A unique approach to metal-induced Bergman cyclization: Long-range enediyne activation by ligand-to-metal charge transfer

Article abstract of DOI:10.1002/anie.200461825

Dramatic differences are found in the temperatures at which Bergman cyclizations occur when Mo^IV-enedithiolate-enediyne complexes are used (see scheme; S: yellow, Mo: red), and this can be directly attributed to a long-range electronic polariza

Full text of DOI:10.1002/anie.200461825

Communications
Metal-Induced Cyclization
A Unique Approach to Metal-Induced Bergman
Cyclization: Long-Range Enediyne Activation by
Ligand-to-Metal Charge Transfer**
Sibaprasad Bhattacharyya, Maren Pink,
Mu-Hyun Baik,* and Jeffrey M. Zaleski*
The development of stable enediyne constructs and subse-
quent low-temperature routes to Bergman-cyclized diradical
formation are paramount for this class of molecule to realize
its potential in biological applications. Metals have been
shown to thermally activate stable enediynes by both s-donor
coordination[1–5] and p complexation,[6,7] which induce a
marked reduction in the thermal barrier to Bergman cycliza-
tion. Despite these advances, the scope of the metal-activated
Bergman cyclization remains poorly defined.
Scheme 1. Synthesis and X-ray structure of 4 (40% probability).
1) MeOH, 08C, 12 h, 20%; 2) CHCl3/AcOH (3:1), Hg(OAc)2, RT, 12 h,
60%.
Electronic factors[8] that contribute to metal-centered
enediyne activation are more elusive than the established
influences of the geometry around the metal center.[1–5]
Computational[9,10] and experimental[11] evaluations of the
Bergman cyclization reaction coordinate show that s accep-
tor/p donor functionalities at the alkyne termini reduce the
activation barrier to diradical formation. In an effort to
extend this model, we questioned whether binding of a strong
Lewis acid in the vicinity of the alkyne termini would induce
sufficient electron polarization to promote enediyne cycliza-
tion in an analogous manner. Herein, we report the prepa-
ration of MoIV–enedithiolate–enediyne complexes that show
considerable differences in reactivity, which can be directly
attributed to electron polarization rather than geometric
effects of the metal center.
in methanol to yield 5a in situ as a light yellow solution
(Scheme 2). The benzannulated dipotassium salt 5b was
prepared in the same manner from 4b. Both 5a and 5b are
stable at ambient temperature in methanol under nitrogen for
3 hours, and at 808C for 1.5 hours, prior to slow decomposi-
tion to non-Bergman side products.
Reaction of 1,8-dibromooct-4-ene-2,6-diyne (1a) with the
dicesium salt of 1,3-dithiole-2-thione-4,5-dithiolate (DMIT;
2) generates 3a in low (ca. 20%) yield (Scheme 1). Addition
of 3a to a stirred slurry of mercury(ii) acetate in chloroform/
acetic acid (3:1) affords the dithiol-2-one 4a in 60% yield.
The benzannulated counterpart 4b was prepared analogously
using 1,2-bis(3-bromopropynyl)benzene (1b) as the starting
material. Compounds 4a and 4b are stable in solution and do
not cyclize upon heating at 1808C in DMSO/1,4-cyclohexa-
diene (CHD; 1:100) over 12 h.
Scheme 2. Bergman cyclization of 5a and thermal reactivity of 7a.
1) MeOH, KOEt (2 equiv), RT, 15 min; 2) [MoCp2Cl2], CHD, 608C,
30 min, 40%; 3) PhCH2Br, 258C, 80%; 4) DMSO, CHD, 1808C, 24 h,
60%.
The dipotassium salt of enediyne ligand 3,10-dialkyl-
thiacyclododec-1,6-ene-4,8-diyne-1,2-dithiolate (5a) was pre-
pared by addition of two equivalents of EtOK to a slurry of 4a
Heating of 5a in the presence of dichlorobis(h5-cyclo-
pentadienyl)molybdenum(iv) in methanol/CHD (1:100) at
608C for 0.5 h affords the Bergman-cyclized product 6a in
approximately 40% yield, with the remaining mass balance
consisting of insoluble polymeric materials common to Berg-
man cyclization reactions. No metal complexation or product
formation are observed at lower temperatures, while decom-
position occurs without an increase in product yield at higher
temperatures. The X-ray structure of 6a (Figure 1) exhibits a
pseudo-tetrahedrally coordinated MoIV center with two thio-
late ligands from the enediyne chelate and two h5-cyclo-
pentadienyl (Cp) rings bound in the plane perpendicular to
the enedithiolate core. The newly formed aromatic ring is
[*] S. Bhattacharyya, M. Pink, Prof. M.-H. Baik, Prof. J. M. Zaleski
Department of Chemistry
Indiana University
800 E. Kirkwood Avenue, Bloomington, IN 47405 (USA)
Fax: (+1)812-855-8300
E-mail: mbaik@indiana.edu
zaleski@indiana.edu
[**] The support of the National Institutes of Health (R01 GM62541-01)
and the National Science Foundation (0116050) is gratefully
acknowledged.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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DOI: 10.1002/anie.200461825
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Figure 1. X-ray structure of 6a. Thermal ellipsoids are illustrated at
40% probability.
