stereoelectronic umpolung : Converting a p-donor into a σ-acceptor via electron injection and a conformational change

Article abstract of DOI:10.1021/ol400813d

The para-OMe functional group, usually regarded as a conjugative p-donor, acts as an efficient hyperconjugative σ-acceptor in reductive cycloaromatization reactions. This apparent reversal of electronic properties is associated with a conformational change that aligns the σ_O-C orbital with the adjacent aromatic system and provides stabilization to the developing negative charge in the TS of the dianionic cyclization of enediynes. The chameleonic character of the OMe group illustrates the important role of negative hyperconjugation in anionic processes.

Full text of DOI:10.1021/ol400813d

ORGANIC
LETTERS
2013
Vol. 15, No. 9
2238–2241
“Stereoelectronic Umpolung”: Converting
a p‑Donor into a σ‑Acceptor via Electron
Injection and a Conformational Change
Paul W. Peterson, Nikolay Shevchenko, and Igor V. Alabugin*
Department of Chemistry and Biochemistry, Florida State University, Tallahassee,
Florida 32306, United States
alabugin@chem.fsu.edu
Received March 25, 2013
ABSTRACT
The para-OMe functional group, usually regarded as a conjugative p-donor, acts as an efficient hyperconjugative σ-acceptor in reductive
cycloaromatization reactions. This apparent reversal of electronic properties is associated with a conformational change that aligns the
σ*OꢀC orbital with the adjacent aromatic system and provides stabilization to the developing negative charge in the TS of the dianionic
cyclization of enediynes. The chameleonic character of the OMe group illustrates the important role of negative hyperconjugation in anionic
processes.
The utility of electronic substituent effects in organic
chemistry is, to a large extent, based on reliable and
predictable patterns of electronic behavior, associated
with the common functional groups. The donor proper-
ties of the OMe group, documented by its σpara (ꢀ0.12)
is the key step in the mechanism of biological activity of
natural enediyne antibiotics.3 This process and related
reactions4 continue to find new applications in organic
synthesis5 and materials science.6
Due to the poor communication between orthogonal
π-systems, remote substituents attached to the out-of-plane
aromatic π-system of benzannelated enediynes cannot
transmit electronic effects to the developing in-plane
σ-radicals in the Bergman cyclization.7,8 Earlier, we pro-
vided computational evidence that analogous substituent
þ
and σpara (ꢀ0.78) values, served as a reliable reference
in numerous mechanistic studies based on the Hammett
analysis. In this work, we will show how a conformational
change with the concomitant switch in stereoelectronics
can convert this well-known p-donor into a hyperconju-
gative σ-acceptor capable of controlling the regioselec-
tivity of anionic cycloaromatizations.
Motivation for this work came from studies aimed at a
better understanding of electronic effects in cycloaro-
matization reactions. These reactions provide a versatile
platform for testing theoretical concepts related to or-
ganic reactivity because they involve concomitant elec-
tronic reorganization in two orthogonal π-systems.1 The
most famous of these reactions, the Bergman cyclization,2
(4) For a glimpse of the diversity of cycloaromatization reactions,
see: 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. Sullivan, R. W.; Coghlan, V. M.; Munk, S. A.;
Reed, M. W.; Moore, H. W. J. Org. Chem. 1994, 59, 2276. Engels, B.;
Lennartz, C.; Hanrath, M.; Schmittel, M.; Strittmatter, M. Angew.
Chem., Int. Ed. Engl. 1998, 37, 2067. Schmittel, M.; Rodriguez, D.;
Steffen, J. P. Angew Chem., Int. Ed. 2000, 39, 2067. Ionic and metal-
catalyzed cycloaromatizations: Peterson, P. W.; Mohamed, R. K.;
Alabugin, I. V. Eur. J. Org. Chem. 2013, DOI: 10.1002/ejoc.201201656.
(5) Bowles, D. M.; Palmer, G. J.; Landis, C. A.; Scott, J. L.; Anthony,
J. E. Tetrahedron 2001, 57, 3753.
(6) John, J. A.; Tour, J. M. J. Am. Chem. Soc. 1994, 116, 5011. Chen,
X.; Tolbert, L. M.; Hess, D. W.; Henderson, C. Macromolecules 2001,
34, 4104.
(1) Mohamed, R. K.; Peterson, P. W.; Alabugin, I. V. Chem. Rev.
2013, DOI: 10.1021/cr4000682.
(2) Bergman, R. G. Acc. Chem. Res. 1973, 6, 25.
(3) Nicolaou, K. C.; Smith, A. L.; Yue, E. W. Proc. Natl. Acad. Sci.
U.S.A. 1993, 90, 5881.
(7) Choy, N.; Kim, C. S.; Ballestero, C.; Argitas, L.; Diez, C.;
Lichtenberg, F.; Shapiro, L.; Russell, K. C. Tetrahedron Lett. 2000,
41, 6995.
r
10.1021/ol400813d
Published on Web 04/22/2013
2013 American Chemical Society

