Orbital Crossings Activated through Electron Injection: Opening Communication between Orthogonal Orbitals in Anionic C1-C5 Cyclizations of Enediynes

Article abstract of DOI:10.1021/jacs.6b08540

Generally, the long-range electronic communication between spatially orthogonal orbitals is inefficient and limited to field and inductive effects. In this work, we provide experimental evidence that such communication can be achieved via intramolecular electron transfer between two degenerate and mutually orthogonal frontier molecular orbitals (MOs) at the transition state. Interaction between orthogonal orbitals is amplified when the energy gap between these orbitals approaches zero, or at an “orbital crossing”. The crossing between two empty or two fully occupied MOs, which do not lead to stabilization, can be “activated” when one of the empty MOs is populated (i.e., electron injection) or one of the filled MOs is depopulated (i.e., hole injection). In reductive cycloaromatization reactions, such crossings define transition states with energies defined by both the in-plane and out-of-plane π-systems. Herein, we provide experimental evidence for the utility of this concept using orbital crossings in reductive C1-C5 cycloaromatization reactions of enediynes. Communication with remote substituents via orbital crossings greatly enhances regioselectivity of the ring closure step in comparison to the analogous radical cyclizations. We also present photophysical data pertaining to the efficiency of electron injection into the benzannelated enediynes.

Full text of DOI:10.1021/jacs.6b08540

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Article
Orbital Crossings Activated Through Electron Injection:
Opening Communication between Orthogonal
Orbitals in Anionic C1-C5 Cyclizations of Enediynes
Paul W Peterson, Nikolay E. Shevchenko, Boris Breiner, Mariappan Manoharan,
Forat Lufti, Jess Delaune, Margaret Kingsley, Kirill Kovnir, and Igor V. Alabugin
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 06 Nov 2016
Downloaded from http://pubs.acs.org on November 6, 2016
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Orbital Crossings Activated Through Electron
Injection: Opening Communication between
Orthogonal Orbitals in Anionic C1-C5 Cyclizations of
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Enediynes
Paul W. Peterson, Nikolay Shevchenko, Boris Breiner, Mariappan Manoharan, Forat Lufti, Jess
Delaune, Margaret Kingsley, Kirill Kovnir, and Igor V. Alabugin*
Department of Chemistry and Biochemistry, Florida State University, 95 Chieftain Way, Tallahassee, FL 32301
USA.
*corresponding email: alabugin@chem.fsu.edu
____________________________________________________________________________
ABSTRACT:
Generally, the long-range electronic communication between spatially orthogonal orbitals is
inefficient and limited to field and inductive effects. In this work, we provide experimental
evidence that such communication can be achieved via intramolecular electron transfer between
two degenerate and mutually orthogonal frontier molecular orbitals (MOs) at the transition state.
Interaction between orthogonal orbitals is amplified when the energy gap between these orbitals
approaches zero, or at an “orbital crossing”. The crossing between two empty or two fully
occupied MOs, which do not lead to stabilization, can be “activated” when one of the empty MOs
is populated (i.e., electron injection) or one of the filled MOs is depopulated (i.e., hole injection).
In reductive cycloaromatization reactions, such crossings define transition states with energies
defined by both the in-plane and out-of-plane π-systems. Herein, we provide experimental
evidence for the utility of this concept using orbital crossings in reductive C1-C5
cycloaromatization reactions of enediynes. Communication with remote substituents via orbital
crossings greatly enhances regioselectivity of the ring closure step in comparison to the
analogous radical cyclizations. We also present photophysical data pertaining to the efficiency of
electron injection into the benzannelated enediynes.
______________________________________________________________________________
INTRODUCTION:
The usual paradigm for using electronic effects in organic chemistry is based on the notion
that efficient orbital overlap is needed to transmit conjugation1 and hyperconjugation.2 For
example, the importance of orbital overlap is the conceptual foundation for the concept of
stereoelectronic effects.3 Although this paradigm served well many generations of chemists and
will continue to apply to the majority of organic reactions, it cannot help to control those
reactions where such overlap is missing. A textbook example for the interruption of electronic
communication imposed by spatial orthogonality is provided by steric inhibition of resonance
(Figure 1). For example, once the acceptor nitro group is rotated so its π-system is orthogonal to
the aromatic π-system of nitrobenzene, the accelerating effect of the acceptor on nucleophilic
aromatic substitution is greatly diminished.4
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Figure 1: Steric inhibition of resonance: interruption of electronic communication imposed
by spatial orthogonality.
C1-C6 cyclizations of enediynes as a probe of remote substituents:
A less known but conceptually analogous example of poor communication between
orthogonal π-systems is provided by the inefficiency of remote substituent effects in the
Bergman cyclization5 of benzannelated enediynes. Because remote substituents attached to the
out-of-plane aromatic π-system cannot transmit electronic effects to the developing σ-radicals
created from the orthogonal (in-plane) π-system,6 the rate of this reaction is insensitive to the
substituent effects (Figure 2).7,8 This limitation has practical consequences because the Bergman
cyclization and related cycloaromatization reactions9 find applications in the design of antitumor
agents,10 sequence-specific DNA cleavers,11 synthesis of polycyclic compounds,12 and
preparation of polymeric materials.13 The same limitation in the substituent control applies every
time when a reaction involves breaking of a σ- or a π-bond in the presence of an orthogonal π-
system (e.g., C-X bond scission in vinyl or aryl halides, other neutral cycloaromatization
reactions etc).
Figure 2: The inefficiency of substituent effects in the Bergman cyclizations of the
benzannelated enediynes originates from orthogonality of the developing radical centers and the
aromatic π-system. In contrast, the same remote substituents have pronounced effect on the
activation energies of radical-anionic Bergman cyclization UBLYP/6-31G** barriers vs.
Hammett σ constants).
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Earlier, we provided computational evidence that analogous substituent effects become
surprisingly large upon one-electron reduction of the enediynes (Figure 2).14 This unusual trend
suggested a new approach for overcoming inefficiency of orbital control in cycloaromatization
processes where transition state energies are determined by both the out-of-plane and the in-
plane MOs coupled via intramolecular electron transfer. This approach allows one to manipulate
the TS energies efficiently by utilizing reactant stabilization/destabilization as a way to control
the activation barrier. The conceptual advantage of this approach is in its ability to fine-tune the
relative energies of the two “non-interacting” MO sets in a rational way.15
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Figure 3: MO energy changes in the radical anionic Bergman cyclization. Changes in the
out-of-plane enediyne MO energies are independent of changes in the in-plane enediyne MOs.
The possibility of independent manipulation of MO energies allows one to control the relative
energy needed to reach the crossing point between the two MO sets by either stabilization or
destabilization of one of the sets while the other set is kept constant. Electron donors raise the
out-of-plane MO energies (reactant destabilization). Electron acceptors decrease the out-of-plane
MO energies (reactant stabilization).
In this approach, even negligible orbital interactions are sufficiently amplified when the
energy gap between the interacting orbitals approaches zero (or when orbitals and the electronic
states16 corresponding to the different population of these orbitals “cross”). This behavior follows
from the known inverse dependence17 of the orbital interaction energy, ꢀEstab, between the
energy gap between the interacting orbitals ꢀEA-B (Figure 4). The role of the energy gap on the
interaction energies is well-documented.18 For example, it provides the basis of the common
HOMO-LUMO approximation for the description of organic reactivity.
