Ortho effect in the Bergman cyclization: Interception of p-benzyne intermediate by intramolecular hydrogen abstraction

Article abstract of DOI:10.1021/jo051857n

Intramolecular hydrogen atom (H-atom) abstraction from the o-OCH ₃ group effectively intercepts the p-benzyne intermediate in the Bergman cycloaromatization of 2,3-diethynyl-1-methoxybenzene (1) before this intermediate undergoes either retro-Bergman ring opening or external H-atom abstraction. This process leads to the formation of a new diradical and renders the cyclization step essentially irreversible. Chemical and kinetic consequences of this phenomenon were investigated through the combination of computational and experimental studies.

Full text of DOI:10.1021/jo051857n

Ortho Effect in the Bergman Cyclization: Interception of p-Benzyne
Intermediate by Intramolecular Hydrogen Abstraction
Tarek A. Zeidan, Mariappan Manoharan, and Igor V. Alabugin*
Department of Chemistry and Biochemistry, Florida State UniVersity, Tallahassee, Florida 32306-4390
alabugin@chem.fsu.edu
ReceiVed September 2, 2005
Intramolecular hydrogen atom (H-atom) abstraction from the o-OCH3 group effectively intercepts the
p-benzyne intermediate in the Bergman cycloaromatization of 2,3-diethynyl-1-methoxybenzene (1) before
this intermediate undergoes either retro-Bergman ring opening or external H-atom abstraction. This process
leads to the formation of a new diradical and renders the cyclization step essentially irreversible. Chemical
and kinetic consequences of this phenomenon were investigated through the combination of computational
and experimental studies.
Introduction
Since the computed activation energies for the cyclization of
the two enediynes are almost identical, we suggested that this
observation may result from trapping of the p-benzyne inter-
mediate by intramolecular hydrogen abstraction from the OMe
group. In the absence of further facile intramolecular deactiva-
tion pathways, such interception of the p-benzyne diradical
should accelerate the Bergman cyclization by rendering it
effectively irreversible, vide infra.4
From a chemical perspective, this sequence of steps is
interesting because it produces a new diradical with a different
topology and lifetime. Moreover, since many natural enediyne
antibiotics have an OCHR substituent similarly positioned
relative to the p-benzyne intermediate5 (Scheme 1), one can
speculate that such a “radical relay” mechanism with the
concomitant formation of a longer lived diradical may occur in
natural antibiotics as well.6 Because Bergman cyclization is
strongly endothermic, the equilibrium between enediyne and
p-benzyne species is heavily biased toward enediyne, and thus
the equilibrium concentration of DNA-damaging species is
extremely small. Although this situation may be beneficial for
Control of cycloaromatization reactions through substituent
effects provides a promising approach toward practical applica-
tions of this chemistry.1,2 Recently, we reported that the
Bergman cyclization of 2,3-diethynyl-1-methoxybenzene (1)
proceeds faster than the cyclization of 1,2-diethynylbenzene (2).3
(1) Maier, M. E.; Greiner, B. Lieb. Ann. Chem. 1992, 855. Schmittel,
M.; Kiau, S. Chem. Lett. 1995, 953. Hoffner, J.; Schottelius, M. J.;
Feichtinger, D.; Chen, P. J. Am. Chem. Soc. 1998, 120, 376. Choy, N.;
Kim, C. S.; Ballestero, C.; Artigas, L., Diez, C.; Lichtenberger, F.; Shapiro,
J.; Russell, K. C. Tetrahedron Lett. 2000, 41, 6955. Jones, G. B.; Warner,
P. M. J. Am. Chem. Soc. 2001, 123, 2134. Ko¨nig, B.; Pitsch, W.; Klein,
M.; Vasold, R.; Prall, M.; Schreiner, P. R. J. Org. Chem. 2001, 66, 1742.
Prall, M. Wittkopp, A.; Fokin, A. A.; Schreiner, P. R. J. Comput. Chem.
2001, 22, 1605. Alabugin, I. V.; Manoharan, M. J. Phys. Chem. A 2003,
107, 3363. Alabugin I. V.; Manoharan, M. J. Am. Chem. Soc. 2003, 125,
4495. Basak, A.; Mandal, S.; Bag, S. S. Chem. ReV. 2003, 103, 4077. Rawat,
D. S.; Zaleski, J. M. Synlett 2004, 393.
(2) Nagata, R.; Yamanaka, H.; Okazaki, E.; Saito, I. Tetrahedron Lett.
1989, 30, 4995. Myers, A. G, Kuo, E. Y.; Finney, N. S. J. Am. Chem. Soc.
1989, 111, 8057. Nagata, R.; Yamanaka, H.; Murahashi, E.; Saito, I.
Tetrahedron Lett. 1990, 31, 2907. Myers, A. G.; Dragovich, P. S.; Kuo, E.
Y. J. Am. Chem. Soc. 1992, 114, 9369.
(3) Alabugin, I. V.; Manoharan, M.; Kovalenko, S. V. Org. Lett. 2002,
4, 1119.
(4) Lockhart, T. P.; Mallon, C. B.; Bergman, R. G. J. Am. Chem. Soc.
1980, 102, 5976.
10.1021/jo051857n CCC: $33.50 © 2006 American Chemical Society
Published on Web 01/04/2006
954
J. Org. Chem. 2006, 71, 954-961

