Twisted Cycloalkynes and Remote Activation of “Click” Reactivity

Article abstract of DOI:10.1016/j.chempr.2017.07.011

The “twisted and bent” cyclodecyne structural motif, intertwined with dormant electronic effects, opens a conceptually powerful way to control “click” reactivity. The endocyclic heteroatoms of cyclodecynes provide dual electronic activation via hyperconju

Full text of DOI:10.1016/j.chempr.2017.07.011

Article
Twisted Cycloalkynes and Remote Activation
of ‘‘Click’’ Reactivity
Trevor Harris, Gabriel dos
Passos Gomes, Suliman
Ayad, ..., Megan Tuscan,
Kenneth Hanson, Igor V.
Alabugin
alabugin@chem.fsu.edu
HIGHLIGHTS
Increased ‘‘click’’ reactivity
through remote activation
Gram-scale, one-step preparation
of enantiopure cycloalkynes
Twisted cyclodecynes approach
reactivity of cyclooctynes
Experiments and computational
analysis reveal activating role of
remote interactions
Interaction between donor and acceptor groups incorporated in the backbone of
cycloalkynes can be partially disrupted by twisting. The additional electronic
energy accumulated as a result of this disruption can be harvested in the alkyne/
azide cycloaddition transition state, where an optimal conjugation pattern at a
remote location is restored. The design provides electronically activated
cyclodecynes that approach ‘‘click’’ reactivity of cyclooctynes. In addition, the
twisted cyclodecynes are chiral and thus add axial chirality to the toolbox of
properties introduced via ‘‘click’’ chemistry.
Harris et al., Chem 3, 1–12
October 12, 2017 ª 2017 Elsevier Inc.
http://dx.doi.org/10.1016/j.chempr.2017.07.011

Please cite this article in press as: Harris et al., Twisted Cycloalkynes and Remote Activation of ‘‘Click’’ Reactivity, Chem (2017), http://dx.doi.org/
10.1016/j.chempr.2017.07.011
Article
Twisted Cycloalkynes and Remote
Activation of ‘‘Click’’ Reactivity
Trevor Harris,1 Gabriel dos Passos Gomes,1 Suliman Ayad,1 Ronald J. Clark,1 Vladislav V. Lobodin,2
Megan Tuscan,1 Kenneth Hanson,1 and Igor V. Alabugin1,3,
*
SUMMARY
The Bigger Picture
Non-catalyzed alkyne/azide
cycloaddition, a widely used
‘‘click’’ reaction in interdisciplinary
scientific research, offers a
modular, practical, and metal-free
approach to building molecular
complexity in environments where
toxic and redox active species
should be avoided. In this paper,
we describe a fundamental
concept for increasing ‘‘click’’
reactivity through remote
The ‘‘twisted and bent’’ cyclodecyne structural motif, intertwined with dormant
electronic effects, opens a conceptually powerful way to control ‘‘click’’ reac-
tivity. The endocyclic heteroatoms of cyclodecynes provide dual electronic
activation via hyperconjugative (direct) and conjugative (remote) effects.
These effects are weakened by the geometric constraints imposed by the
twisted backbone, but structural reorganization in the transition state (TS) re-
moves these constraints and unlocks the power of remote electronic effects
for selective TS stabilization. Gram-scale synthesis and purification by recrystal-
lization make this an efficient and practical approach to enantiopure cycloal-
kynes. Experimental kinetics confirm that these twisted cyclodecynes can be
more reactive toward azides than activated cyclononynes and approach the
reactivity of cyclooctynes. Furthermore, cycloalkynes with a twisted polyaro-
matic backbone can potentially add axial chirality to the ‘‘click’’ chemistry
toolbox.
interactions with the hope of
leading to the development of
creative technological
innovations. This work also
introduces axial chirality as a
molecular property that can be
achieved by ‘‘click’’ chemistry,
which opens the door for the
future controlled creation of chiral
objects and environments from
achiral small molecules, polymers,
and surfaces.
