Design of leaving groups in radical C-C fragmentations: Through-bond 2c-3e interactions in self-terminating radical cascades

Article abstract of DOI:10.1002/chem.201402843

Radical cascades terminated by β-scission of exocyclic C-C bonds allow for the formation of aromatic products. Whereas β-scission is common for weaker bonds, achieving this reactivity for carbon-carbon bonds requires careful design of radical leaving groups. It has now been found that the energetic penalty for breaking a strong σ-bond can be compensated by the gain of aromaticity in the product and by the stabilizing two-center, three-electron "half-bond" present in the radical fragment. Furthermore, through-bond communication of a radical and a lone pair accelerates the fragmentation by selectively stabilizing the transition state. The stereoelectronic design of radical leaving groups leads to a new, convenient route to Sn-functionalized aromatics.

Full text of DOI:10.1002/chem.201402843

DOI: 10.1002/chem.201402843
Full Paper
&
Cascade Reactions
Design of Leaving Groups in Radical CꢀC Fragmentations:
Through-Bond 2c–3e Interactions in Self-Terminating Radical
Cascades
Sayantan Mondal, Brian Gold, Rana K. Mohamed, and Igor V. Alabugin*[a]
Abstract: Radical cascades terminated by b-scission of exo-
cyclic CꢀC bonds allow for the formation of aromatic prod-
ucts. Whereas b-scission is common for weaker bonds, ach-
ieving this reactivity for carbon–carbon bonds requires care-
ful design of radical leaving groups. It has now been found
that the energetic penalty for breaking a strong s-bond can
be compensated by the gain of aromaticity in the product
and by the stabilizing two-center, three-electron “half-bond”
present in the radical fragment. Furthermore, through-bond
communication of a radical and a lone pair accelerates the
fragmentation by selectively stabilizing the transition state.
The stereoelectronic design of radical leaving groups leads
to a new, convenient route to Sn-functionalized aromatics.
Introduction
The alkyne group is a high-energy carbon-rich functionality
that can serve as a perfect starting point for the preparation of
conjugated molecules and materials.[1] For example, controlled
cascade transformations[2] featuring alkyne cyclizations[3] pro-
vide practical means for the preparation of graphene nanorib-
bons.[1,4] On the other hand, alkenes, the reduced chemical
cousins of alkynes, cannot serve as direct precursors for conju-
gated systems, as alkenes cyclize to products that require an
extra oxidizing step for aromatization.
Recently, we amplified the subtle chemical differences be-
tween alkenes and alkynes by utilizing dynamic covalent
chemistry[5] for the development of a regio- and chemoselec-
tive radical transformation of aromatic enynes into indenes.[6]
Although both alkyne and alkene p bonds are indiscriminately
attacked by Bu3Sn radicals, the pool of four equilibrating iso-
meric radical intermediates is selectively depleted (“kinetically
self-sorted”) through the “matched” 5-exo-trig cyclization of
the most reactive of the four radicals at the more reactive
alkene p bond.
Scheme 1. Kinetic self-sorting of the pool of equilibrating radicals and
change in reaction path on alkene substitution.
a small amount of naphthalene byproduct 3, aromatized by
the loss of an alkyl group (Scheme 1). Inspired by the observa-
tion that such b-scission of a CꢀC bond is a viable alternative
to H-atom abstraction as the final step, we envisaged a route
to aromatic products in which the alkene moiety potentially
serves as a synthetic alkyne equivalent. If this cyclization cas-
cade can be efficiently extended by incorporating the frag-
mentation step, this route leads to aromatization without an
external oxidizing agent or radical. We tested the possibility of
promoting this minor reaction path through the rational
design of radical leaving groups.