effects are strongly amplified in reductive cycloaromatiza-
tions ofenediynes where transition statescorrespondtothe
crossing between frontier MOs of different symmetries.9
In order to test this theoretical model, we turned to the
reductive C1ꢀC5 cyclizations of enediynes as a probe of
remote substituent effects. Previously, we had unraveled
the combination of factors that facilitate this path in
comparison the Bergman (C1ꢀC6) pathway.9 Although
the thermal version of this process (SchreinerꢀPascal
cyclization) is difficult,10 this cyclization can be carried
out either via reduction with Li-napthalenide11 or, for
activated enediynes with acceptor substituents, via photo-
induced electron transfer (PET).12 In the latter case, the
reaction cascade continues toward the formation of more
reduced (indene) products. From a practical perspective,
the formal transfer of four H-atoms from the environ-
ment doubles the DNA-damaging potential relative to
the Bergman cyclization. This process can lead to the
ratios of double strand (ds) to single strand (ss) DNA
cleavage that rival13 and exceed14 those of the natural
antibiotic calicheamicin and to pronounced cytotoxicity
toward a variety of cancer cell lines.15
Figure 1. Comparison of thermal and reductive Bergman and
C1ꢀC5 cycloaromatizations of enediynes.
Scheme 1. Li-Naphthalenide-Mediated C1ꢀC5 Cyclization of
Enediynes Proceeds via a Dianion
Conveniently, one can use the regioselectivity of the
nonsymmetric C1ꢀC5 ring closure step as an alternative
experimental probe for the remote substituent effects
(Figure 1). The comparison of two alternative reactions
of the same reactant avoids the complications associated
with differences in the reduction potentials for enediynes
with different substituents.
The seminal study of Whitlock and co-workers11 found
that the Li-naphthalenide-promoted C1ꢀC5 cyclization
of enediynes proceeds via a dianion (Scheme 1). The
evidence included incorporation of two deuterium atoms
upon quenching with D2O and with the need for 2 equiv
of the reducing agent for the full enediyneffulvene
conversion. The didehydrofulvene dianion is stable to-
ward further reduction and furnishes fulvene upon
quenching with a proton source.
We had reproduced this result and investigated the
potential energy surface for this process computationally.
This analysis indicated a significant redistribution of
electron density in the TS with the most pronounced
accumulation of the negative charge at the unsubstituted
endocyclic fulvene carbon (Figure 2).
The reasons for this electronic reorganization are two-
fold: (a) the conversion of delocalized π-anions into
a localized endocyclic σ-anion and, to some extent, (b)
additional polarization of the exocyclic π-system toward
the core with the concomitant increase in the aromatic
cyclopentadienyl-anion character of the newly formed
five-membered ring. Interestingly, unlike the thermal TS
and the anionic reactant and product, the core of the
anionic TS is distinctly nonplanar. This nonplanarity
assists in the negative charge delocalization by allowing
the mixing of “in-plane” and “out-of-plane” orbitals at
the MO crossing point (Figure 2).
Due to the observed negative charge accumulation in
the ring, 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 regioselectivity via selective destabili-
zation of the respective transition states (“Type D”
products, Figure 3).
(8) Alabugin, I. V.; Manoharan, M.; Kovalenko, S. V. Org. Lett.
2002, 4, 1119. The analogous ortho substituents can impose much larger
effects via through space interaction and intramolecular interception of
the initially formed diradical: Zeidan, T.; Kovalenko, S. V.; Manoharan,
M.; Alabugin, I. V. J. Org. Chem. 2006, 71, 962. Baroudi, A.; Mauldin,
J.; Alabugin, I. V. J. Am. Chem. Soc. 2010, 133, 967.
(9) Alabugin, I. V.;Manoharan, M. J. Am. Chem. Soc. 2003, 125, 4495.
(10) 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.
(11) Whitlock, H. W., Jr.; Sandvick, P. E.; Overman, L. E.; Reichardt,
P. B. J. Org. Chem. 1969, 34, 879.
(12) Alabugin, I. V.; Kovalenko, S. V. J. Am. Chem. Soc. 2002, 124,
9052. Electron transfer from DNA: Breiner, B.; Schlatterer, J. C.;
Kovalenko, S. V.; Greenbaum, N. L.; Alabugin, I. V. Angew. Chem., Int.
Ed. 2006, 45, 3666.
(13) Kovalenko, S. V.; Alabugin, I. V. Chem. Commun. 2005, 1444.
Conversion of ss damage into ds damage: Breiner, B.; Schlatterer, J. C.;
Alabugin, I. V.; Kovalenko, S. V.; Greenbaum, N. L. Proc. Natl. Acad.
Sci. U.S.A. 2007, 104, 13016. Activation at the lower pH: 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.
(14) Yang, W.-Y.; Roy, S.; A., R.; Phrathep, B.; Rengert, Z.;
Alabugin, I. V. J. Med. Chem. 2011, 54, 8501.
(15) Review: Breiner, B.; Kaya, K.; Roy, S.; Yang, W.-Y.; Alabugin,
I. V. Org. Biomol. Chem. 2012, 10, 3974.
The OMe-substituted enediynes 1b,c have a higher
reduction potential and react with Li-naphthalenide more
slowly but display remarkable regioselectivity (Figure 4).
Surprisingly, the cyclizations of nonsymmetric enediynes
with the OMe group, either at the core or at the terminus,
led to the formation of “Type A” products (Figure 3)
where the OMe group was in electronic communication
with the position of negative charge accumulation in the
Org. Lett., Vol. 15, No. 9, 2013
2239