As the energy gap between the two interacting orbital approaches zero, the orbital mixing
pattern changes from the 2nd to the 1st order and even small orbital overlap can be converted into
a significant electronic interaction (Figure 4 bottom). In reductive cycloaromatization reactions,
the electronic communication at the MO crossing enables electron transfer between the
orthogonal π-systems. Because the crossing from the reactant to product electronic states
involves an out-of-plane MO and in-plane MO, the TS energy is sensitive to both orthogonal π-
arrays (vide infra).
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E
A and B are separated energetically
A
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A: empty
ꢀEA-B
ꢀEA-B is large: spatial overlap,
SA-B, between A and B is
needed to achieve stabilization
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B
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ꢀEstab
B: occupied
ꢀEstab ~ S2A-B/ꢀEA-B
structural or electronic change
"MO crossing": states mix
E
A: empty
B: empty
A
A
B
B
B: occupied
ꢀEA-B ~ 0
A: occupied
Figure 4: Amplification of orbital interactions by decreasing energy gap between the interacting
orbitals. Orbital crossings allow intramolecular electron transfer between the orthogonal orbitals
A and B.
Creating an “orthogonal MO” crossing:
Two conditions are necessary for creating an MO crossing: 1) one MO should significantly
change its energy and 2) the second MO should either stay at the same energy level or move
towards the first MO (i.e., a higher energy MO moves up as a lower energy MO moves down).
These conditions are satisfied if a bond is either broken or distorted in the presence of an
orthogonal π-system.19 In particular, cycloaromatization reactions provide a very convenient tool
for the study of MO crossings because these reactions always include two orthogonal π-systems,
one of which directly participates in the formation of new bonds whereas the other remains an
apparent bystander.20 This situation creates two crossings that typically correspond to the
HOMO/HOMO-1 crossing in the occupied manifold and LUMO/LUMO+1 crossing in the
virtual orbitals.
This situation is illustrated in Figure 5. As a direct result of the bond-forming interaction, the
in-plane π-orbitals are transformed into a σ-bond and a pair of non-bonding MOs (two radical
centers). Consequently, the highest occupied in-plane MO (HOMO-1) at the TS is destabilized to
the extent where it becomes the new HOMO. On the other hand, the respective unoccupied in-
plane MO (LUMO+1) is stabilized and becomes the LUMO in the TS. In other words, the
reactant HOMO and LUMO correspond to out-of-plane orbitals whereas, at the shorter C1-C6 or
C1-C5 distances, the frontier MOs are localized at orthogonal (in-plane) non-bonding (radical)
orbitals.
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Figure 5. Crossings of in-plane and out-of-plane frontier MOs in neutral and radical-anionic Bergman
cyclizations (similar crossings for photochemical, dianionic and radical-cationic cyclizations involve the
same MOs but differ in the number of electrons).
Because MOs in the top crossing in Figure 5 left are populated with zero electrons whereas
MOs in the bottom crossing have four electrons, these MO crossings have little importance in the
thermal Bergman cyclization. Interactions between two orbitals which are either fully filled or
completely empty do not lead to stabilization.
Role of electron injection: Only once the donor orbital is at least partially filled (with either
one or two electrons) and/or once the acceptor orbital is at least partially empty (either zero or
one electrons), the stabilization is possible, as illustrated in the simplest case by 1e,2c, 2e,2c and
3e,2c bonding patterns in Figure 6. Note that each of these patterns is directly accessible in
cycloaromatization reactions if either an electron or a hole is “injected”. In particular, the top
crossing in Figure 5 (left) can be activated by electron reduction whereas the bottom crossing in
Figure 5 (right) can be activated via oxidation. The reductive MO crossings are likely to be
important in the σ-C-Hal bond scission in the radical anions of aromatic halides, a process that
starts to find a number of elegant synthetic applications.21 (PP: references added)
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Figure 6. Difference in the number of electrons involved in the MO crossings activated by reduction
or oxidation of a molecule containing orthogonal π-arrays. Labels “in” and “out” correspond to the in-
plane and out-of-plane MOs. Note also that photochemical excitation (not shown here) will activate both
1e and 3e (hole) crossings.
Vanishing HOMO-LUMO gap, or when “forbidden reactions” are not really forbidden:
As we discuss above, a MO crossing has to involve an empty and a filled orbital in order to
influence chemical reactivity. In this situation, the HOMO-LUMO energy gap approaches zero.
Engineering such situation in a closed shell molecule in its ground state is difficult, even though
many applications in molecular electronics aim at minimizing this parameter. Furthermore, the
“symmetry forbidden”22 scenario where the reactant HOMO correlates with the product LUMO
and vice versa, imposes additional electronic penalty on the activation barrier.
However, when such crossings are activated either via an electron or a hole injection, the
situation is different and the energy penalty due to the “forbiddeness” is minor. For example, the
LUMO-SOMO23 gap in the radical anions (Figure 5, Figure 7) is significantly lower than the
HOMO-LUMO gap in the neutral molecules and, thus, no substantial additional barrier is
imposed by the crossings. As the results, the anionic cycloaromatizations are “forbidden” only in
a formal sense without a substantial energy penalty associated with the MO crossing.
virtual MOs
virtual MOs
virtual MOs
smaller gap
smaller gap
LUMO
HOMO
LUMO
SOMO
ꢀEHOMO/LUMO
ꢀESOMO/LUMO
LUMO
electron
injection
electron
injection
large
gap
ꢀEHOMO/LUMO
HOMO
occupied MOs
occupied MOs
occupied MOs
Figure 7. Changes in the HOMO/LUMO (and SOMO/LUMO) gaps due to the injection of one and two
electrons in a typical molecule with a substantial ground state HOMO-LUMO. Hole injection (one-
electron oxidation) will also lead to a molecule with a low gap between SOMO (corresponding to the
HOMO in the neutral reactant) and the next occupied MO (HOMO-1 in the neutral reactant). For
simplicity, the effect of charge injection on MO energies is neglected.
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In summary, the one-electron reduction of enediyne to the corresponding radical-anion
populates the out-of-plane LUMO of the enediyne moiety. At the TS (the crossing), the electron
is “transferred” between the orthogonal π−systems to the new (in-plane) LUMO. Moreover,
analysis of electron density changes along the reaction path found that the activation barrier for
both C1-C6 and C1-C5 cyclizations of enediyne radical-anions can be described as the avoided
crossing between states corresponding to the population of the out-of-plane and in-plane MOs.14
As long as the electron population of the two crossing MOs is different, even small electronic
coupling between the two MOs will lead to communication between the orthogonal orbitals.
Such crossings do not affect thermal reactions whether the participating MOs are either empty or
completely occupied because neither zero- nor four-electron interactions are stabilizing.
However, both reduction and oxidation can activate the effect. This work reports experiments
aimed to determine the relative efficiency of such electronic control through 1e- and 2e-MO
crossings.
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C1-C5 cyclizations of enediynes as a probe of remote substituent effects: Although such
MO crossings are general and should occur in a range of processes where either a σ- or a π-bond
is broken in the vicinity of an orthogonal π-system in the transition state where a structural
change could lead to crossings of in-plane and out-of-plane MO’s, we will concentrate on
reductive C1-C5 cyclizations of enediynes.
There are several reasons for the choice of C1-C5 cyclization as a model reaction. Our
previous theoretical studies unraveled the combination of factors that renders the C1-C5
cyclization more favorable than the Bergman (C1-C6) pathway. Although the thermal version of
this process is difficult,24 this cyclization can be carried out either via a classic chemical
reduction with Li-naphthalenide (Whitlock and coworkers)25 for enediynes with terminal Ph
substituents or via photoinduced electron transfer (PET) for activated enediynes with acceptor
tetrafluoropyridinyl (TFP) substituents.26 In the latter case, the reaction cascade continues
towards the formation of more reduced (indene) products via an additional PET step.