While investigating the scope of enyne cyclizations, we ob-
served that alkyl substitution at the alkene changes the regio-
selectivity of the cyclization, by directing the formation of 6-
endo product 2 in 65% yield (Scheme 1).[7] This process does
not provide a conjugated product, because it is terminated by
hydrogen-atom abstraction. However, we also observed
[a] Dr. S. Mondal,+ B. Gold,+ R. K. Mohamed, Prof.Dr. I. V. Alabugin
Department of Chemistry and Biochemistry
Florida State University
Tallahassee, Florida 32306-4390 (USA)
E-mail: alabugin@chem.fsu.edu
[+] These authors contributed equally to this work.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201402843.
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This can be useful. For example, electrophilic (S-centered)
Et3SiS radicals formed in a fragmentation-driven O!C transpo-
sition sequence[10b–e] can be utilized for polarity-reversal cataly-
sis.[11] However, in the case of sensitive substrates, the depart-
ing radicals can also induce undesired side reactions.
Results and Discussion
Design of radical leaving groups
To break unstrained CꢀC bonds under relatively mild condi-
tions, both thermodynamics and kinetics of this process must
be optimized.[8] In the present example, the energetic penalty
for the homolytic cleavage of a strong CꢀC bond is partially
compensated by the aromatic stabilization gained in the prod-
uct. However, the other product (the propyl radical) is a high-
energy, unstable species. We envisioned that stabilization of
the alkyl radical would further promote the fragmentation
(Figure 1). To accelerate this reaction, this stabilization should
In self-terminating cascades, introduced by Wille et al.,
stable fragmenting radicals exit the reaction without participat-
ing in subsequent transformations.[10f] Only a few such process-
es involve CꢀC bond scission with the formation of C-centered
radicals.[10g–j]
Our design of stabilized radical leaving groups was guided
by the electronic structure of super-stable radicals such as mo-
lecular oxygen, nitric oxide, and 2,2,6,6-tetramethylpiperidine
1-oxyl (TEMPO), in which a half-filled orbital is stabilized by an
adjacent lone pair. In the extreme, such strong two-center,
three-electron (2c–3e) interactions correspond to a bond order
1
of = and can be referred to as half-bonds.
2
Stabilization provided by the 2c–3e interactions depends on
the relative electronegativity of the heteroatom (Figure 2).
Figure 1. CꢀC bond homolysis facilitated by product stabilization.
develop early and become sufficiently large in the transition
state (TS).[9]
Radical fragmentations provide a valuable option for the ter-
mination of cascade transformations.[10] The reactivity of radi-
cals formed in the fragmentation step dictates the outcome of
the competition between propagation and termination of radi-
cal cascades (Scheme 2). In particular, reactive radicals (i.e.,
alkyl or thiyl) can react further to propagate the chain process.
Figure 2. 2c–3e interactions (middle) stabilize half-bonds in many important
compounds (left). Radical stabilizations calculated at the UM06-2X/LanL2DZ
level by using the isodesmic equation are shown on the right.
When electronegativities of the interacting atoms are closer,
stabilization is greater. NMe2 substitution provides about
10 kcalmolꢀ1 stabilization to the departing radical, whereas OR
groups account for about one-half of that value (ca. 5 kcal
molꢀ1). Phenyl substitution also provides substantial radical
stabilization (>10 kcalmolꢀ1).
We expected that such strong stabilization through incorpo-
ration of heteroatoms adjacent to the radical center would in-
crease the efficiency of the self-terminating fragmentation and
also render the fragmented radical relatively inert, preventing
undesirable side reactions. Allylic oxygen, nitrogen, and aro-
matic substituents can be easily incorporated at the ene termi-
nus by using well-established CꢀC coupling procedures
(Figure 3) to afford the requisite set of substrates. Indeed, het-
eroatom incorporation completely switched the selectivity in
favor of the self-terminating fragmentation (Figure 4). Further-
more, the fragmentation is sufficiently fast to compete with 6-
exo-dig radical cyclization (Figure 4, bottom).
