two effects: (a)
conjugation with a π*CO versus hyperconjugation with a
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determined for the three alkynes. Comparison of the rate
constants for the two esters at 80 °C shows ∼1000-fold
acceleration of cycloaddition upon fluorination.
The relative rates for the formation of two regioisomers for
each of the alkynes are particularly interesting. In full agreement
with the stereoelectronic analysis presented in the previous
sections, for the two alkynes 1 and 3 with a dominant acceptor
substituent at the triple bond, the formation of the 1,4-isomer
proceeds ∼4−8 times faster. In contrast, the reaction of 4,4,4-
trifluoro-2-butynoate, which bears two acceptor groups,
provides the two isomers in an almost 1:1 ratio. Interestingly,
in the latter case the formation of the 1,4-isomer, which
positions the CF3 group away from the benzyl substituent,
becomes slightly favorable at the higher temperatures (see
Supporting Information) suggesting that the formation of two
regioisomers have different entropies of activation and, likely,
the degree of organization in the TS.
The activation parameters for the formation of each of
the two regioisomers were experimentally determined from
the Arrhenius and Eyring plots (Figure 18). The activation
enthalpy and entropy provided by the Eyring plots are
especially useful in the case of ethyl 4,4,4-trifluoro-2-butynoate,
where the regioisomer predicted to have a lower activation
barrier, both in the gas phase and when single point corrections
are considered, is major at room temperature and 40 °C but
becomes minor at higher temperatures. The Eyring plot reveals
this is due to entropic effects. The favorable interactions leading
to transition state stabilization also lock in specific con-
formations, making these structures entropically less favorable.
For both CF3-substituted substrates, the proximity of alkyne
trifluoromethyl to the azide methylene in the TS leads to a
more negative activation entropy as the result of additional
conformational rigidity in the TS, providing experimental
evidence in favor of the C−H···F interactions identified in
this work. In the cases of ethyl 2-butynoate and 2-(3,3,3-
trifluoroprop-1-ynyl)pyridine, the regioisomer with the lower
activation enthalpy also has a less negative entropy term, so the
switch in selectivity is not observed.
The experimental activation energies for the formation of
1-(4-fluorobenzyl)-5-(trifluoromethyl)-1H-1,2,3,-triazole-4-
carboxylate regioisomers are close to the computational data.
The gas phase B3LYP data are in excellent agreement (within
0.1 kcal/mol) with the experimental values. The single point
solvation correction brings the calculated barriers slightly higher
than the experimental values, but still in reasonable agreement
with the experiment. Although such close agreement is
probably fortuitous because B3LYP is not expected to treat
noncovalent interactions accurately, both theory and experi-
ments agree that the lower energy TS is stabilized by both the
Me···F electrostatic interaction and the π → π*C−O assistance.
The experimental activation energies for the formation of
2-(3,3,3-trifluoroprop-1-ynyl)pyridine (middle) and ethyl
2-butynoate regioisomers also match reasonably well. Impor-
tantly, in both cases theory and experiments find the same
regioisomer to be favored. The agreement between theory and
experiment validates both the CH···X interactions and
(hyper)conjugative assistance as sources of transition state
stabilization in cycloaddition reactions, providing a benchmark
for this level of theory and thus confirming its effectiveness in
predicting relative trends useful for the future design of new
reagents for copper-free click chemistry.
Figure 15. Geometries and energies of the transition states of methyl
2-butynoate (top), methyl 4,4,4-trifluoro-2-butynoate (middle), and 2-
(3,3,3-trifluoroprop-1-ynyl)pyridine (bottom)/p-F-benzyl azide cyclo-
additions calculated at B3LYP/6-31G* levels of theory including zero
point corrections. All energies are given in kcal/mol, bond lengths
in Å, angles in degrees.