The photoreductive C1-C5 cyclization is also interesting from a practical perspective. Most
importantly, the overall enediyneꢀ indene transformation corresponds to the formal transfer of
four “H-atoms” from the environment – twice that of the Bergman cyclization. We have shown
that ratio of double strand (ds) to single strand (ss) DNA cleavage by bis-TFP enediynes/lysine
conjugates27,28 rivals that of natural antibiotic calicheamicin29 whereas the analogous bis-lysine
conjugates provide even greater ds:ss ratios.30 We established that PET is indeed involved in the
mechanism of DNA photodamage31 and that it is possible to direct such DNA-cleavers towards
the damaged DNA site, thus amplifying the damage and converting it into double stranded
cleavage.32 pH-Gated photophysics of these compounds led to the development of pH-activated
DNA-cleavers which exhibit a dramatic increase in the ds:ss ratio at the lower pH of cancer cells.
This family of DNA-photocleavers induced efficient cleavage of intracellular DNA and lead to
pronounced cytotoxicity to a variety of cancer cell lines upon photochemical activation.33
Conveniently, the five-membered ring products have lower symmetry than the Bergman
cyclizations products and thus, one can use the regioselectivity of the non-symmetric C1-C5 ring
closure step as an alternative experimental probe for the remote substituent effects. The
comparison of two alternative reactions of the same reactant is more straightforward than the
comparison of rates for different reactants because it avoids the complications associated with
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differences in the reduction potentials and electron transfer rates for enediynes with different
substituents and the known effect of accelerating charge introduction on reaction rates.34,35
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Figure 8. Comparison of regioselectivity for the Bergman and C1-C5 cycloaromatizations of enediynes.
Formation of regioisomers in the C1-C5 closure allows observation of remote substituents effects on the
cycloaromatization barriers.
Because C1-C5 cyclization involves a crossing between orthogonal MOs in the same way
Figure 9 left) as the Bergman cyclization, this reaction also becomes highly sensitive to remote
(
substitution upon electron injection.36 The variations in the calculated activation energies exceed
20 kcal/mol, which suggests the possibility of dramatic variations in the cyclization rates. Figure
9
illustrates that the accelerating effect of donor substituents corresponds to classic reactant
destabilization whereas the decelerating effect of acceptors stems from reactant stabilization.37
Figure 9. Left: Partial MO correlation diagram for radical-anionic C1-C5 cyclization of enediynes. Right:
The MO-crossing model of the role of remote substituents in defining the activation barrier for the radical
anionic C1-C5 cyclization.
In summary, the effects of remote substituent on regioselectivity of reductive C1-C5
cyclizations should provide experimental verification of MO-crossings between orthogonal
orbitals as a new fundamental concept for the control of chemical reactivity. The comparison of
radical-anionic and dianionic processes will reveal how the number of electrons involved in the
crossings modulates communication between the electronic states during the cyclization process.
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Additionally, such substituent effects may resolve mechanistic ambiguities regarding the
possible oxidation state of cyclizing species (vide infra).
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Computational details and methods
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Reaction energies and activation barriers were calculated at the M06-2x/6-31+G** level of
theory using Gaussian-09 software.38 M06-2x was used because it can describe
cycloaromatization reactions with sufficient accuracy.39 The LanL2DZ basis set was used for
calculations of Sn-containing species. Transition states were determined using the QST3 method.
Frequency calculations were performed to confirm each stationary point as a minimum or a first-
order saddle point. NBO analysis was used to analyze the electronic structures of reactants and
transition states.40 Electrostatic maps were processed by Molekel.41
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Results and Discussion
Experimental design. We investigated the regioselectivity of C1-C5 cyclization of enediynes
under two sets of reducing conditions: Li naphthalenide-promoted cyclizations of enediynes with
terminal phenyl substituents and cyclization of bis-TFP substituted enediynes promoted by
photoinduced electron transfer (PET).
Scheme 1. The proposed use of C1-C5 cyclization of benzannulated enediynes as an experimental probe
for the role of substituent effects in reductive cycloaromatizations. The three alternative ring closure
modes provide different mechanistic information and regioselectivity. In each case, the enediyne
reactants can form two fulvene regioisomers. See text for the discussion of contrasting expectations for
the regioselectivity.
For the Li naphthalenide reduction (the middle path in Scheme 1), the earlier work of
Whitlock and coworkers25 illustrated that two moles of the one-electron donor are needed. For
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the PET-cyclization in the bottom part of Scheme 1, an earlier work from our group also
confirmed the intermediacy of at least two electron transfer steps in the overall
enediyneꢀfulveneꢀindene transformation.42 For reductive cyclizations, both regioisomers are
produced from a common intermediate. In these reactions, the regioselectivity should be
determined by the MO crossing-mediated effect of remote substitution on the cycloaromatization
transition states.
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For comparison, we have also carried out Bu3Sn-promoted radical cyclizations of the same
substrates.43 In the latter case, the two fulvene regioisomers are formed from different
intermediates, each resulting from attack of the neutral radical species at one of the enediyne
triple bonds (top of Scheme 1). This process was not expected to show significant
regioselectivity. The Bu3Sn-mediated reaction turned out to be a convenient alternative way for
the preparation of the minor products of these highly selective anionic cycloaromatizations.
Experimental results:
Synthesis of enediynes: Phenyl and TMS substituted enediynes were synthesized via
Sonogashira cross-coupling of the corresponding 3,4-diiodosubstituted benzenes (prepared as
shown in Scheme 2 and discussed in the SI part) with phenylacetylene and TMS acetylene
respectively. The substitution of the trimethylsilyl moiety by the TFP group was performed via a
one-pot deprotection-nucleophilic coupling procedure using pentafluoropyridine and cesium
fluoride.44
Scheme 2: Synthesis of substituted benzannelated enediynes
Enediyne cyclizations induced by Li naphthalenide:
Whitlock and coworkers were the first to use lithium naphthalenide to achieve reductive
cyclization of 1,2-diethynylphenylbenzene into the respective fulvene25 They also reported
incorporation of two deuterium atoms upon quenching with D2O as evidence that the cyclization
proceeds via a dianion. The intermediacy of a dianion is also consistent with the need for two
equivalents of the reducing agent for the reaction to proceed to completion.
The
didehydrofulvene dianion is stable towards further reduction and furnishes fulvene upon
quenching with a proton source.45
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Ph
Ph
Ph
D
1. Li-Naphthalenide
(> 2 eq)
2. D2O
Ph
Ph
7
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Ph
D
2a-d2
1a
9
Scheme 3: D2O Quenching of the Li-naphthalenide-mediated cyclizations of enediynes leads to complete
deuterium incorporation at each of the two vinyl carbons indicating the intermediacy of a dianion.25
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To our delight, not only were the cyclizations of enediynes with a remote substituent at the
benzene core regioselective but the degree of selectivity depended on the substituent X at the
aromatic core. The greatest selectivity (>19:1) was observed for X=OMe, whereas X=F and Me
had shown lower selectivity (8:1 and 2:1, respectively).
Scheme 4: Experimentally determined products for the dianionic C1-C5 cyclization, their yields, and the
corresponding ratio of regioisomers.