Scheme 2. Selected examples of radical fragmentations in synthesis. Left:
Scission of a weak CꢀS is used to shift the equilibrium for an unfavorable re-
arrangement.[10b–d] Center: Rare example of b-scission of a CꢀC bond, report-
ed by Zard et al.[10f,g] Right: Self-terminating radical cascades with the expul-
sion of NO2, reported by Wille et al.[10e]
The self-terminating nature of the fragmentation is support-
ed by the need to use a stoichiometric amount of initiator
(0.5 equiv of 2,2’-azobisisobutyronitrile (AIBN) produces 1 equiv
of isobutyronitrile radical) for full conversion (Table 1). Whereas
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Table 1. Optimization of equivalents of AIBN.[a]
Bu3SnH [equiv]
AIBN [equiv]
t [h]
Yield [%][b]
USM [%][b]
1D
1D
1D
1D
1D
1.2
1.2
1.2
1.2
1.2
0.1
0.2
0.2
0.4
0.5
12
12
12
12
12
11
31
10[c]
65
42
19
24
9
78
0
[a] See Figure 4 for reaction conditions. [b] Unconverted starting material,
determined by 1H NMR spectroscopy with Ph3CH as internal standard.
[c] With 0.2 equiv PhSH.
bond dissociation energies (BDE) suggest propagation through
C
hydrogen abstraction by CH2X from Bu3SnH to be a thermody-
namically favorable process (HꢀCH2OH, BDE=96 kcalmolꢀ1
versus Bu3SnꢀH, BDE=74 kcalmolꢀ1),[12] kinetics of such a pro-
cess may be relatively slow, as both species are nucleophilic.
We envisioned that the fragmented radical could be coerced
into propagating the radical chain through polarity-reversal
catalysis.[11] In such processes, H-atom transfer between two
nucleophilic radicals is promoted by an “H-shuttle” with an
electrophilic radical. However, our attempt to increase the effi-
ciency of propagation steps using thiophenol as the H-shuttle
decreased the naphthalene yield (Table 1, entry 3). Although
10% of 3 was formed, we also obtained significant amounts of
reduced acyclic products (along with 24% of the reactant).
Product 3 is derived from the least stable of the equilibrating
radicals, which suggests the radical pool can be depleted if the
more stable radicals (incapable of cyclization) find a suitable
reaction path. This is consistent with the previous reports of
polarity-reversal catalysts prematurely terminating radical cas-
cades by trapping relatively unreactive intermediates.[11g,13]
Another possibility for preventing propagation is the facility
of further fragmentation of the CH2XR radical.[14] We are cur-
rently investigating the mechanistic details in hopes of obtain-
ing fragmented species and finding conditions for efficient
propagation.
Figure 3. Synthesis of starting materials (see the Supporting Information for
further details).
Computational analysis
Further insights into electronic factors responsible for the
facile fragmentations came from DFT calculations. Free ener-
gies DG of fragmentation were negative due to a combination
of radical stabilization and the favorable entropic contribution.
Because nitrogen is a better donor than oxygen[15] and because
lone pairs are better donors than CꢀH/CꢀC bonds,[16] we ex-
pected reaction energies to reflect the importance of the
donor abilities of lone pairs in the stabilization of the frag-
mented radical in an order analogous to that in Figure 2:
CH2NMe2 >CH2OMe/CH2OH>CH2Alkyl. However, the calculated
exergonicities for the fragmentation of O-containing substrates
(CH2OMe/CH2OH) were lower than that for the propyl-substi-
tuted substrate (Figure 5). This unexpected observation sug-
gests the presence of a new remote electronic effect that sta-
bilizes the benzylic reactants containing a b-CꢀX bond and
thus decreases the exergonicity of their fragmentation. We
suggest that this effect is a through-bond (TB) coupling of the
Figure 4. Top: Switch from H abstraction to fragmentation promoted by 2c–
3e bonds. Bottom: Loss of CH2OR group successfully competes with 6-exo
cyclization.