Figure 16. Synthesis of ethyl 4,4,4-trifluoro-2-butynoate 2 and
2-(3,3,3-trifluoroprop-1-ynyl)pyridine 3.
constant at the biological temperature (∼40 °C) is approaching
that for the other alkynes used for bioconjugation.17 In contrast,
the reaction of ethyl 2-butynoate is very slow under these
conditions and only occurs at a reasonable rate upon heating.45
The rate constants for the formation of both regioisomers were
In summary, we have identified two stereoelectronic strategies
for selective TS stabilization in catalyst-free azide/alkyne
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Figure 17. (Left) Rate constants (80 °C) for the formation of two regioisomers in the cycloaddition of activated alkynes 1−3 and long-range
correlations in HMBC spectra used for the structural assignments. Full details are given in Supporting Information. (Right) ΔE⧧calc, ΔE⧧exp, ΔH⧧
,
exp
and ΔS⧧exp, for each of the regioisomers in the cycloaddition of activated alkynes 1−3. ΔE⧧ and ΔH⧧ are shown in kcal/mol, ΔS⧧ is given in cal/mol.
cycloadditions. Whereas the transition state for the
formation of the 1,5-isomer can be stabilized via C−H···X
interactions, both the 1,4- and 1,5-TS can be stabilized via
hyperconjugative assistance for alkyne bending and for
C···N bond formation. Such assistance provides a new
strategy for efficient control of alkyne reactivity in click
cycloadditions. DFT barriers suggest that judicious combi-
nation of the two independent TS-stabilizing effects can
lead to ∼1 million-fold acceleration of cycloaddition with
methyl azide. Experimental kinetic studies confirm large
accelerating effects of σ-acceptors. Combination of the
above strategies with strain activation and other non-
covalent effects should lead to the rational design of robust
acyclic and cyclic alkyne reagents for fast and tunable “click
chemistry”. Hyperconjugative assistance is not limited to
alkynes but should be applicable to other π-systems as well. For
example, the faster cycloaddition reactions of oxanorbornenes
in comparison to their all-carbon analogues46 can be attributed
to the analogous TS stabilization imposed by the allylic σ*C−O
orbitals.
EXPERIMENTAL SECTION
■
General Information. 1H NMR and 13C NMR spectra were
recorded on a at 400 and 100 MHz correspondingly and at 600 and
150 MHz; 19F NMR was recoreded at 375 MHz; and the 2D NMR
experiments (HSQC and HMBC) were performed on a 600 MHz
spectrometer. The chemical shifts are reported in parts per million
(ppm) relative to the residual chloroform peak (7.26 ppm for 1H
NMR and 77.0 for 13C NMR). Coupling constants are reported in
hertz (Hz). IR spectra were recorded on a FTIR spectrometer with
diamond ATR accessory as thin film. Mass spectra were recorded on a
MS JMS 600H spectrometer. GS−MS analyses were performed on GS
system with DB-5MS+DG 30 m × 0.25 mm, 0.25 μm capillary column
coupled with MS detector.
1
Yields refer to isolated material judged to be >95% pure by H
NMR spectroscopy following silica gel chromatography (F-254 silica,
230−499 mesh particle size). All chemicals were used as received
unless otherwise noted.
4-Fluorobenzyl Azide.
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Figure 18. Arrhenius (left) and Eyring (right) plots for cycloaddition of ethyl 4,4,4-trifluoro-2-butynoate (top), 2-(3,3,3-trifluoroprop-1-
ynyl)pyridine (middle), and ethyl 2-butynoate (bottom) with p-fluorobenzyl azide.
A mixture of 4-fluorobenzyl bromide (1.7 g, 8.91 mmol) and
sodium azide (1.45 g, 22.27 mmol) in 17 mL of DMF was
stirred under a nitrogen atmosphere for 4 h at 60 °C. The
reaction mixture was cooled, quenched with 150 mL of
water, and extracted with benzene (since diethyl ether was
unavailable). The organic layer was washed with brine and
dried with Na2SO4, and the solvent was removed under
reduced pressure to afford 1.4 g of crude p-fluorobenzyl
azide. Purification by column chromatography afforded 0.90 g
(67%) of the pure product. Spectral data were in good
agreement with the literature.47 1H NMR (CDCl3, 400
MHz): δ 4.31 (s, 2H), 7.05−7.10 (m, 2H), 7.28−7.31
Spectral data for the product was in good agreement with
literature.Yield 11 g (89%); H NMR (CDCl3, 400 MHz): δ
0.86 (t, 3H), 3.80 (q, 2H), 7.48−7.51 (m, 6H), 7.57 (m, 3H),
7.65 (m, 6H)
1,1,1-Trifluoro-3-pyridin-2-yl-3-(triphenylphosphoranyli-
dene) Acetone.