Since lithium naphthalenide reduces most acceptor groups such as a nitro or an acyl group,46
we were limited in the choice of substituents. For example, for X = Cl, the cyclization was
accompanied by reductive dechlorination leading to the formation of the unsubstituted fulvene
2a. Even when the relative amount of lithium naphthalenide was reduced from four to one
equivalent, the dechlorinated enediyne was formed in 64% yield as the only observed product.
This result is not surprising considering the high reactivity of lithium naphthalenide - a strong
reducing agent47 with a reduction potential of -3.0 eV.48,49
Scheme 5: Dianionic C1-C5 cyclization of enediynes and reductive dechlorination induced by lithium
naphthalenide.
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Effect of terminal substituents:
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In order to gain further understanding of electronic effects in the TS, we have investigated the
regioselectivity of reductive enediyne cyclizations in non-symmetric enediynes where one of the
terminal groups was changed from Ph to a different aromatic group.
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Figure 10: Cyclization of enediynes 1k-1m with lithium naphthalenide
Experimental results summarized in Figure 10 revealed an interesting reactivity pattern.
Whereas the selectivity for the F-substituted substrate is relatively low (2.4:1 in favor of isomer
2l with F-Ph at the endocyclic position), presence of the strongly donor p-OMe-group in 1k
changes the observed selectivity in favor of the opposite isomer with the donor group at the
exocyclic carbon. The acceptor Py group of 1m prefers an endocyclic position, forming a single
fulvene regioisomer 2m.
PET-promoted reductive cyclizations:
Not surprisingly, the TFP moiety is unstable in the presence of Li naphthalenide. Due to this
high reactivity, the cyclizations of the TFP-substituted enediynes were studied under milder
reducing conditions which utilized photoinduced electron transfer (PET) from 1,4-
cyclohexadiene (1,4-CHD). We have shown earlier that this electron transfer is highly
exothermic and fast.26
+
.
TFP
(or) 2
=
TFP
*
TFP
TFP
TFP
TFP
PET
*
X
+
TF
P
TFP
X
hv
X
X
MeCN
4a - 4j
5a - 5j
1f-1j
4 : 5 Yield
NA
X =
H
1f
22%
1g
1h
1i
Me
F
~1 : 1
5 : 1
30%
36%
18%
28%
MeO
23 : 1
9 : 1
1j Cl
Scheme 6: Experimentally determined products for the PET-C1-C5 cyclization, their yields, and the
corresponding ratio of regioisomers.
The observed selectivity followed the same trends as above in the case of Li-mediated
cyclizations of Ph-substituted enediynes (Scheme 6). This result reinforces the notion that the
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cyclizing species in the photoinduced cyclization of the TFP-enediynes is also a reduced form of
enediyne (either a radical-anion or a dianion) and that similar MO crossings are involved in the
control of regioselectivity via a one-electron reduction. Changing the Ph to a TFP group at the
enediyne termini and the significant differences in reaction conditions had a surprisingly small
effect on cyclization regioselectivity in case of X=OMe and F. The relatively low regioselectivity
for the cyclization of Me-substituted diphenyl enediyne 1b decreased even further for the
cyclization of analogous di-TFP enediyne 1f. Interestingly, we have not observed reductive
dechlorination (X=ClꢀX=H) in the TFP-substituted enediynes under PET conditions.
Qualitatively, the effects for the Li- and PET-promoted cyclizations were expected to be
similar because, the MO crossings in both the radical-anionic and the dianionic
cycloaromatization reactions coincide with the transition states. As the result, p-donor
substituents should control regioselectivity in a similar way. However, unlike the dianionic
cyclizations, orbital crossings in radical-anionic cycloaromatizations involve MOs populated
with one electron and one could expect a weaker remote substituent effect. We will address this
question below in the computational section of this work.
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Photophysics: The rate of formation of OMe-substituted indenes 2i/3i in the photochemical
cyclization was very slow compared to the other entries. To understand the reasons for this
behavior, Stern-Volmer analysis was performed on all TFP-substituted enediynes (discussed in
detail in the SI part).
Although the OMe-derivative 1i had the longest excitation lifetime (4.2 vs. 1.5-2.6 ns), it also
has the lowest driving force for the PET from 1,4-CHD in comparison to the other tested
enediynes. The ~100-fold differences in the rate of electron transfer (108 vs. 1010 M-1s-1) explains
the slower reaction with the OMe-substrate. This example illustrates why it is easier to interpret
substituent effects on selectivity than the effects on the overall reaction rates and yields in these
systems.
Structure determination:
The structure of the major fulvene isomer for the F-substituted indene 4h was unequivocally
proven by X-ray crystallography (Figure 11). Interestingly, even in the crystal, 8% of the other
regioisomer was still present as a disordered component of the crystal lattice.
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Figure 11: Left: X-ray crystal structure of F-substituted bis-TFP indene, 4h, confirms the
regioselectivity of the cyclization. Right: Crystal packing of indene 4h. Hydrogen and fluorine atoms
are omitted for clarity.
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The regioselectivity for the cyclization of other enediynes was determined by analyzing the
structures of the two isomers with multinuclear 2D NMR spectroscopy (see the SI section). The
separation of the isomeric indenes derived from methyl-substituted enediyne proved to be
difficult even with preparative HPLC. Because the H NMR isomer ratio for this case was very
close to 1:1, identification of the two isomers in this system has not been pursued.
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1
The unambiguous assignment of the exo- and endocyclic vinylic protons in fulvenes can be
accomplished using selective deuteration at one of the two vinylic positions as described by us
earlier using either the Bu3SnH/DCl or Bu3SnD/HCl combination of reagents.43b The exocyclic
C-H in these fulvene structures is deshielded by ~0.4 ppm relative to the endocyclic C-H.
Scheme 7: Selective deuteration provides access to four fulvene isotopomers and allows unambiguous
assignment of NMR signals for the endo- and exocyclic vinyl protons.
Further structural assignments were carried out by combining HSQC and HMBC analysis as
analyzed in detail in the SI section. The general trends for the fulvene isomers agreed well with
the relative NMR values for similar structures published by Lautens and Wu.50
Tributyltin-Mediated Radical Cyclization of Enediynes
Radical 5-exo-dig cyclizations of the phenyl substituted enediynes were carried out using the
Bu3SnH/AIBN system.43, 51 The advantage of this method is that the Bu3Sn group can be
removed by protic acids to afford the same fulvenes as in the Li-mediated cyclizations. Optimal
conditions involved addition of a tributyltin hydride/AIBN mixture via syringe pump to the
solution of enediyne in toluene under reflux, followed by protodestannylation of the cyclized
products with HCl (or AcOH for electron-rich and acid-sensitive OMe-substituted fulvene). In
addition to the convenient conditions and the preparatively useful 70-80% yields, the radical
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reactions provide a greater amount of isomers corresponding to the minor products of the
dianionic ring closures.
The observed 5-exo selectivity is consistent with the known preferences for the radical
cyclizations of alkynes.52 The regioselectivity of these reactions is dependent on the initial
chemoselectivity of the addition of tributyltin radical; rather than on orbital crossings. The ratios
of products ranged from 1:1 to 1.5:1 indicating that both triple bonds have similar reactivity
towards the intermolecular addition of the tin radical.53
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Figure 12: Summary of tributyltin hydride promoted cyclization of enediynes. Transition state energies
for the cyclizations are given relative to the vinyl radicals produced upon tin addition to each triple bond
and were calculated at the M06-2X/LanL2DZ/6-31G** level. The calculated energies of the initial tin
addition products are within 0.5 kcal/mol of each other.