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an important role in “aborted” sigmatropic shifts, an unusual
class of pericyclic reactions in which the geometry correspond-
ing to the cyclic TS is more stable than the acyclic reactants.[9c]
However, the role of TB coupling between radical centers and
lone pairs in 2c–3e systems is not commonly recognized, per-
haps due to the decreased driving force for the fragmentation
of monoradicals, whereby one of the formed bonds is the 2c–
3e half-bond (Figure 6).[20]
Comparison of data in Figures 2 and 5 provides a way to
evaluate the magnitude of three-electron TB stabilization. For
X=OH, the DDErxn (relative to X=propyl) is about 5–6 kcal
molꢀ1 less negative than one would expect from stabilization
energies provided by Figure 2 (see Supporting Information for
the full analysis).
Increased TB interaction in the fragmentation TS
Figure 5. Calculated energy profiles [kcalmolꢀ1] for the fragmentation at the
UM06-2X/LanL2DZ level of theory. DG calculated at 384 K.
Reactant stabilization is a potentially counterproductive factor
in the design of fragmentations. However, the surprisingly
large magnitude of kinetic effects in the calculated activation
energies in Figure 5 suggest that these stabilizing interactions
become even more important in the transition state and facili-
tate the fragmentation.[9]
two nonbonding orbitals populated with three electrons (see
below).
To differentiate thermodynamic contributions to the barrier
(the consequence of the increased stability of reaction prod-
ucts) from stabilizing effects intrinsic to the transition state, we
turned to Marcus theory.[21] This approach dissects reaction
energy as a combination of intrinsic energy and thermodynam-
ic contribution [Eq. (1)].
TB interactions in odd-electron systems
Such electronic effects are well-known when both of the non-
bonding orbitals are singly occupied (e.g., in 1,4-diradicals). In
these systems, TB coupling of radical centers[17] increases the
population of the s* bridge orbital, which ultimately leads to
fragmentation into two 2c–2e bonds. The same effect is re-
sponsible for rendering the Bergman cyclization a symmetry-al-
lowed reaction[18] and providing about 3–5 kcalmolꢀ1 stabiliza-
tion to p-benzyne.[19] Symmetry-enforced TB interactions play
ꢀ
z
z
1
z
DE ¼ DE0 þ 2DErxn þ DEr2xn 16DE0
ð1Þ
Stereoelectronic differences in the TS can be identified by
z
examining the intrinsic barrier DE0 , that is, the barrier of a ther-
moneutral process lacking the thermodynamic contributions.[22]
The intrinsic barrier can be estimated if both the activation
and reaction energies are known (Figure 7).
From the Marcus model, one would expect that the effect
on the activation barrier should be significantly smaller than
1
effect on the reaction energy (DDG° ꢁ = DDG). Contrary to
2
these expectations, the effect on DG° rivals the effect on DG
in the case of X=CH2NMe2. The relatively small and sometimes
negative activation entropies are surprising for a fragmentation
reaction and suggest an increased degree of structural organi-
zation in the TS. To eliminate the complication associated with
the difference in the entropic penalties, we focused our atten-
tion on reaction energies DE and discovered even more strik-
ing trends (e.g., DDE° =22.0 with DDE=21.4 kcalmolꢀ1 for 1A
versus 1E, respectively; see Supporting Information). These
surprising observations suggest that the stabilizing effect of
the heteroatom starts to manifest itself before a radical center
is fully developed at the adjacent carbon atom.
The intrinsic reaction barriers are given in Figure 7. Clearly,
when thermodynamic contributions to the barrier are re-
moved, significant differences in the transition-state energies
remain (1–2 kcal for X=CH2OR and ca. 6 kcalmolꢀ1 for X=
CH2NMe2). These large effects on the fragmentation barrier
Figure 6. Top: Transformation of TB electronic coupling between nonbond-
ing orbitals in 1,4-diradicals and b-heteroatom-substituted radicals in a CꢀC
bond fragmentation. Bottom: Energy penalty for inclusion of an additional
electron in the fragmenting system.
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Figure 9. Left: Optimized geometry for the fragmentation TS (X=CH2OH).
Right: Orbital alignment with the s* orbital of the bridge facilitates TB cou-
pling between the nonbonding orbitals leading to the fragmentation.
adopt the coplanar arrangement between the radical center
and the p-type lone pair on the oxygen atom (Figure 9).