INTRODUCTION
‘‘Click’’ chemistry brings functional group orthogonality, high yields, and broad
scope to diverse applications ranging from surface functionalization to drug de-
livery.1,2 However, the utility of the prototypical ‘‘click’’ reaction, the Cu-catalyzed
alkyne-azide cycloaddition,3–7 is hampered by the toxicity of copper salts toward
living systems and their deleterious effects on redox-sensitive nanoparticles.8–10
The strain-promoted alkyne-azide cycloaddition was shown to overcome these
limitations in bioorthogonal chemistry11–13 and surface chemistry.14–16 However,
strain-activated cycloalkynes often balance at the edge of instability, which
complicates both synthesis and applications of such reactive molecules.17,18
The search for more reactive ‘‘click’’ combinations continues as illustrated
by the inverse electron-demand Diels-Alder reaction between trans-cyclooc-
tenes and tetrazines and 1,3-dipolar cycloadditions between diazo groups and
acrylates.19–22
The seminal report by Baskin et al.23 of a ꢀ50-fold increase in reactivity of a di-
fluorinated cyclooctyne (DIFO) over the parent cyclooctyne indicated that other
factors can be harnessed to supplement strain activation. Our computational anal-
ysis illustrated that rate enhancement stems from hyperconjugative assistance in
the transition state (TS) promoted by the alignment of the sigma acceptor C–X
bond with the reacting alkyne p bond (Figure 1A).24 Because the C–X bond should
adopt antiperiplanar geometry to maximize the reactivity of cycloalkynes, the
optimal position for the heteroatom X is inside the cycle. Even though hypercon-
jugative assistance in cyclooctynes provides stabilization to both the reactant
Chem 3, 1–12, October 12, 2017 ª 2017 Elsevier Inc.
1

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10.1016/j.chempr.2017.07.011
TS
A
Reactant
destabilization
stabilization
Me
N
N
N
Increasing stability
and reactivity
+
X
X
F
Spring
loaded
Hyperconjugative
assistance
Blend activating effects
JOC, 2012
JACS, 2013
B
C
Planar
Twisted
Less Twisted
Planar
Twisted
N
Bn
‡
N
N
*
c-x
Direct
Direct
Remote
H
X
X
H2N
X
N
X
nx
*
Ar
Remote
X
X=C,O
H
Conjugated amines as stereoelectronic
chameleons
constrain and
twist
relief of
twist
unconstrained
structure
cyclodecynes
click TS
Figure 1. Modifying Reactivity with Stereoelectronic Effects
For a Figure360 author presentation of Figure 1, see http://dx.doi.org/10.1016/j.chempr.2017.07.011#mmc2.
(A) The combination of alkyne distortion and sigma acceptors in cyclooctynes leads to reactivity enhancement in click cycloadditions.24,25
(B) Disruption of nitrogen resonance by conformational changes affects the electronic properties of nitrogen.
(C) Structural changes in the backbone of cyclodecynes turn on direct and remote electronic effects.
Figure360: an author presentation of Figure 1.
(counterproductive for reactivity) and the cycloaddition TS, the overall reaction
acceleration is observed because the TS stabilization is greater.25 Although the
synthesis of endocyclic heteroatoms in cycloalkynes has been challenging, the
available results are promising.26–29 For example, Ni et al.27 have shown that a
cyclononyne with an endocyclic oxygen and nitrogen is comparable in reactivity
to DIFO.
The previous success of using C–X bonds in cycloalkynes relies heavily on their
utility as s acceptors. However, because of their dual nature to also serve as nX
donors, we thought to access this untapped potential through conjugative assis-
tance. For creative inspiration, we looked to twisted amides and twisted enamines
where their reactivity is coupled to bond rotation (Figure 1B).30–35 These ‘‘stereo-
electronic chameleons’’36 can switch their electronic nature simply by rotation
relative to the rest of the molecule. In this work, we offer a new approach to
selective TS stabilization in ‘‘click’’ cycloadditions through a combination of stereo-
electronic effects37 where the endocyclic heteroatom acts as both an acceptor,
through direct activation, and a donor, through remote activation (Figure 1C).