Figure 4. Li naphthalenide-mediated cyclization of enediynes
with the core and terminus OMe-substitution.
How can the OMe group, the classic electron donating
functionality, act as an anion-stabilizing group? In order to
answer this question, we had analyzed the cyclization of
enediynes 1b and 1c computationally.
Figure 2. Evolution of electron density during cycloaromatiza-
tion of the delocalized enediyne dianion into the partially loca-
lized benzofulvene dianion is illustrated using selected NBO
charges in the reactant, TS, and the product together with ESP
of the TS. Changes in charge in the 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. The
MO diagram illustrates that the TS corresponds to the MO
crossing where in-plane and out-of-plane MOs are degenerate.
Geometric distortions at this point allow strong orbital mixing.
Figure 5. M06-2X/6-31þG** activation barriers and reaction
energies of dianionic cyclizations of enediynes 1b and 1c.
The calculated activation barriers at the M06-2X/
6-31þG** level of theory agree well with the experimental
results. For enediyne 1b, the p-OMe group acts as an
anion stabilizing substituent leading to an ∼1.5 kcal/mol
decrease in the activation barrier for the formation of
the experimentally preferred regioisomer (Figure 5).
The activation barrier for the other isomer formation
(25.5 kcal/mol) is identical to that for the parent enediyne
1a. For enediyne 1c, the preferred TS does not show
additional stabilization, suggesting that the OMe group
offers the same stabilization to the reactant and product.
On the other hand, the TS for the less favorable isomer
formation is slightly raised in energy (26.4 kcal/mol)
Stereoelectronic Switch via Rotation: Trading Conjuga-
tion for Hyperconjugation. The explanation for this see-
mingly anomalous behavior of the OMe group came from
the analysis of structures and NBO delocalizing interac-
tions of the calculated transition states.
Figure 3. Expected substituent effects on the regioselectivity of
the anionic C1ꢀC5 ring closure. Site with the largest accumula-
tion of the negative charge in the TS (the endocyclic vinyl carbon
of fulvene moiety) is indicated with a larger red circle.
TS! The regioselectivity of cyclizations was determined by
HSQC and HMBC spectra as described in the Supporting
Information (SI).16
(16) The minor fulvene isomers were prepared using Bu3SnH-
mediated 5-exo-dig cyclizations of enediynes as described earlier:
Kovalenko, S. V.; Peabody, S.; Manoharan, M.; Clark, R. J.; Alabugin,
I. V. Org. Lett. 2004, 6, 2457. Peabody, S.; Breiner, B.; Kovalenko, S. V.;
Patil, S.; Alabugin, I. V. Org. Biomol. Chem. 2005, 3, 218. Alabugin,
I. V.; Gilmore, K.; Patil, S.; Manoharan, M.; Kovalenko, S. V.; Clark,
R. J.; Ghiviriga, I. J. Am. Chem. Soc. 2008, 130, 11535. Byers, P.;
Alabugin, I. V. J. Am. Chem. Soc. 2012, 134, 9609.
2240
Org. Lett., Vol. 15, No. 9, 2013