Ortho Effect in the Bergman Cyclization
SCHEME 1. Donor C-H Bonds in p-Benzynes Derived
from OMe Enediyne 1 and from Natural Enediyne
Antibiotics
As a result, the rate of cyclization of benzannelated enediynes
depends on the H-atom donor concentration,10 and thus k2 and
k3 contribute to the overall kinetic expression. Since H-atom
abstraction from 1,4-cyclohexadiene (1,4-CHD) is highly exo-
thermic, formation of either of the three possible monoradicals
can be considered irreversible. In the absence of intramolecular
H-atom abstraction and other side reactions, the rate of
disappearance for the enediyne reactant can be described by eq
1 (derived in Supporting Information):11
k2[HD]
1k2[HD] + k-1
keff ) k
(1)
protecting microorganisms that produce enediynes from auto-
damage, it may also decrease efficiency once the cellular target
is reached. Moreover, such internal transformation of a transient
radical to a longer lived species based on the above intramo-
lecular H-atom abstraction is interesting because its efficiency
should depend on the position of the OCHR moiety, which is,
in turn, controlled by molecular environment, e.g., the mode of
DNA-binding.7 Thus, one can envision a scenario where the
DNA-binding itself renders the cyclization step irreversible and
becomes a necessary condition for the formation of persistent
radical species.
where rate constants are defined in Scheme 2 and HD stands
for H-atom donor. However, when the OMe group is capable
of serving as H-atom donor and intercepting the p-benzyne
radical, the effective rate for the disappearance of OMe enediyne
increases and this process becomes less dependent on the
“external” H-atom donor concentration. In the extreme case,
when k3 is much faster than the rate of intermolecular H-atom
abstraction (k2[HD] , k3), the expression for keff becomes
independent of the concentration of H-atom donor, eq 2:
The goal of this work is to determine the consequences of
this mode of intramolecular H-abstraction through a combination
of computational, chemical, and kinetic studies. To achieve this
goal, we developed and tested a quantitative kinetic model that
extends beyond the Bergman cyclization and incorporates further
steps along the cycloaromatization pathway.
k1k3
keff
)
(2)
k-1 + k3
A direct consequence from the above model is that keff should
be influenced by relative values of k2[HD] and k-1, providing
an explanation to the earlier experimental observations of
Semmelhack et al.10 If k-1 (the rate of the retro-Bergman ring
opening) is significantly faster in comparison with intermo-
lecular H-atom abstraction by the p-benzyne diradical (k2[HD]),
the effective rate for the enediyne disappearance will depend
on the concentration of the H-atom donor. In contrast, if the
intramolecular H-atom abstraction is fast, effective rate for the
disappearance of OMe enediyne should increase and become
less dependent on the “external” H-atom donor concentration.
As a first step, we probed the activation and reaction energies
for the H-atom abstraction computationally using UBLYP/6-
31G** and UB3LYP/6-31G** computations.12 The six-mem-