The final computational evidence was provided by natural
bond orbital (NBO) analysis of the initial radical, transition
state, and half-bonded radical fragments, which revealed the
presence of very strong stabilizing interactions between the
radical, the lone pair of the oxygen atom, and the bridge orbi-
tals (Table 2). Although communication through the s bridge is
present in the radical, the effects become much larger in the
TS. The increased interactions can be understood from the
second-order perturbation energies E(2) provided by NBO analy-
sis [Eq. (2)]
Figure 7. Stereoelectronics of the fragmentation viewed through the
window of Marcus theory. Top inset: Summary of differences in reaction and
activation free energies imposed by the substituents. Bottom inset: Intrinsic
reaction barriers for the fragmentation. Energies in kcalmolꢀ1
.
Fi2j
i DEij
Eð2Þ ¼ q
ð2Þ
where qi is the donor orbital occupancy, DEij is the energy dif-
ference between interacting orbitals, and Fij is the off-diagonal
NBO Fock matrix element.
Table 2. NBO analysis at the UM062X/LanL2DZ level of theory. Interaction
energies in kcalmolꢀ1
.
SM
TS[a]
Interaction
a spin
b spin
a spin
b spin
nC!s*CꢀC
nO!s*CꢀC
sCꢀC!nC
5.9
3.9
–
1.7
4.9
5.0
89.6
2.7
–
13.4
30.7
79.9
[b]
[b]
[a] The given Lewis structure was obtained using the $CHOOSE keyword
(see the Supporting Information). [b] Below the threshold of 0.5 kcal
molꢀ1
Figure 8. Electronic coupling between nonbonding orbitals in 1,4-diradicals
and b-heteroatom-substituted radicals strengthens in the TS and facilitates
CꢀC bond fragmentation. Additional stabilization due to TB coupling
through a breaking bridging bond is shown as DE. The s and s* energies in
the starting radical are shown in gray.
During fragmentation the energy of the s-bonding orbital is
raised as that of the s* orbital is lowered, and the DEij term for
interactions with nonbonding orbitals (i.e., the radical and lone
pair) is decreased. In addition, as fragmentation progresses,
the approximately sp3 s bond is transformed into two p orbi-
tals (one p-bonded in naphthalene and the other in a 2c–3e
half-bond), and this increases overlap between interacting or-
bitals. Together, these interactions are responsible for selective
TS stabilization for the fragmentation process (see Supporting
Information for full analysis).
originate from electronic communication between the non-
bonding orbitals, which weakens the bridging s bond in the
TS (Figure 8).
To test whether the long-range communication between
nonbonding orbitals in the three-electron systems facilitates
the fragmentation, we performed intrinsic reaction coordinate
(IRC) analysis of the fragmentation step for the least sterically
encumbered substrate, the allylic alcohol, in which stereoelec-
tronic aspects of the fragmentation can fully develop (see Sup-
porting Information). The evolution of the IRC geometries illus-
trates that molecular geometry in the CCOH group changes to
Conclusion
We have described a radical cascade that self-terminates by ex-
pulsion of primary C-centered radicals. Even though the ener-
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is significant, the combination of two stabilizing effects (the ar-
omatic stabilization gained in the product and stabilization of
radical leaving groups by 2c–3e bonds) can compensate for
the cost of CꢀC bond cleavage. In the reaction sequence, a rad-
ical center is relocated to a position where it can communicate
with a donor lone pair through a CꢀC bridge (TB interaction).
Such communication leads to selective TS stabilization for the
CꢀC bond cleavage. This work illustrates the potential of 2c–3e
interactions in the design of radical leaving groups. Incorpora-
tion of CꢀC bond cleavage into self-terminating radical cas-
cades allows the use of alkenes as alkyne equivalents for the
preparation of aromatic structures.