The heteroatom, which is remote from the alkyne, is misaligned with the adjacent
paryl system in the cycloalkyne, rotates, and forms stronger conjugative interactions
in the reaction TS, thereby unlocking the power of remote activation of ‘‘click’’
1Department of Chemistry & Biochemistry,
Florida State University, Tallahassee, FL 32306,
USA
reactivity.
Generally, the structural design of cycloalkynes in ‘‘click’’ chemistry includes alkyne
bending,13 sometimes amplified by other external factors such as ion sensing.38
The present design introduces twisting along the cycloalkyne backbone that starts
from the alkyne and passes through the endocyclic C–X bonds to a biaryl core.
We show that electronic energy stored in the twisted structure can be harvested
2National High Magnetic Field Laboratory,
Tallahassee, FL 32310, USA
3Lead Contact
*Correspondence: alabugin@chem.fsu.edu
http://dx.doi.org/10.1016/j.chempr.2017.07.011
2
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10.1016/j.chempr.2017.07.011
X
X
Cs2CO3, CH3CN
23°C, 24 hr
XH
XH
+
TsO
OTs
1
Ts = tosyl
Ns = nosyl
2-8
BIPOC, 2
rac-BINOC, 3
99%-(R)-BINOC, 4
BIPAC-Ts, 6
BIPAC-Ns, 7
BIPAC, 8
99%-(S)-BINOC, 5
O
O
O
O
O
O
O
O
TsN
NTs
NsN
NNs
HN
NH
68%
79%
80%
~1.5 g, 63%
79%
73%
44%
32%
~1.6 g, 68%
after single recrystallization
Figure 2. Synthesis of Cyclodecynes
For 2–7, 1H nuclear magnetic resonance yield determined with an internal standard. For 6–8, dimethylformamide, 35ꢁC, 72 hr. For 8, isolated yield; one-
pot cyclization-deprotection; see Supplemental Information.
in the ‘‘click’’ cycloaddition TS. In addition, the biaryl moiety introduces axial chirality
because restricted bond rotation creates atropisomers.39
RESULTS AND DISCUSSION
Introduction of a twisted chiral backbone into a cycloalkyne requires larger cycles
(i.e., cyclodecynes), which are intrinsically less strained than smaller cycloalkynes.
The loss of strain associated with the larger cycles makes the use of stereoelectronic
effects critical for the activation of cyclodecynes toward ‘‘click’’ cycloadditions. We
envisioned that the chiral architecture and the endocyclic heteroatoms could be
incorporated into the cycle from commercially available 2,20-biaryl nucleophiles
(Figure 2, top). A few examples of cycloalkynes incorporating a biaryl backbone
have been reported,40,41 with one example reported after this paper was submitted
for peer review.42
Assembly of the cyclodecyne frame involves simple nucleophilic substitutions. The
direct nucleophilic substitution approach to make smaller cycloalkynes is difficult
because of the entropic and enthalpic penalty for the formation of strained rings.
Instead, previous success of cyclononyne synthesis relied heavily on the Nicholas
reaction to assemble the ring, an approach that activates the electrophilic partner
but requires two additional steps to protect and deprotect the alkyne.27,28 Here,
direct access to the cycloalkyne is feasible through the favorable combination of
the mild base and low ring strain of cyclodecyne products. Furthermore, the use
of a mild base prevents undesired alkyne-allene isomerization.
Cesium carbonate was found to be an excellent base for the cyclization (Table S1).
Bistosylate of but-2-yne-1,4-diol 1 is a readily available electrophile (we prepared
22 g of 1 in a one-step 98% yield operation) with excellent reactivity toward
heteroatomic nucleophiles.43 Its reaction with 2,20-biphenol gave the target
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Figure 3. Structural Properties of Chiral Cyclodecynes
(A) Overlap of circular dichroism spectra for (R)-BINOC and (S)-BINOC.
(B) Summary of X-ray and solvent-corrected density functional theory (DFT) geometries. DFT values, (SMD = CHCl3)/M06-2X(D3)/6-311++G(d,p) level of
theory, are in parentheses. Angles are in degrees and shown as the absolute values. (SMD = CHCl3)/M06-2X(D3)/6-31+G(d,p) level for BIPAC-Ts.
(C) Correlation of chameleonic torsion and alkyne bending with the use of X-ray data.