1
(m, 2H).
Ethyl 4,4,4-Trifluoro-3-oxo-2-(triphenylphosphoranylidene)
Butanoate.
Acylation of the (triphenyl(pyridin-2-ylmethyl)phosphonium
chloride with trifluoroacetic anhydride in the presence of
triethylamine was carried out analogous to a literature
procedure,43 affording 1,1,1-trifluoro-3-pyridin-2-yl-3-
(triphenylphosphoranylidene)acetone. Yield 4.5 g (91%),
1
white crystals, mp 97−99 °C. H NMR (400 MHz, CDCl3):
δ 6.85 (t, J = 6.0 Hz, 1H), 7.28 (d, J = 7.8 Hz, 1H), 7.37−
7.42 (m, 7H), 7.49−7.53 (m, 3H), 7.59−7.64 (m, 6H), 6.19
(d, J = 4.0 Hz, 1H). 13C NMR (150 MHz, CDCl3): δ 0.0,
120.6, 123.9, 124.8, 128.7, 128.8, 129.5, 132.2, 132.2, 133.7,
133.8, 135.4, 148.7. 19F NMR (377 MHz, CDCl3): δ −68.7.
HRMS (EI): calcd for C26H19F3NOP 449.1151, found
449.1149.
Acylation of the (carbethoxymethyl)triphenylphosphonium
bromide with trifluoroacetic anhydride in the presence of
triethylamine was carried out following a literature procedure.43
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Ethyl 4,4,4-Trifluoro-2-butynoate.
Article
Ethyl 2-Butynoate. Reaction of 0.11 g (1 mmol) of ethyl
2-butynoate and 0.15 g (1 mmol) of p-fluorobenzyl azide at 80 °C
(neat) provided two products as a mixture of stereoisomers, which
were separated by column chromatography.
Thermolysis of 4,4,4-trifluoro-3-oxo-2-(triphenylphos-
phoranylidene)butanoate at 190−230 °C (ca. 1 mmHg)
according to the known procedure gave ethyl 4,4,4-trifluoro-
2-butynoate.43 Spectral data was in good agreement with
previous literature reports. Yield 2.9 g (79%). 1H NMR
(CDCl3, 400 MHz): δ 1.38 (t, 3 H, J = 7.16), 4.40 (q, 2 H, J =
7.16)
Ethyl 1-(4-Fluorobenzyl)-4-methyl-1H-1,2,3-triazole-5-
carboxylate.
2-(3,3,3-Trifluoroprop-1-ynyl)pyridine.48
Yield 0.06 g (24%), colorless oil. 1H NMR (600 MHz, CDCl3): δ
1.37 (t, J = 7.3 Hz, 3H), 2.54 (s. 3H), 4.36 (q, J = 7.3 Hz, 2H),
5.85 (s, 2H), 7.01 (t, J = 8.8 Hz), 7.32 (dd, J = 8.8, 5.3 Hz). 13
C
Thermolysis of 1,1,1-trifluoro-3-pyridin-2-yl-3-(triphenyl-
phosphoranylidene)acetone gave 2-(3,3,3-trifluoroprop-1-
ynyl)pyridine. Yield 0.98 g (57%), colorless liquid, bp 153−
NMR (150 MHz, CDCl3): δ 12.5 (CH3−Ar), 14.1 (CH3CH2),
53.1 (CH2−Ph), 61.5 (OCH2), 115.5 (d, J = 20.9 Hz, 2C), 124.2
(Ctriazole), 129.8 (d, J = 7.7 Hz, 2C), 131.2 (Cq), 148.6 (Ctriazole),
156.9 (CO), 162.6 (d, J = 247.6 Hz, Cq). 19F NMR (377 MHz,
CDCl3): δ −113.6. HRMS (EI): calcd for C13H14FN3O2
263.1070, found 263.1070.