Radical cyclization was also expanded to include terminally-substituted enediynes to further
test selectivity in the absence of anionic MO crossings. Again, the ratio of products in these
radical reactions is based solely on the chemoselectivity of addition to one of the two triple
bonds instead of orbital crossing. Interestingly, even though the reaction produces essentially a
1:1 mixture of both isomers, the preference for the attack at the triple bond slightly increases in
the following order: F>H>OMe.
Figure 13: Bu3SnH-promoted radical cyclization of terminal substituted enediynes.
Unexpectedly, the reaction of nucleophilic tributyl tin radical to 2-pyridyl enediyne 1m is
fully chemoselective but does not provide a cyclic product. Instead, the reaction proceeds via
formal syn-addition at the Py-substituted alkyne. The stereochemistry was assigned based on the
64 Hz value of the vicinal H-Sn coupling constant.54 Although the regiochemistry of addition
could not be determined unambiguously, the HMBC correlations are in a better agreement with
the Sn-attack at the carbon atom away from the pyridine (see the SI part).
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Figure 14: Reaction of tributyltin hydride with Py-substituted alkyne 1m gave an acyclic product.
Computational analysis of reductive cycloaromatizations
Analysis of computational data revealed a very interesting electronic reorganization that
occurs along the reaction coordinate. The reasons for this electronic reorganization are two-fold:
a) delocalized π-anions are converted into a localized endocyclic vinyl anion and, to some extent,
b) the exocyclic π-system undergoes additional polarization towards the core with the
concomitant increase in the aromatic cyclopentadienyl-anion character of the newly formed five-
membered ring.
Figure 15. Evolution of electron density during cycloaromatization of delocalized enediyne
dianion into partially localized benzofulvene dianion is illustrated using selected NBO charges in
the reactant and product. Changes in charge in TS relative to the reactant are shown in blue bold
italics. Negative and positive values indicate an increase and a decrease in electron density,
respectively.
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Interestingly, unlike the thermal TS and the anionic reactant and product, the core of the anionic
TS is distinctly non-planar. This non-planarity assists in the negative charge delocalization by
allowing the mixing of “in-plane” and “out-of-plane” orbitals at the MO crossing point (Figure
15). The single most dramatic change at the atomic level is the accumulation of ~0.3 electron at
the endocyclic carbon that corresponds to the localized vinyl anion in the product.
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Model for substituent effects in reductive C1-C5 cyclizations:
Due to the observed negative charge accumulation patterns for the parent cyclorearomatization,
one can suggest a simple model to predict and rationalize substituent effect on the selectivity of
ring closure. In this model, one would expect the introduction of acceptor groups at the para
position relative to the endocyclic anionic carbon to have the largest stabilizing influence. An
acceptor at the exocyclic anionic center is expected to have a lower impact. Donor substituents
should have an opposite effect on regioselectity via selective destabilization of the respective
transition states (“Type D” products, Figure 16).
Figure 16. Expected substituent effects on the regioselectivity of anionic C1-C5 ring closure. Site with the
largest accumulation of the negative charge in the TS (the endocyclic vinyl carbon of fulvene moiety) is
indicated with a larger negative charge sign.
Computed substituent effects at two reductive levels:
We have initiated computational studies for testing the above model for the observed
regiochemistry with the focus on the same selection of substituents that was compatible with the
experimental conditions. The computational analysis paints a complicated picture which is
different for Ph- and TFP-substrates at the different reduction stages (Figure 17).
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Figure 17. Calculated activation and reaction energies (kcal/mol) at the M06-2X/6-31+G(d,p) level for
radical anionic (left) and dianionic (right) cyclizations. Definitions for “meta” and “para”
regioselectivities for the ring closure are given in Figure 16. Additionally, a graphical representation of
these results is given in the Computational Analysis part of the SI.
For the radical-anionic cyclizations of Ph enediynes, all substituents favor formation of the Type
A (“para”) product. The differences are larger (0.5-0.8 kcal) for the F- and OMe-substituted
substrates, whose cyclizations were found the most selective experimentally. The methyl
substituted enediynes were not predicted to display significant regioselectivity in their reductive
cyclization. This matches the experimentally observed ~1:1 ratio of products. The methyl group
cannot act as a strong σ-acceptor and the C-C bond from the benzene ring to the methyl
substituent is only weakly polar. These results agree with the experimental trends. In contrast,
the computational data for the analogous TFP-substrates show the opposite trend. According to
the computational results, the terminal aromatic groups have a large effect on the reactions since
they participate strongly in delocalization of the excessive electronic density. This effect is
probably exaggerated in comparison to the experiments where solvent and counter-ion effects
can strongly attenuate the importance of delocalization.
Computed energies for the dianionic cyclizations of Ph substrates, do not follow the
experimental trend. For these substrates, computed selectivities for each substituent are very low.
There are two possible explanations for the clear disagreement with the experiment – 1) a trivial
one (the problems with the available theory) and 2) a more interesting one (the cyclizations occur
at the radical-anionic stage and the 2nd reduction occurs after the cyclization). The second
scenario is reasonable because, after cyclization, the two non-bonding orbitals of the product are
spatially separated, so the molecule should be less reluctant to accept one more negative charge.
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Because radical-anionic cyclizations are endothermic, fast reduction of the cyclic product may
play a significant role in driving the process forward to the formation of cyclic species. Note that
reactions of Ph-substrates proceed under the dissolving metal conditions where concentration of
electrons is always relatively large and, thus, the transiently formed cyclic species can be
trapped.
The trends for the cyclizations of mono- and di-reduced species are reversed for the TFP-
enediynes. Whereas the calculated trends for the radical-anionic pathways do not follow the
experimental selectivities, the calculated trends for dianionic cyclizations do, supporting a
different reductive state for the cyclizing species relative to the case of Ph-enediynes. One can
rationalize the difference by remembering that reaction conditions for the two reductive
processes are drastically different. For the photochemical processes, the transiently formed cyclic
product is unlikely to receive the 2nd electron in time to prevent the retro-C1C5 ring opening.55
Thus, the radical-anionic pathway remains unproductive and, only the 2nd electron is
transferred,56 the cyclization is possible. This scenario is consistent with the significant
exothermicity (=effective irreversibility) of the dianionic cycloaromatization.
Overall, the computated selectivities agree with the experimental selectivities if Ph-substrates
cyclize at the radical-anionic stage whereas the ring closure of TFP-substrates only happens upon
the formation of a dianion. In this scenario, the similarity between observed substituent effects
on the Li-promoted cyclizations of Ph-enediynes and PET-promoted cyclization of TFP-
enediynes seems fortuitous. One can rationalize this intriguing situation by suggesting that
additional charge injection is needed for forcing the more stabilized and less reactive TFP
substrates to undergo the cyclization path. This suggestion seems reasonable but it is also clear
that these processes pose is a considerable challenge for theory. Most likely, inclusion of explicit
Li counterions as well as the solvation effects is necessary to model such systems confidently.
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In summary, although experimental trends are clear and large substituent effects are observed,
their computational description is so far problematic. Such reductive cycloaromatization
reactions clearly present a challenge to the DFT theory available for these relatively large
systems. Effects of solvation and introduction of explicit counter ions may be necessary,
especially for the highly charged dianionic species.
Conclusions
Transition states of the reactions that involve a bond-breaking event in the direct vicinity of
an orthogonal π-system activate orbital crossings between the two orthogonal orbital systems.
When at least one of the crossing MO levels is neither completely empty nor completely
occupied, such crossings correspond to intramolecular electron transfer between the two
orthogonal systems and can be used to effectively control activation barriers and reaction
energies.