Scheme 3. Contrasting reactivities of 7b and 9. 1) PhCH2Br, 258C,
80%; 2) DMSO, CHD, 1808C, 24 h; 3) MeOH, [MoCp2Cl2], 608C,
30 min, 42%; 4) DMSO, CHD, 1208C, 5 h, 15%.
poised above the Mo–S2C2 plane as a consequence of the two
pairs of sp3 sulfur and carbon atoms between the metal–
enedithiolate and aromatic substructures.
leads to gradual decomposition of both starting material and
cyclized product. The X-ray structures of metalloenediyne 9
and cyclized product 6b (Figure 2) reveal similar pseudo-
tetrahedral structures to that of 6a. The separations of the
alkyne termini (C2···C7) in 4a and 9 are identical (4.05 ꢀ),
which suggests an electronic rather than a geometric origin for
the observed cyclization temperatures. Consistent with this
premise, MoIV complexes 6a, 6b, and 9 show characteristic
S!MoIV ligand-to-metal charge-transfer transitions between
500 and 535 nm with significant molar extinction coefficients
of e ꢁ 1300–1700 mꢀ1 cmꢀ1 (Figure 3).
To evaluate whether s coordination or p complexation
promoted the cyclization reaction, 5a was benzylated to 7a by
reaction with benzyl bromide (Scheme 2). Compound 7a is
highly stable, but can be cyclized to 8 in 60% yield by heating
in solution (DMSO/CHD, 1:100) for 24 h at 1808C. In
contrast, the refluxing of 7a with [MoCp2Cl2] in methanol/
THF solution at 608C in the presence of excess CHD results
in no reaction, thereby disqualifying a p interaction between
the enediyne fragment and molybdenum as the origin of
enediyne activation. DFT calculations[12] confirm the
enhancement in reactivity by molybdenum complexation,
and predict an activation enthalpy of 17.7 kcalmolꢀ1 to give
the transition state 7c-TS, whereas the transition state 7a-TS
for the benzylated analogue 7a has an activation enthalpy of
21.9 kcalmolꢀ1. The structures of the transition states are
analogous to that previously described elsewhere for a
prototype reaction.[13] These activation parameters are in
excellent agreement with the kinetics for conversion of 5a!
6a (DH° = 14.25 kcalmolꢀ1; DS° = ꢀ31.52 eu). Since cycliza-
tion of 7a!8 requires heating between 1508C (no reaction)
and 1808C (24 h, 60%), the reaction barrier is estimated from
a simple Arrhenius proportion to be 3–5 kcalmolꢀ1 higher
than that for formation of 6a, which is also in good agreement
with the trend of the calculated enthalpies of activation for
these compounds.
Parallel reactions were performed with the benzannulated
ligand 5b, which is thermally more stable toward Bergman
cyclization than 5a as a result of the higher endothermicity of
the Bergman reaction, which makes the retrocyclization
competitive with H-atom abstraction.[14,15] Within this
theme, heating of benzylated derivative 7b (prepared in an
analogous manner to 7a) at 1808C for 24 h in DMSO/CHD
(1:100) results in no reaction, which reflects the added
enediyne
stability
introduced
by
benzannulation
(Scheme 3). As a consequence of the enhanced stability and
in contrast to the reactivity of 5a, reaction of 5b with
[MoCp2Cl2] at 608C for 0.5 h gives the uncyclized enediyne
complex 9 in 42% yield. Subsequent heating of 9 at 1208C for
5 h activates the ligand and generates Bergman-cyclized
product 6b in 15% yield, with considerable recovery of
starting material (60%). Heating at higher temperatures
Figure 2. X-ray structures of metalloenediyne 9 and subsequent
cyclized product 6b. Thermal ellipsoids are illustrated at 40%
probability.