1
155 °C. H NMR (400 MHz, CD3CN): δ 7.40 (ddd, J = 7.5,
4.9, 0.8 Hz, 1H), 7.60 (d, J = 7.5 Hz, 1H), 7.76 (dt, J = 7.5,
1.9 Hz, 1H), 8.67 (d, J = 4.9 Hz, 1H). 19F NMR (377 MHz,
CD3CN): δ −51.1.
Cycloadditions. Ethyl 4,4,4-Trifluoro-2-butynoate. Reaction
of 0.17 g (1 mmol) of ethyl 4,4,4-trifluoro-2-butynoate and 0.15 g
(1 mmol) of p-fluorobenzyl azide in CH3CN at 22 °C provided two
products as a mixture of stereoisomers, which were separated by
column chromatography.
Ethyl 1-(4-Fluorobenzyl)-5-methyl-1H-1,2,3-triazole-4-
carboxylate.
Ethyl 1-(4-Fluorobenzyl)-4-(trifluoromethyl)-1H-1,2,3-
triazole-5-carboxylate.
Yield 0.18 g (69%), colorless oil. 1H NMR (600 MHz, CDCl3):
δ 1.42 (t, J = 7.3 Hz, 3H), 2.47 (s. 3H), 4.41 (q, J = 7.3 Hz,
2H), 5.52 (s, 2H), 7.04 (t, J = 8.7 Hz), 7.18 (dd, J = 8.7,
5.3 Hz). 13C NMR (150 MHz, CDCl3): δ 9.0, 14.3, 51.2, 60.9,
116.0 (d, J = 22.0 Hz), 129.0 (d, J = 8.8 Hz), 137.0, 138.1,
161.6, 162.7 (d, J = 248.7 Hz). 19F NMR (377 MHz, CDCl3):
δ −112.8. HRMS (EI): calcd for C13H14FN3O2 263.1070,
found 263.1070.
2-(3,3,3-Trifluoroprop-1-ynyl)pyridine. Reaction of 0.17 g
(1 mmol) of 2-(3,3,3-trifluoroprop-1-ynyl)pyridine and 0.15 g
(1 mmol) of p-fluorobenzyl azide in CH3CN (2 mL) at 80 °C pro-
vided two products as a mixture of stereoisomers, which were
separated by column chromatography.
Yield 0.147 g (46%), colorless oil. 1H NMR (600 MHz, CDCl3): δ
1.37 (t, J = 7.2 Hz, 3H), 4.40 (q, J = 7.2 Hz, 2H), 5.90 (s, 2H),
7.40 (t, J = 8.7 Hz), 7.38 (dd, J = 8.7, 5.3 Hz). 13C NMR (150
MHz, CDCl3): δ 13.6 (CH3), 53.4 (CH2−Ph), 63.0 (OCH2),
116.0 (d, J = 22.0 Hz, 2C), 119.8 (q, J = 268.5 Hz, CF3), 126.5
(Ctriazole), 129.8 (Cq), 130.4 (d, J = 8.8 Hz, 2C), 139.9 (q, J = 39.6
Hz, C−CF3), 156.9 (CO), 163.0 (d, J = 248.7 Hz, Cq). 19F NMR
(377 MHz, CDCl3): δ −112.4, −60.9. HRMS (EI): calcd for
C13H11F4N3O2 317.0787, found 317.0787.
2-(1-(4-Fluorobenzyl)-5-(trifluoromethyl)-1H-1,2,3-triazol-4-
yl)pyridine.
Ethyl 1-(4-Fluorobenzyl)-5-(trifluoromethyl)-1H-1,2,3-
triazole-4-carboxylate.