(D) ORTEP of BIPOC, rac-BINOC, BIPAC, and BIPAC-Ts. Ellipsoids are at the 50% probability level. All non-hydrogen atoms were refined anisotropically,
whereas all hydrogen atoms were placed in their geometrically calculated positions and fixed. (Bottom) Various twisting modes in chiral cyclodecynes:
alkyne torsion, chameleonic torsion, and biaryl torsion. BIPAC has a similar framework (C(sp2)-NH-CH2-C(sp)) to cyclononyne ABSACN,28 however the
cyclononyne is more bent (159ꢁ).
2,20-biphenyldioxacyclodecyne (BIPOC) 2 in a 68% yield (Figure 2, bottom). The
optimized cyclization conditions can be extended to the more sterically demanding
racemic 2,20-binaphthol (BINOL) to obtain rac-2,20-binaphthyldioxacyclodecyne
(rac-BINOC) 3 in 79% yield. The individual (R) and (S) enantiomers of BINOL
(ꢀ99% purity) gave enantiopure (R)-BINOC 4 and (S)-BINOC 5 in 80% and
79% yields, respectively, without loss of chiral integrity (Figure S19). Circular
dichroism spectra of (R)- and (S)-BINOC displayed Cotton effects that resemble
the atropisomeric binaphthyl backbones of (R)- and (S)-BINOL (Figure 3A). To
compare the effect of endocyclic heteroatoms on reactivity, we also prepared
the nitrogen analogs BIPAC-Ts 6 and BIPAC-Ns 7 from the corresponding
bistosylate and bisnosylate of 2,20-biphenyldiamine. Under these conditions, the
direct use of 2,20-biphenyldiamine gave recovered starting diamine and tosylate,
presumably as a result of lower nucleophilicity of unsubstituted anilines. How-
ever, a one-pot cyclization-deprotection sequence with the more reactive nosylate
4
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10.1016/j.chempr.2017.07.011
produced the free bisamine 8 (2,20-biphenyldiaminocyclodecyne, BIPAC) in 32%
yield.
Twisting and bending of the cyclodecynes were elucidated with X-ray analysis and
computations (Figures 3B and 3D). The magnitude of alkyne bending (163ꢁ–169ꢁ)
is comparable (or slightly lower) with that in known cyclononynes.27 The alkyne
torsions F1 range from 4ꢁ to 25ꢁ, indicating trans-bent geometry, an overlooked
structural distortion in cycloalkynes, most likely caused by the twisted backbone
(Figure S11). The ‘‘chameleonic’’ torsion F2 shows the alignment of the C(sp3)–X
bonds with the aryl ring and reflects delocalization (or lack thereof) of heteroatom
lone pairs into the aryl ring. In the near-perpendicular geometries (99ꢁ–111ꢁ)
observed, the heteroatoms p-type lone pair is misaligned with the aromatic
p system. The biaryl torsions F3 range from 107ꢁ to 115ꢁ, much closer to the perpen-
dicular geometry than 2,20-biphenol (torsion angle of 48ꢁ).44,45
Remarkably, crystal data of (R)-BINOC revealed three distinct molecules (mol1, mol2,
and mol3) in the asymmetric unit cell (Figure S7). The variable geometries observed
for the three molecules of (R)-BINOC indicate that the backbone of cyclodecynes is
sufficiently flexible to respond to changes in its chemical environment. Analysis of
the structural parameters for the cyclodecynes reveals a strong correlation between
‘‘chameleonic’’ torsion F2 and alkyne bending (Figure 3C); forcing the C(sp3)–X bonds
to be orthogonal to the aryl ring partially alleviates alkyne bending. Both effects are
destabilizing and the tug-of-war between them can be used to store potential energy
that can be released en route from reactants to products.