The present work highlighted the effect of MO crossings on the regioselectivity of C1-C5
cyclorearomatization reaction of benzannelated enediynes. We have shown experimentally that
reductive C1-C5 cyclization reactions of substituted benzannelated enediynes are regioselective,
especially in the presence of anion stabilizing donor groups.
The regioselectivity of the C1-C5 cycloaromatization reaction of benzannelated enediynes is
efficiently controlled by remote substitution.
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From a practical point of view, we had found substitution patterns capable of controlling the
regioselectivity and efficiency of reductive C1-C5 cyclizations of enediynes. The increased
chemical yields and amplified regioselectivity confirm the increased importance of remote
substitution and orbital crossings. This work, for the first time, illustrates a new paradigm for
control of reaction rates based on electronic communication between orthogonal orbitals
activated via electron injection. Studies of analogous effects promoted by hole injection are
underway.
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The observed experimental data can be only reconciled with the computational results if
cyclizations at the different reduction state are suggested for the Ph- and TFP-substituted
enediynes. The experimental selectivities for Ph-enediynes are consistent with the calculated
barriers for the radical anionic ring closures. In contrast, the observed selectivities of TFP-
enediyne cyclizations are consistent with the computed barriers for the dianionic pathways,
suggesting the stabilized anionic species are more reluctant to undergo cycloaromatization.
Acknowledgements
I.A. is grateful to the National Science Foundation (CHE-1465142) for support of this
research project. We also acknowledge help and advice from Michael Shatruk, Flynt Goodson,
and Sourav Saha.
Supplementary Information
Supplementary information is available free of charge online. The supplementary information
includes NMR spectra and full characterization data for all new compounds, coordinates for all
computational results, crystallography data, UV spectra, and Stern-Volmer analysis details, as
well as analysis of 2D NMR data.
References
1 Milián-Medina, B.; Gierschner, J. WIREs Comput. Mol. Sci. 2012, 2, 513.
2 Alabugin, I. V.; Gilmore, K. M; Peterson, P. W. WIREs Comput. Mol. Sci. 2011, 1, 109. Cramer, C. J. J. Mol.
Struct., Theochem. 1996, 370, 135.
3
Deslongchamps, P. Stereoelectronic Effects in Organic Chemistry, Pergamon Press: Oxford, England, 1983
.
Kirby, A. J. Stereoelectronic Effects, Oxford University Press, Oxford, England, 1996. Juaristi, E.; Cuevas, G. Acc.
Chem. Res. 2007, 40, 961. Alabugin, I. V. Stereoelectronic Effects: the Bridge between Structure and Reactivity.
John Wiley & Sons Ltd, Chichester, UK, 2016.
4 Birtles, R. H.; Hampson, G. C. J. Chem. Soc. 1937, 10.
5 (a) Jones, R. R.; Bergman, R. G. J. Am. Chem. Soc. 1972, 94, 660. (b) Bergman, R. G. Acc. Chem. Res. 1973, 6,
25.
6 Galbraith, J. M.; Schreiner, P. v. R.; Harris, N.; Wei, W.; Wittkopp, A.; Shaik, S. Chem. Eur. J. 2000, 6, 1446.
7 Choy, N.; Kim, C. S.; Ballestero, C.; Argitas, L.; Diez, C.; Lichtenberg, F.; Shapiro, L.; Russell, K. C. Tetrahedron
Lett. 2000, 41, 6995. The correlation of the reaction rate with the Hammett σm value revealed a low sensitivity to
substituents (ρ = 0.654). The Swain-Lupton model yielded a field parameter (0.662) larger than the resonance
parameter (0.227), indicating that conjugative effects in the out-of-plane π-system are of lesser importance than field
effects.
8 Alabugin, I. V.; Manoharan, M.; Kovalenko, S. V. Org. Lett. 2002, 4, 1119. Zeidan, T.; Kovalenko, S. V.;
Manoharan, M.; Alabugin, I. V. J. Org. Chem., 2006, 962. Zeidan, T.; Manoharan, M.; Alabugin, I. V. J. Org.
Chem., 2006, 71, 954.
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9 For representative examples of a variety of cycloaromatization reactions, see: (a) Nagata, R.: Yamanaka, H.;
Okazaki, E.; Saito, I. Tetrahedron Lett. 1989, 30, 4995. Myers, A. G.; Dragovich, P. S.; Kuo, E. Y. J. Am. Chem.
Soc. 1992, 114, 9369. (b) Nakatani, K. Isoe, S.; Maekawa, S.; Saito, I. Tetrahedron Lett. 1994, 35, 605. Sullivan,
R. W.; Coghlan, V. M.; Munk, S. A.; Reed, M. W.; Moore, H. W. J. Org. Chem. 1994, 59, 2276. (c) Toda, F.;
Tanaka, K.; Sano, I.; Isozaki, T. Angew. Chem., Int. Ed. Engl. 1994, 33, 1757. (d) Nicolaou, K. C.; Skokotas, G.;
Maligres, P.; Zuccarello, G.; Schweiger, E. J.; Toshima, K.; Wendeborn, S. Angew. Chem., Int. Ed. Engl. 1989, 28,
1272. (e) Engels, B.; Lennartz, C.; Hanrath, M.; Schmittel, M.; Strittmatter, M. Angew. Chem., Int. Ed. Engl. 1998,
37, 2067. (f) Schmittel, M.; Steffen, J. P.; Angel, M. A. W.; Engles, B.; Lennartz, C.; Hanrath, M. Angew. Chem.,
Int. Ed. 1998. 37, 2067. (g) Schmittel, M.; Rodriguez, D.; Steffen, J. P. Angew Chem., Int. Ed. 2000, 39, 2067. (h)
Kawatkar, S. P.; Schreiner, P. R. Org. Lett., 2002, 4, 3643. (i) Mondal, S.; Mitra, T.; Mukherjee, R.; Addy, P. S.;
Basak, A. Synlett 2012, 23, 2582. (j) Das, J.; Das, E.; Jana, S.; Addy, P. S.; Anoop, A.; Basak, A. J. Org. Chem.
2016, 81, 450. (k) Review: Mohamed, R. K.; Peterson, P. W.; Alabugin, I. V. Chem. Rev., 2013, 7089. (l)
Radical/ionic dichotomy: Peterson, P. W.; Mohamed, R. K.; Alabugin, I. V. Eur. J. Org. Chem., 2013, 2013, 2505.
10 (a) Enediyne Antibiotics as Antitumor Agents; Borgers, D. B., Doyle, T. e., Eds; Marcel Dekker: New York,
1995. (b) Neocarzinostatin: The Past, Present, and Future of an Anticancer Drug; Maeda, H., Edo, K., Ishida, N.,
Eds.; Springer: New York, 1997.
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11
12
13
14
15
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52
53
54
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59
60
11 Wu, M.; Stoermer, D.; Tullis, T.; Townsend, C. A. J. Am. Chem. Soc. 2000, 122, 12884.
12 Bowles, D. M.; Palmer, G. J.; Landis, C. A.; Scott, J. L.; Anthony, J. E. Tetrahedron 2001, 57, 3753. Bowles, D.
M.; Anthony, J. E. Org. Lett. 2000, 2, 85.
13 Chen, X.; Tolbert, L. M.; Hess, D. W.; Henderson, C. Macromolecules. 2001, 34, 4104. Shah, H. V.; Babb, D.A.;
Smith, Jr., D. W. Polymer. 2000, 41, 4415. John, J. A.; Tour, J. M. J. Am. Chem. Soc. 1994, 116, 5011.