Experimental Section
Cyclization
The starting enyne (0.34 mmol) was degassed in 4 mL of toluene
and heated to reflux. Separate solutions of AIBN (0.5 equiv) and
Bu3SnH (1.2 equiv), each in 3 mL of toluene, were added by syringe
pump through the top of a condenser over 4 h to the refluxing so-
lution. The reaction mixture was allowed to stir at reflux. Reaction
progress was monitored by TLC. After completion, the solvent was
evaporated and the product was dissolved in 20 mL of CH2Cl2 and
washed with 1m HCl. The product was purified on silica gel by
using a gradient of ethyl acetate/hexane as eluent.
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Acknowledgements
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We are grateful to the National Science Foundation (CHE-
1213587) for support of the research project.
Keywords: alkynes · cyclization · domino reactions · radical
reactions · through-bond interactions
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[4] a) L. T. Scott, Angew. Chem. Int. Ed. 2004, 43, 4994; b) M. B. Goldfinger,
T. M. Swager, J. Am. Chem. Soc. 1994, 116, 7895; c) U. H. F. Bunz, Chem.
Rev. 2000, 100, 1605. Selected examples from our work: d) I. V. Alabu-
gin, K. Gilmore, S. Patil, M. Manoharan, S. V. Kovalenko, R. J. Clark, I. Ghi-
viriga, J. Am. Chem. Soc. 2008, 130, 11535; e) P. Byers, I. V. Alabugin, J.
Am. Chem. Soc. 2012, 134, 9609; f) P. M. Byers, J. I. Rashid, R. K. Mo-
hamed, I. V. Alabugin, Org. Lett. 2012, 14, 6032; g) K. Pati, A. M. Hughes,
H. Phan, I. V. Alabugin, Chem. Eur. J. 2014, 20, 390.
[5] S. J. Rowan, S. J. Cantrill, G. R. L. Cousins, J. K. M. Sanders, J. F. Stoddart,
Angew. Chem. 2002, 114, 938; Angew. Chem. Int. Ed. 2002, 41, 898.
[6] S. Mondal, R. K. Mohamed, M. Manoharan, H. Phan, I. V. Alabugin, Org.
Lett. 2013, 15, 5650.
[22] For the application of Marcus theory to radical reactions, see: a) ref. 5b;
b) I. V. Alabugin, M. Manoharan, J. Am. Chem. Soc. 2005, 127,12583;
c) I. V. Alabugin, M. Manoharan, J. Am. Chem. Soc. 2005, 127, 9534. For
potential caveats, see: S. Osuna, K. N. Houk, Chem. Eur. J. 2009, 15,
13219.
[7] The reasons for this change in regioselectivity will be reported in due
course.
[8] Recent review on CꢀC fragmentations: M. A. Drahl, M. Manpadi, L. J.
Williams, Angew. Chem. 2013, 125, 11430; Angew. Chem. Int. Ed. 2013,
52, 11222.
[9] For recent use of TS stabilization for control of alkyne reactivity, see
a) B. Gold, G. B. Dudley, I. V. Alabugin, J. Am. Chem. Soc. 2013, 135,
1558; b) B. Gold, N. Shevchenko, N. Bonus, G. B. Dudley, I. V. Alabugin, J.
Received: March 31, 2014
Published online on && &&, 0000
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&
Chem. Eur. J. 2014, 20, 1 – 7
www.chemeurj.org
6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Full Paper
FULL PAPER
&
Cascade Reactions
S. Mondal, B. Gold, R. K. Mohamed,
I. V. Alabugin*
&& – &&
Design of Leaving Groups in Radical
CꢀC Fragmentations: Through-Bond
2c–3e Interactions in Self-Terminating
Radical Cascades
Half-bonds to halve bonds: Cyclization
followed by fragmentation allows the
use of alkenes as alkyne equivalents.
The energetic penalty for breaking
a strong CꢀC bond is compensated by
the gain of aromaticity in the product
and by stabilizing 2c–3e half-bonds in
the radical fragments. Kinetic accelera-
tion of the fragmentation is provided by
selective transition-state stabilization
through 2c–3e through-bond interac-
tions (see scheme).
Chem. Eur. J. 2014, 20, 1 – 7
www.chemeurj.org
7
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