We have used computations to quantify the effect of strain on the reactivity of four
cyclodecynes twisted in relation to the carbocyclic analog biphenylcyclodecyne
(BIPC). First, the cycloadditions of BIPOC and BIPAC are ꢀ8 kcal/mol more exergonic
than that of BIPC, indicating greater energy ‘‘stored’’ in the heterocyclic cyclode-
cynes. Furthermore, in sharp contrast to the analogous cyclooctynes,25 the presence
of endocyclic oxygen atoms does not alleviate strain in relation to BIPC (Figure 4A,
left). We attribute this finding to the twisted geometry adopted by the starting
materials where the C–X bond must make a choice whether to align with the aryl
group or with the alkyne. Another stark difference to cyclooctynes is that ring fusion
decreases the cyclodecyne strain energy (by ꢀ2–3 kcal/mol). This behavior can be
attributed to the removal of torsion strain and transannular interactions.
Initially, the reactivity of cyclodecynes was evaluated from competition between
BIPOC and an analogous electronically activated acyclic alkyne toward benzyl azide
(Scheme S1). In agreement with the superior reactivity of BIPOC, less than 1% of the
product was derived from the linear alkyne as per 1H nuclear magnetic resonance
analysis of the reaction mixture. Given that thiols are common competing traps for
cyclooctynes, we tested the selectivity of the cycloaddition with an azide in the pres-
ence of an equimolar amount of thiophenol. The reaction gave 92% of the triazole
product (Scheme S2).46
Experimental second-order rate constants and activation parameters provided
quantitative evaluation of the ‘‘click’’ reactivity of twisted cyclodecynes BIPOC,
BINOC, BIPAC-Ts, and BIPAC in reaction with benzyl azide (Figures 4B and
S20–S39 and Schemes S3–S10 for Arrhenius and Eyring plots). These experimental
trends were corroborated with computational analysis (Figure 4A, right). Although
endocyclic acceptors have a different effect on ring strain, they increase reactivity
similar to cyclooctynes25 and cyclononynes,27,28 suggesting
a common TS
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Reactivity Evaluation
Strain Evaluation
N
Bn
N
N
X
X
X
X
X
+
X
X
BnN3
X
X = CH2 = BIPC
H
X
CH2
NH
O
6.6
3.9
7.5
O
O
X
X
X
X
E‡
E
X
CH2 16.9
-78.4
-85.9
-86.4
X
X
O
O
NH
13.4
O
12.7
CH2 20.6
H
X
CH2
NH
O
NH
18.5
X
X
3.2
1.5
5.9
H = 8.2
O
E‡
E
13.8
(SMD=CHCl3)/
M06-2X(D3)/6-311++G(d,p)
Gold et al,
JACS, 2013
(SMD=H2O)/ M06-2X(D3)/
6-311++G(d,p)
10.6 -85.7
Energies in kcal/mol
BIPAC-Ts
BIPOC
BIPAC
rac-BINOC
INCREASING REACTIVITY
F
F
OR2
Ts
9
9
9
O
O
10
X
X
N
10
S
8
9
Ts
R
N
O
OMe
O
R1
OMe
OMe
DIFN
2014
0.059
Tomooka
2015
BIPOC/BIPAC
2017
BONO
2012
BINOC
2017
OCT
Tomooka
2015
2004
X=O, 0.16
X=NH, 0.17
k (x10-3) M-1s-1
0.081
0.46
0.62
2.4
19
1.0
1.4
2.8
7.8
11
41
320
relative rate
Figure 4. Strain and Reactivity of Cyclodecynes
(A) Computational evaluation of strain and reactivity with isodesmic equations and activation energies, respectively.
1
(B) Experimental second-order rate constants determined through H nuclear magnetic resonance kinetics with benzyl azide at 25ꢁC in CDCl3 and
activation parameters (in kcal/mol). Kinetic experiments were performed in triplicate and the average rate is reported. The second-order rate constant
for BIPOC with benzyl azide at 25ꢁC in CD3CN is 0.18 3 10ꢂ3 Mꢂ1 sꢂ1
.
(C) Correlation between X-ray chameleonic torsion and experimental DGz for BIPOC, BINOC, BIPAC-Ts, and BIPAC.