14 Alabugin, I. V.; Manoharan, M. J. Am. Chem. Soc. 2003, 125, 4495.
15 The ability of fine tuning of relative energies of two non-orthogonal but still pseudoindependent orbital systems
has been a basis of creative photophysical designs. For example: Zucchero, A. J.; McGrier, P. L.; Bunz, U. H. F.;
Acc. Chem. Res. 2010, 43, 397. McGrier, P. L.; Solntsev, K. M.; Miao, S.; Tolbert, L. M.; Miranda, O. R.; Rotello,
V. M.; Bunz, U. H. F.: Chemistry - A European Journal. 2008, 14, 4503. Wilson, J. N.; Bunz, U. H. F.: J. Am.
Chem. Soc. 2005, 127, 4124.
16 The term “MO crossings” used in this paper is analogous in meaning to “state crossings” used in photochemical
literature.
17 Reed, A. E, Curtiss, L. A, Weinhold, F. Chem. Rev. 1988, 88, 899.
18 For the role of energy gap on the acceptor ability of σ-bonds, see: Alabugin I. V.; Zeidan, T. A. J. Am. Chem.
Soc. 2002, 124, 3175-3185.
19 For an application of this electronic phenomenon to alkyne cycloadditions, see: Gold, B.; Shevchenko, N.; Bonus,
N.; Dudley, G. B.; Alabugin, I. V. J. Org. Chem. 2012, 77, 75. Gold, B.; Dudley, G. B.; Alabugin, I. V. J. Amer.
Chem. Soc., 2013, 135, 1558. Synopsis: Alabugin, I. V.; Gold, B. J. Org. Chem., 2013, 78, 7777.
20 The “unreactive” out-of-plane π-system still plays an important role by providing electronic stabilization to the
product. For an in-depth discussion of the contrasting role of the two orthogonal π-systems, see: Alabugin, I. V.;
Breiner, B.; Manoharan, M. Advances in Physical Organic Chemistry, 2007, 42, 1-35. See also: Alabugin I. V.;
Manoharan, M. J. Phys. Chem. A 2003, 107, 3363.
21 Selected recent examples: (a) Das, A.; Ghosh, I.; Konig, B. Chem. Commun., 2016, 52, 8695. (b) Ghosh, I.;
Konig, B. Angew. Chem. Int. Ed. 2016, 55, 7676. (c) Ghosh, I.; Marzo, L.; Das, A.; Shaikh, R.; Konig, B. Acc.
Chem. Res. 2016, 49, 1566. (d) Meyer, A. U.; Slanina, T.; Yao, C.-J.; Konig, B. ACS Catal. 2016, 6, 369.
22 Hoffmann, R.; Woodward, R. B.; Acc. Chem. Res., 1968, 1, 17.
23 For “ SOMO-HOMO level conversion” where SOMO is lower than the HOMO, see
: (a) Gryn’ova, G.;
Marshall, D. L.; Blanksby, S. J.; Coote, M. L. Nature Chem. 2013,5, 474.. (b) Ishiguro, K.; Kamekura, Y.; Sawaki,
Y. Mol. Cryst. Liq. Cryst. 1993, 233, 113. (c) Kusamoto, T.; Kume, S.; Nishihara, H. J. Am. Chem. Soc. 2008, 130,
13844. (d) Kobayashi, Y.; Yoshioka, M.; Saigo, K.; Hashizume, D.; Ogura, T. J. Am. Chem. Soc. 2009, 131, 9995.
(e) Sugawara, T.; Komatsu, H.; Suzuki, K. Chem. Soc. Rev. 2011, 40, 3105.
24 Prall, M.; Wittkopp, A.; Schreiner, P.R. J. Phys. Chem. A., 2001, 105, 9265. Vavilala, C.; Byrne, N.; Kraml, C.
M.; Ho, D. M.; Pascal, R. A. J. Am. Chem. Soc. 2008, 130, 13549.
25 Whitlock, Jr. H. W.; Sandvick, P. E.; Overman, L. E.; Reichardt, P. B. J. Org. Chem. 1969, 34, 879.
26 Alabugin I. V.; Kovalenko, S.V. J. Am. Chem. Soc. 2002, 124, 9052.
27 Kovalenko, S. V.; Alabugin I. V. Chem. Comm. 2005, 1444.
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28 Yang, W.-Y.; Breiner, B.; Kovalenko, S. V.; Ben, C.; Singh, M.; LeGrand, S. N.; Sang, A. Q.-X.; Strouse, G. F.,
Copland, J. A.; Alabugin I. V. J. Am. Chem. Soc., 2009, 131, 11458.
29 Elmroth, K.; Nygren, J.; Martensson, S.; Ismail, I. H.; Hammarsten, O. DNA Repair 2003, 2, 363.
30 Yang, W.-Y.; Roy, S.; A. R.; Phrathep, B.; Rengert, Z.; Zorio, D. A. R.; Alabugin, I. V. J. Med. Chem., 2011, 54,
8501. For further correlations between structure and DNA-cleaving activity, see: Kaya, K.; Roy, S.; Nogues, J. C.;
Rojas, J. C.; Sokolikj, Z.; Zorio, D. A. R.; Alabugin, I. V. J. Med. Chem., 2016, 10.1021/acs.jmedchem.6b01164.
31 Breiner, B.; Schlatterer, J. C.; Kovalenko, S. V.; Greenbaum, N. L.; Alabugin I. V. Angew. Chem., Int. Ed. 2006,
45, 3666.
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32 Breiner, B.; Schlatterer, J. C.; Alabugin I. V.; Kovalenko, S. V.; Greenbaum, N. L. Proc. Natl. Acad. Sci., 2007,
104, 13016.
33 Review: Breiner, B.; Kaya, K.; Roy, S.; Yang, W.-Y.; Alabugin, I. V. Org. Biomol. Chem. 2012, 10, 3974-3987.
34 VB analysis: Shaik, S.; Shurki, A. Angew. Chem., Int. Ed. 1999, 38, 586.
35 (a) Bellville, D. J.; Wirth, D. D.; Bauld, N. L. J. Am. Chem. Soc. 1981, 103, 718. (b) Bellville, D. J.; Bauld, N. L.;
J. Am. Chem. Soc. 1982, 104, 2665. (c) Pabon, R. A.; Belville, D. J.; Bauld, N. L. J. Am. Chem. Soc. 1983, 105,
5158. (d) Bernardi, F.; Bottoni, A.; Olivucci, M.; Venturini, A.; Robb, M. A.; J. Chem. Soc. Faraday Trans. 1994,
90, 1617. (e) Jungwirth, P.; Bally, T. J. Am. Chem. Soc. 1993, 115, 5783.
36 Alabugin, I. V.; Manoharan, M. J. Am. Chem. Soc. 2003, 125, 4495.
37 In benzannelated enediynes, the MO crossing between the two orthogonal π-arrays has an additional role since it
transforms an antiaromatic π-anion into a localized σ-anion. During this change, an anti-aromatic reactant stabilizes
itself by sending an in-plane electron to an out-of plane orbital and regaining aromaticity.
38 Gaussian 03, Revision C.02, Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Montgomery, Jr., J. A.; Vreven, T.; Kudin, K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.;
Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.;
Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene,
M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.;
Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.;
Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas,
O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford,
S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.;
Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen,
W.; Wong, M. W.; Gonzalez, C.; and Pople, J. A.; Gaussian, Inc., Wallingford CT, 2004.