Yield 0.130 g (41%), colorless oil. 1H NMR (600 MHz, CDCl3): δ
1.41 (t, J = 7.3 Hz, 3H), 4.45 (q, J = 7.3 Hz, 2H), 5.74 (s, 2H),
7.06 (t, J = 8.5 Hz), 7.38 (dd, J = 8.5, 5.3 Hz). 13C NMR (150
MHz, CDCl3): δ 14.0 (CH3), 54.3 (CH2−Ph), 62.3 (OCH2),
116.1 (d, J = 22.0 Hz, 2C), 119.1 (q, J = 270.7 Hz, CF3), 128.3 (q,
J = 42.9 Hz, C−CF3), 129.1(Cq), 129.6 (d, J = 8.8 Hz, 2C), 139.8
(Ctriazole), 158.9 (CO), 163.1 (d, J = 248.7 Hz, Cq). 19F NMR (377
MHz, CDCl3): δ −112.0, −56.5. HRMS (EI): calcd for
C13H11F4N3O2 317.0787, found 317.0787.
Yield 0.24 g (76%), colorless oil. 1H NMR (600 MHz, CDCl3):
δ 5.81 (s, 2H), 6.89 (t. 2H, J = 8.52 Hz), 7.03 (t, 2H), 7.44 (m,
2H), 7.79 (t, 1H), 8.80 (d, 1H, J = 4.56 Hz). 13C NMR
(150 MHz, CDCl3δ 9.0 (CH3−Ar), 14.3 (CH3CH2), 51.2
(CH2−Ph), 60.9 (OCH2), 116.0 (d, J = 22.0 Hz, 2C), 129.0 (d,
J = 8.8 Hz, 2C), 137.0 (Ctriazole), 138.1 (Ctriazole), 161.6 (CO),
162.7 (d, J = 248.7 Hz, Cq). 19F NMR: δ −56.09, −112.59.
HRMS (ESI+): calcd for C15H10F4N4 345.0739, found
345.0751.
87
dx.doi.org/10.1021/jo201434w | J. Org. Chem. 2012, 77, 75−89

The Journal of Organic Chemistry
Article
2-(1-(4-Fluorobenzyl)-4-(trifluoromethyl)-1H-1,2,3-triazol-5-
yl)pyridine.
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I. A.; Agard, N. J.; Lo, A.; Bertozzi, C. R. Proc. Natl. Acad. Sci. U.S.A.
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Yield 0.05 g (17%), colorless oil. 1H NMR (600 MHz, CDCl3):
δ 5.74 (s, 2H), 7.06 (m, 2H), 7.30 (m, 3H), 7.81 (m, 1H), 7.93
(d, 1H, J = 7.92), 8.68 (d, 1H, J = 4.56). 13C NMR (150 MHz,
CDCl3): δ 53.0, 114.9 (d, J = 21.9), 122.4 (d, J = 51.5), 128.6
(d, J = 8.52), 135.6, 147.2 (d, J = 76.2), 148.6, 161.1 (d, J =
246.4). 19F NMR: δ −59.2, −113.03. HRMS (ESI+): calcd for
C15H10F4N4 345.0739, found 345.0736.
ASSOCIATED CONTENT
* Supporting Information
(20) Jewett, J. C.; Sletten, E. M.; Bertozzi, C. R. J. Am. Chem. Soc.
2010, 132, 3688.
■
S
(21) Some acceleration can be achieved via removal of steric
interactions in the TS. For example, Goddard identified negative steric
interactions between o-hydrogens of the benzene rings of DIBO and
the alkyl azide. Chenoweth, K.; Chenoweth, D.; Goddard, W. A. III
Org. Biomol. Chem. 2009, 7, 5255 . Tummatorn and Dudley reported
SPAAC coupling of a benzocyclononyne that included a methylene
spacer to minimize this steric interaction; see ref 25f.
(22) Ess, D. H.; Jones, G. O.; Houk, K. N. Org. Lett. 2008, 10, 1633.
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I. V.; Manoharan, M.; Kovalenko, S. V. Org. Lett. 2002, 4, 1119.
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2003, 125, 14014. (e) Alabugin, I. V.; Manoharan, M. J. Org. Chem.
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Geometries, energies and distortion analysis for all reactants,
products and transition states, 1D and 2D NMR spectra of
synthetic intermediates and products. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: alabugin@chem.fsu.edu.
■
ACKNOWLEDGMENTS
■
I.A. and G.D. are grateful to the National Science Foundation
(Grants CHE-0848686 and CHE-0749918) for support of this
research project.
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