(D) Literature precedents of non-catalyzed cycloadditions of alkynes with benzyl azide. Note: all kinetics display second-order rate constants in Mꢂ1 sꢂ1
at 25ꢁC in CD3CN.13,27 BIPOC and BINOC rate constants reported are in CDCl3. The changes in reactivity for BIPOC in different solvents are small.
stabilizing effect, i.e., hyperconjugation. The enthalpy of activation for BIPOC is low
(11.4 kcal/mol) but, as expected for a bimolecular process, the unfavorable entropic
contribution raises the free energy of activation (23.0 kcal/mol at 37ꢁC). BINOC
with an enthalpy of activation of 10.7 kcal/mol is ꢀ10-fold more reactive than BIPOC.
The experimental kinetics suggest strong correlation between the free energy of
activation and ‘‘chameleonic’’ torsion F2 (Figure 4C). The more the molecules are
6
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Figure 5. Distortion-Interaction Analysis
(A) Activation, reaction, interaction, and distortion energies.
(B) Correlation of total distortion energy and activation energy.
twisted from the perpendicular geometry, the lower is the activation barrier (see
Figures S12–S16 for additional correlation graphs). Similar but slightly weaker corre-
lation was found with alkyne bending (Figure S17).
It is instructive to compare the reactivity of BIPOC and BINOC with known cycloal-
kynes in Figure 4D. Gratifyingly, twisted cyclodecynes outcompete many of their
smaller rivals, cyclononynes. For example, BINOC is more reactive than difluori-
nated cyclononyne (DIFN),47 including an activated cyclononyne with endocyclic
nitrogen and sulfur atoms and BONO.48 Furthermore, BINOC reacts only four times
slower than OCT, a monosubstituted cyclooctyne. Surprisingly, when a strong
acceptor C(sp3)–O is exchanged for a weaker C(sp3)–N acceptor (BIPOC/BIPAC),
neither the experimental rate nor the free energy of activation change; BIPAC is
very similar in reactivity to BIPOC.
Furthermore, BIPAC-Ts reacts with benzyl azide ꢀ100-fold slower than BIPAC. This
observation further contradicts the expectation that a stronger acceptor should
increase reactivity. The lower reactivity of BIPAC-Ts agrees well with an activation
enthalpy of 15.8 kcal/mol and the decreased alkyne angle strain (169ꢁ) in the X-ray
geometry. Distortion-interaction energy analysis49 (Figure 5B) revealed that, relative
to the all-carbon analog BIPC, the endocyclic acceptors lower total distortion
energies. This trend is consistent with hyperconjugative assistance of propargylic
C–X acceptors to alkyne bending and alkyne-azide bond formation identified by
us earlier.25 However, BIPAC does not follow the usually observed correlation
between the activation barrier and the total distortion penalty. Although BIPAC’s
alkyne geometry distorts the most from the ground state geometry in the TS
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(166ꢁ–159ꢁ), paradoxically this TS also has the lowest total distortion energy among
the four entries in Figure 5A.
The paradoxical features of BIPAC stem from unique constraints that twisted
cyclodecynes impose on the propargylic heteroatoms connected to the biaryl
core. Each C–X moiety is sandwiched between the triple bond and the aryl group.
In the absence of structural constraints, the C–X bridge is expected to play distinctly
different electronic roles toward functionalities at its opposing ends: serve as a
s*C–X acceptor (hyperconjugation) in relation to the alkyne but act as the nX donor
in relation to the aryl group (conjugation). Because of the geometric constraint
in the twisted cycloalkyne framework, both interactions are weakened. As the cyclo-
decynes structurally reorganize in the TS, these conjugative interactions are
strengthened and stabilize the TS.
We quantified the conjugative nX/pꢃCCaryl interactions with natural bond orbital
(NBO) analysis by deleting the orbital specific interactions and recalculating the
wavefunction energy. Although the usual conjugation (nX/pꢃCCaryl) is weakened
in the cycloalkynes by geometric constraints, this interaction increases in the
TS. For oxygen, which has two lone pairs, conjugation cannot be completely
switched off in the cycloalkyne, and the change from ground state to TS is
moderate as reflected in a 4 kcal/mol increase in the NBO energies of the respec-
tive interactions (DEdel). However, unlike oxygen, nitrogen has only one lone
pair and the change in NBO (nX/pꢃCCaryl) conjugation energy is much larger
(DEdel ꢀ10 kcal/mol) (Figure 6A). The geometric assistance to resonance is further
facilitated by rehybridization50 of the nitrogen lone pair (sp5 to sp7). This increase
in conjugative stabilization through the activation of remote stereoelectronic inter-
actions explains the low total distortion energy in the TS for BIPAC and similar
reactivity to BIPOC.