39 (a) Mohamed, R.K.; Mondal, S.; Jorner, K.; Faria Delgado, T.; Lobodin, V. V.; Ottoson, H.; Alabugin, I.V. J. Am.
Chem. Soc. 2015, 137, 15441 (b) Hoye, T. R.; Baire, B.; Niu, D.; Willoughby, P. H.; Woods, B. P. Nature. 2012,
490, 208.
40 Glendening, E. D.; Badenhoop, J. K.; Reed, A. E.; Carpenter, J. E.; Bohmann, J. A.; Morales, C. M.; Weinhold,
F. NBO 5.0. 2001, Theoretical Chemistry Institute, University of Wisconsin, Madison.
41 Varetto, U. <MOLEKEL 4.3>; Swiss National Supercomputing Centre: Lugano (Switzerland)
42 Alabugin, I. V.; Kovalenko, S. V. J. Am. Chem. Soc. 2002, 124, 9052.
43
(a) Kovalenko, S. V.; Peabody, S.; Manoharan; M.; Clark, R. J.; Alabugin I. V. Org. Lett., 2004, 6, 2457. (b)
Peabody, S.; Breiner, B.; Kovalenko, S. V.; Patil, S.; Alabugin I. V. Org. Biomol. Chem. 2005, 3, 218.
44 Artamkina G. A.; Kovalenko S. V.; Beletskaya I. P.; Reutov O. A. Russ. J. Org. Chem. 1990, 26, 225.
45 If an excess of reducing agent was still present at the end of reaction, it was essential to carry out the quenching
step quickly, i.e., with ammonium chloride and crushed ice. When a less reactive source of protons was used, such
as cold methanol, the formation of overreduced (indene) products was observed, suggesting that residual lithium
remained while the fulvene dianion was protonated to give the neutral fulvene molecule, susceptible to the further
reduction.
46 (a) Zang, H.; Karasawa, T.; Yamada, H.; Wakamiya, A.; Yamaguchi, S. Org. Lett. 2009, 11, 3076. (b)
Yamaguchi, S.; Xu, C.; Tamao, K. J. Am. Chem. Soc. 2003, 125, 13662. (c) Xu, C.; Wakamiya, A.; Yamaguchi, S.
J. Am. Chem. Soc. 2005, 127, 1638. (d) Xu, C.; Wakamiya, A.; Yamaguchi, S. Org. Lett. 2004, 6, 3707.
47 Whitlock Jr, H.W.; Sandvick, P.E.; Overman, L.E.; Reichardt, P.B. J. Org. Chem. 1969, 34, 879.
48 Rele, S.; Talukdar, S.; Banerji, A.; Chattopadhyay, S. J. Org. Chem. 2001, 66, 2990. Li Naphthalenide is reactive
not only toward aryl chlorides but also towards a variety of functionalities including geminal dihalides (Ashby, E.
C.; Deshpande, A. K. J. Org. Chem. 1995, 60, 4530), benzyl ethers (Liu, H-J; Yip, J. Tetrahedron Lett. 1997, 38,
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2253), α,β-epoxy ketones (Jankowska, R.; Mhehe, G. L.; Liu, H.-J. Chem. Commun. 1999, 16, 1581), α-cyano
ketones (Liu, H.-J.; Zhu, J.-L.; Shia, K.-S. Tetrahedron Lett. 1998, 39, 4183).
49 Interestingly, this experimental observation is consistent with the spontaneous loss of chloride anion observed
during DFT geometry optimization of 1n at B3LYP/6-31G**, but not for B3LYP/6-31+G** and M05-2X/6-31+G**
levels of theory. The terminal phenyl rings stabilized the anions sufficiently enough that barrierless dechlorination
did not occur in silico. The optimized geometry of the radical anion of 1e did not indicate the loss of chloride anion
in gas or solvent phase calculations.
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50 (a) Bryan, C. S., Lautens, M. Org. Lett. 2010, 12, 2754. (b) Ye, S.; Wu, J. Org. Lett. 2011, 13, 5980.
51 For an earlier report of radical-mediated cyclization of enediynes, see: Koenig, B.; Pitsch, W.; Klein, M.; Vasold,
R.; Prall, M.; Schreiner, P. R. J. Org. Chem. 2001, 66, 1742.
52 Rules for anionic and radical alkyne cyclizations: Alabugin, I. Gilmore, K.; Manoharan, M. J. Am. Chem. Soc.
2011, 133, 12608. Alabugin, I. V.; Gilmore, K. Chem. Commun., 2013, 49, 11246. Review: Gilmore, K.; Alabugin,
I.V. Chem. Rev. 2011, 111, 6513. Note that the alternative 5-endo-dig cyclization in these systems are expected to
be slow: Alabugin, I. V.; Timokhin, V. I.; Abrams, J. N.; Manoharan, M.; Ghiviriga, I., Abrams, R. J. Am. Chem.
Soc., 2008, 130, 10984. Alabugin I.V.; Manoharan, M. J. Am. Chem. Soc. 2005, 127, 9534.
53 Note, however, that this feature does not always lead to low selectivity. Highly selective radical cyclizations can
be designed in multifunctional systems where initial selectivity of radical attack is low: (a) Alabugin, I. V.;
Gilmore, K.; Patil, S.; Manoharan, M.; Kovalenko, S. V.; Clark, R. J.; Ghiviriga, I. J. Am. Chem. Soc., 130, 2008,
11535. (b) Mondal, S.; Mohamed, R. K.; Manoharan, M.; Phan, H.; Alabugin, I. V. Org. Lett., 2013, 15, 5650. (c)
Mondal, S.; Gold, B.; Mohamed, R. K.; Alabugin, I. V. Chem. Eur. J., 2014, 20, 8664. (d) Mondal, S.; Gold, B.;
Mohamed, R.; Phan, H.; Alabugin, I. V. J. Org. Chem., 2014, 79, 7491. (e) Mohamed, R. K.; Mondal, S.; Gold, B.;
Evoniuk, C. J.; Banerjee, T.; Hanson, K.; Alabugin, I. V. J. Am. Chem. Soc. 2015, 137, 6335. (h) Pati, K.; Gomes,
G. P.; Harris, T.; Hughes, A.; Phan, H.; Banerjee, T.; Hanson, K.; Alabugin, I. V. J. Am. Chem. Soc. 2015, 137,
1165. (i) Evoniuk, C. J.; Ly, M.; Alabugin, I. V. Chem. Commun. 2015, 51, 12831. (k) Pati, K.; Michas, C.;
Allenger, D.; Piskun, I.; Coutros, P. S.; Gomes, G. P.; Alabugin I. V. J. Org. Chem., 2015, 80, 11706. (l) Mohamed,
R. K.; Mondal, S.; Guerrera, J. V.; Eaton, T.M.; Albrecht-Schmitt, T. E.; Shatruk, M.; Alabugin, I. V. Angew.
Chem. Int. Ed., 2016, 55, 12054.
54 For cis Sn-H couplings, J values range from 60 to 70 Hz whereas trans geometries display J values from 120 to
130 Hz: (a) T. N. Mitchell J. C. Podesta, A. Ayala, A. B. Chopa Magn. Reson. Chem. 1988, 26, 497; (b) A. J.
Leusink, H. A. Budding, J. W. Marsman J. Organometal. Chem. 1967, 9, 285.
55 Of course, protonation of the cyclic radical-anion by the radical-cation of the donor may provide another possible
trapping pathway. It is not clear, at this point, when this process may occur.
56 Presence of the two powerful tetrafluoropyridinyl acceptors in the molecule seems to be essential for this process
to occur.
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