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and C3,C6 notably for progression from 7c to 7c-TS (for
example, the differential charges at C2 for 7a!7a-TS and
7c!7c-TS are 0.29 and 0.08, respectively), thus indicating a
net delocalization of charge upon metal complexation, which
lowers the energy of the cyclization transition state by
reducing charge repulsion. This concept is a logical extension
of a previously suggested mechanism that considered deloc-
alization through hyperconjugation and electron repulsion as
key contributions to the energy barriers for Bergman
cyclization.[16–18]
Figure 3. Electronic spectra of 9 (c) and 6b (a) in CH2Cl2.
In addition to the metal-induced electrostatic contribution
to the disparate reactivities of 7a and 7c, there is super-
imposed a more complex ensemble of orbital effects that also
supports a decrease in the activation barrier upon Lewis acid
(for example, MoIV) complexation. The first consequence of
metal binding is a lowering of the symmetric and antisym-
metric enedithiolate orbitals by bonding interactions with the
effective dz2 and dxy orbitals, respectively (see Supporting
Information). Second, the molecular orbitals (MOs) involved
in the formation of the developing C2–C7 s bond, the in-
phase and out-of-phase combinations of the in-plane p orbi-
tals of the diyne (MO-104/MO-107 and MO-99/MO-101 of 7a
and 7c, respectively; Figures 5 and 6), display no direct
To quantify the polarization effect, we examined the
partial charges derived from our DFT-computed total den-
sities (Figure 4) for cyclization of benzylated ligand 7a!7a-
TS and Mo complex 7c!7c-TS. For the 7a!7a-TS trans-
formation, the enediyne carbon atoms C2 and C7 which form
the developing s bond become positively polarized by as
Figure 4. Partial charge changes accompanying the formation of the
respective transition states. Charges are derived from fits of the elec-
trostatic potential generated by the DFT-computed total electron
densities.
Figure 5. MO diagram illustrating the relative energy changes of the
ꢀ
two most important MOs that promote C C bond formation between
the ground and transition states for the benzylated and metal-substi-
tuted enediynes, respectively. Orbital energies are indicated in eV.
much as 0.3–0.4 electron units as a result of the change in
hybridization from sp1 to sp2, while C3 and C6 become the
centers of the diradical electrons and are consequently
negatively polarized. Complexation of the {MoCp2} fragment
reduces the amplitudes of these differential charges at C2,C7
electronic interaction of the Mo center with the p orbitals,
which suggests that the function of the metal center reported
here may be general and valid for any Lewis acid. Third,
comparison of the shapes of the two p MOs of 7a and 7c
reveals that the disposition of the S-based lone-pair orbitals to
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Keywords: charge transfer · cyclization · enediynes ·
.
molybdenum · radicals
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lower energies by Mo complexation allows them to more
efficiently mix with the diyne-based p orbitals. This differ-
ential polarization effect is strongly pronounced in the
transition states; MO-87 of the metal complex (7c-TS)
shows substantially more S character than the corresponding
MO-87 of the benzylated ligand (7a-TS). Interestingly, this
mixing has only a modest influence on the energy change of
these MOs (Figure 5). Upon formation of 7a-TS, MO-104 of
7a becomes stabilized by 3.19 eV to give MO-87 of 7a-TS,
compared to the essentially identical stabilization of MO-99
in 7c (3.15 eV) to give MO-87 in 7c-TS. Thus, binding of the
Lewis acid has only a minor impact on the energetics of s-
bond formation. However, the Mo center stabilizes the
diradicaloid transition state by lowering the energy of MO-
102 in 7c-TS by 0.44 eV relative to its analogue MO-112 in
7a-TS. This effect derives from the fact that MO-102 of 7c-TS
is characterized by a localized diradical, where electron
density arising from a lone pair of electrons on the sulfur atom
that could contribute to electron–electron repulsion in the
transition state has been energetically removed by metal
complexation. In contrast, MO-112 of 7a-TS reveals partic-
ipation of the electron density from the lone pair of electrons
on the sulfur atom in the diradicaloid orbital of the transition
state, which causes a net destabilization and concomitant
decrease in thermal reactivity.
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Summarizing the electronic structure origin of the differ-
ential reactivity of 7a and 7c: 1) many orbitals show s-bond
polarization upon metal complexation without a single
dominant contribution; 2) net polarization caused by MoIV
complexation delocalizes enediyne electron density and
simultaneously removes charge repulsion in the 1,4-diradical
orbital of the transition state; and 3) the net polarization
effect on enediyne reactivity is likely transferable to other
metal–enediyne motifs. More generally, we have demon-
strated that high-valent metals can be effective cofactors for
enediyne activation through electronic rather than geometric
influences.
Received: August 30, 2004
Published online: December 7, 2004
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