Because NBO interaction energy quantifies only a single component from the com-
plex combination of electronic, electrostatic, and structural effects, we have also
evaluated the total energy cost of these distortions directly by using dihedral scans
shown in Figure 6B. The chameleonic torsions for BIPOC and BIPAC (78ꢁ and 72ꢁ,
respectively) indicate the presence of energy stored by the geometric constraints
of a strained cycle. Computational analysis confirmed that the out-of-plane C–X
bonds rotate in the TS to become less twisted and increase conjugation with the
aryl rings. Such change brings only 0.2 kcal/mol (ꢀ0.1 3 2) for BIPOC where,
because of the presence of two lone pairs at oxygens, the resonance cannot
be completely switched off by rotation. However, stabilization is much larger
(ꢀ2 kcal/mol) for BIPAC, a better ‘‘chameleon.’’ Increased reactivity of BIPAC reveals
that the modulation of aniline resonance by structural constraints finds a new role in
alkyne cycloadditions.
An independent experimental confirmation for the suggested changes in conjuga-
tion between the starting 2,20-biaryl nucleophiles, cyclodecynes, and the triazole
products can be provided by UV-visible (UV-vis) spectroscopy (Figure 6C). In the
twisted cyclodecynes, where the lone pairs are misaligned because of geometric
restraint, a hypsochromic shift is observed in relation to the acyclic structures where
the lone pairs can have unobstructed communication with the aryl rings. The
azide/alkyne ‘‘click’’ reaction partially relieves the twisting of the backbone and re-
stores the lone pair/biphenyl communication, leading to a bathochromic shift in
the triazole product in relation to the alkyne. These findings are fully supported by
the trends in the computed spectra that reproduce the magnitude of the spectral
8
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Figure 6. Stereoelectronic Chameleons in Twisted Cyclodecynes
(A) Hybridization, evaluation of conjugation via NBO deletions of nN/pꢃCCaryl interactions for BIPOC and BIPAC, and geometric changes account for
BIPAC’s reactivity.
(B) CXCC dihedral scans for anisole (X = O, red) and N-methylaniline (X = N, blue). The CXCC dihedrals for BIPOC and BIPAC are shown in their
respective parent systems’ potential energy surface (PES) scans to illustrate their ‘‘stored’’ energy. CXCCz indicates dihedrals for their respective click
reactions transition states.
(C) (Left) Experimental UV-vis spectra of 2,20-biaryl nucleophiles, BIPOC, BIPAC, and corresponding triazole products (normalized absorptions). For the
calculated TD-DFT UV-vis spectra of 2,20-biaryl nucleophiles, BIPOC, BIPAC, and corresponding products that show the identical trend, see the
Supplemental Information. (Right) Selected MOs involved in the TD-DFT transitions of BIPOC and BIPAC.
Chem 3, 1–12, October 12, 2017
9

Please cite this article in press as: Harris et al., Twisted Cycloalkynes and Remote Activation of ‘‘Click’’ Reactivity, Chem (2017), http://dx.doi.org/
10.1016/j.chempr.2017.07.011
shifts and illustrate that the heteroatom lone pairs are involved in the multiconfigura-
tional excitations (Figure S1).
In summary, twisted cyclodecynes are stable crystalline compounds available via a
mild and scalable one-step synthetic procedure, which can be isolated by filtration
and purified by recrystallization. Although the present work did not take advantage
of the chirality of twisted cyclodecynes, we hope the large pool of available chiral
biaryls will open synthetic access to many new chiral cycloalkynes in the future,
facilitating applications of ‘‘click’’ chemistry for the creation of asymmetric assem-
blies or the transfer of chirality.51 This work illustrates how structural reorganization
in the TS can unlock the power of remote electronic effects for selective TS stabiliza-
tion. In the present design, the embedded heteroatoms provide TS stabilization dur-
ing the ‘‘click’’ reaction with azides via a combination of hyperconjugative acceptor
and conjugative donor effects. In particular, the aza-cyclodecyne BIPAC draws
increased reactivity from a remote stereoelectronic effect on the basis of modulation
of aniline resonance. We hope that this concept will lead to new creative designs that
can take full advantage of selective TS stabilization for the development of fast and
reliable non-catalyzed ‘‘click’’ reactions.