Figure 6. Preferred TS for the cyclization of enediyne 1b.
The striking difference between the geometries of neu-
tral OMe-substituted enediynes17 and their anionic
forms is the relative orientation of the OMe substituent
(Figure 6). The Me group is rotated 90° in both the
reactant and in the C1ꢀC5 TS. This rotation aligns the
OꢀC bond with the aromatic π-system instead of the
usual orientation where the p-type lone pair of oxygen
is in resonance with the aromatic core (conformation
adopted by the dianionic fulvene product and all species
at the neutral PES; see SI for the geometries).
Such a change has profound stereoelectronic con-
sequences. It “inverts” the electronic character of the
OMe group converting it from a p-donor to a moderately
strong hyperconjugative σ-acceptor.18 Figure 7 illustrates
the generality of such conformational preferences and
the associated electronic effects in the benzylic cation,
radical, and anion. Such “inversion” is favorable because
anionic species benefit from delocalizing interactions with
an acceptor but not from the four-electron interactions
with the donor.19
The acceptor ability of σOꢀC bonds plays an important
role in several stereoelectronic phenomena such as the
gauche effect and anomeric effect.18 Note, however, that
the acceptor ability depends on which end of the other
CꢀO bond participates in the interactions. The acceptor
ability at the oxygen end (i.e, that of σOꢀC bonds) is lower
because σ*CꢀO is polarized toward the carbon atom.20
This work illustrates that, when electron demand is
significant and delocalization of the negative charge is
needed, the acceptor ability of σOꢀC bonds still can be a
decisive factor in the observed selectivity.
Figure 7. Top and center: contrasting properties of the MeO
group as a function of orbital alignment. Bottom left: Stereo-
electronic effects based on acceptor ability of σCꢀO bonds.
Bottom right: Comparison of σCꢀO and σOꢀC bonds as hyper-
conjugative acceptors.
In summary, the regioselectivity of the C1ꢀC5 cyclo-
aromatization reaction of benzannelated enediynes is effi-
ciently controlled by remote substitution. From a practical
point of view, we have found new substitution patterns
capable of controlling the regioselectivity of this process.
From the conceptual point of view, our results high-
light the “stereoelectronic umpolung” of a common
functional group. We have identified a simple conforma-
tional change that converts a p-donor into a σ-acceptor in
order to assist in accommodating the electronic demand
of an electron-rich TS. This interesting finding not only
provides an explanation to the counterintuitive experi-
mental selectivity but also suggests that the acceptor
ability of the alkoxy groups should be taken into con-
sideration in chemical reactions and processes that involve
electron-rich systems. The stereoelectronic character of
orbital interactions suggests the possibility of conforma-
tional control (gating) in such systems and opens interest-
ing opportunities in the design of molecular electronics,
memory, sensors, logical gates, etc.
Acknowledgment. I.A. is grateful to the National
Science Foundation (CHE-1152491) and the FSU GAP
Program for support of this research project.
(17) Zeidan, T.; Manoharan, M.; Alabugin, I. V. J. Org. Chem. 2006,
71, 954.
(18) Alabugin, I. V.; Zeidan, T. A. J. Am. Chem. Soc. 2002, 124, 3175.
Review: Alabugin, I. V.; Gilmore, K. M; Peterson, P. W. WIREs
Comput. Mol. Sci. 2011, 1, 109. Recent examples: Gold, B.; Dudley,
G. B.; Alabugin, I. V. J. Am. Chem. Soc. 2013, 135, 1558. Gold, B.;
Shevchenko, N.; Bonus, N.; Dudley, G. B.; Alabugin, I. V. J. Org. Chem.
2012, 77, 75.
(19) An interesting analogy is provided by the “law of increasing
electron demand” in cationic processes: Brown, H. C. The Nonclassical
Ion Problem; Plenum Press: New York, NY, 1977.
Supporting Information Available. Description of com-
putational details, experimental methods, and results.
This material is available free of charge via the Internet
at http://pubs.acs.org.
(20) Alabugin, I. V. J. Org. Chem. 2000, 65, 3910.
The authors declare no competing financial interest.
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