EXPERIMENTAL PROCEDURES
Circular dichroism spectra were obtained with an AVIV 410 CD spectrometer
with a 2 mm 3 4 cm quartz cuvette in methylene chloride. The UV-vis spectra
were recorded at room temperature with an Agilent Cary 60 UV-vis spectrophotom-
eter with
a 1 cm 3 4 cm quartz cuvette in methylene chloride. All
measurements were performed with neat solvent as the blank. Full details on
the computational analysis and their references are present in the Supplemental
Information. All calculations were performed with Gaussian ’09 D.01. We used
the (SMD = solvent)/M06-2X(D3)/6-311++G(d,p) level of theory; SMD = H2O was
used for the preliminary calculations and ring strain evaluations; SMD = CHCl3
was used for everything else. NBO6 was used to evaluate second-order perturba-
tion interactions at the (SMD
= CHCl3)/M06-2X(D3)/6-311++G(d,p) level of
theory. Because of basis set size restrictions, deletions were performed at
the (SMD = CHCl3)/HF/6-311G(d,p) level of theory with NBO6 interfaced with
Gaussian ’09.
Full experimental procedures can be found in the Supplemental Information.
ACCESSION NUMBERS
The data for X-ray crystallographic structures 2–4, 6, 8, 10, and 12 have been depos-
ited in the Cambridge Crystallographic Database Center under accession numbers
CCDC: 1561087, 1561089, 1561093, 1561091, 1561092, 1561088, and 1561090,
respectively.
SUPPLEMENTAL INFORMATION
Supplemental Information includes computational details, Supplemental Experi-
mental Procedures, 67 figures, 10 schemes, 1 table, and 7 data files and can be
found with this article online at http://dx.doi.org/10.1016/j.chempr.2017.07.011.
AUTHOR CONTRIBUTIONS
T.H. contributed to project conception and development, syntheses, crystal growth,
kinetics, UV-vis, writing of the manuscript and Supplemental Information, and
supervision of M.T.; G.d.P.G. performed all calculations, contributed to theoretical
10
Chem 3, 1–12, October 12, 2017

Please cite this article in press as: Harris et al., Twisted Cycloalkynes and Remote Activation of ‘‘Click’’ Reactivity, Chem (2017), http://dx.doi.org/
10.1016/j.chempr.2017.07.011
discussions, helped create figures, and assisted in writing the manuscript and Sup-
plemental Information; S.A. performed circular dichroism, UV-vis, chiral supercritical
fluid chromatography, and optical rotation experiments; R.J.C. performed the X-ray
crystallography; V.V.L. assisted with mass spectrometry characterization using Four-
ier transform ion cyclotron resonance; M.T. assisted in syntheses and kinetics; K.H.
contributed to interpretation of the photophysical results and supervised S.A;
I.V.A. guided project development and writing of the manuscript and supervised
T.H. and G.d.P.G.; and all authors commented on the manuscript during its
preparation.
ACKNOWLEDGMENTS
We are grateful to the National Science Foundation (NSF) (CHE-1465142) for sup-
port of this research. We are also grateful to Dr. B. Gold and Prof. G. Dudley for help-
ful discussions. We would like to thank the Florida State University Research
Computing Center and the NSF XSEDE (TG-CHE160006) for the allocation of
computational resources. G.d.P.G. is grateful to IBM for the 2016 IBM PhD Scholar-
ship. A portion of this work was performed at the National High Magnetic Field Lab-
oratory, which is supported by NSF Cooperative Agreement no. DMR-1157490 and
the State of Florida. T.H. would also like to thank Logan Krajewski for his assistance
with mass spectrometry.
Received: April 30, 2017
Revised: June 8, 2017
Accepted: July 20, 2017
Published: September 28, 2017
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