bered TS for this reaction is 8 and 11 kcal/mol higher than the
lowest p-benzyne conformer at the two levels of theory,
respectively. At both levels, the reaction is exothermic because
the newly formed radical center is stabilized by n(O) f n(C)
anomeric interaction with the lone pair of the R-oxygen atom.
As a result, the new diradical is protected from conversion back
to the p-benzyne by a ca. 10-15 kcal/mol barrier (Figure 1).13
Noticeable divergence of the two DFT methods is not surprising
due to the known difficulties in describing multiconfigurational
electronic structure of singlet biradicals.14,15 At the higher
multiconfigurational BD(T)/cc-pVDZ//BLYP/6-31G** level,14,16
Results and Discussion
The sequence of steps involved in the Bergman cycloaro-
matization cascade is shown in Scheme 2. Since the cyclization
of benzannelated enediynes is significantly endothermic, the
barrier for the retro-Bergman ring opening of p-benzyne is small
(k-1 is large).8 On the other hand, k2 is an order of magnitude
smaller in p-benzynes than in related phenyl radicals because
of the loss of through-bond (TB) interaction in the first hydrogen
abstraction step, vide infra.9
(5) Enediynes Antibiotics as Antitumor Agents; Doyle, T. W., Borders,
D. B., Eds.; Marcel-Dekker: New York, 1994. Esperamicin: Golik, J.;
Clardy, J.; Dubay, G.; Groenewold, G.; Kawaguchi, H.; Konishi, M.;
Krishnan, B.; Ohkum, H.; Saitoh, K.; Doyle, T. W. J. Am. Chem. Soc. 1987,
109, 3461. Golik, J.; Dubay, G.; Groenewold, G.; Kawaguchi, H.; Konishi,
M.; Krishnan, B.; Ohkum, H.; Saitoh, K.; Doyle, T. W. J. Am. Chem. Soc.
1987, 109, 3462. Calicheamicin: Lee, M. D.; Dunne, T. S.; Siegel, M. M.;
Chang, C. C.; Morton, G. O.; Borders, D. B. J. Am. Chem. Soc. 1987, 109,
3464. Lee, M. D.; Dunne, T. S.; Chang, C. C.; Ellestad G. A.; Siegel, M.
M.; Morton, G. O.; McGahren, W. J.; Borders, D. B. J. Am. Chem. Soc.
1987, 109, 3466.
(6) Interestingly, interaction of esperamicin A with CT-DNA results in
cleavage of the glycosidic bond connecting the sugar to the warhead.
Although hydrogen abstraction at the anomeric carbon has been suggested
as a possible explanation to this process, the exact mechanism by which
the cleavage of the C-O bond occurs is still unknown. Langley, D. R.;
Golik, J.; Krishnan, B.; Doyle, T. W.; Beveridge, D. L. J. Am. Chem. Soc.
1994, 116, 15.
(7) Uesugi, M.; Sugiura, Y. Biochemistry 1993, 32, 4622. Walker, S.;
Murnick, J.; Kahne, D. J. Am. Chem. Soc. 1993, 115, 7954. Ikemoto, N.;
Kumar, R. A.; Dedon, P. C.; Danishefsky, S. J.; Patel, D. J. J. Am. Chem.
Soc. 1994, 116, 9387. Paloma, L. G.; Smith, J. A.; Chazin, W. J.; Nicolaou,
K. C. J. Am. Chem. Soc. 1994, 116, 3697. Kumar, R. A.; Ikemoto, N.;
Patel, D. J. J. Mol. Biol. 1997, 265, 187.
(8) Decrease in retro-Bergman barrier for benzannelated enediynes:
Haberhauer, G.; Gleiter, R. J. Am. Chem. Soc. 1999, 121, 4664. Koseki,
S.; Fujimura, Y.; Hirama, M. J. Phys. Chem. 1999, 103, 7672.
(9) Logan, C. F.; Chen, P. J. Am. Chem. Soc. 1996, 118, 2113.
Schottelius, M. J.; Chen, P. J. Am. Chem. Soc. 1996, 118, 4896.
(10) Semmelhack, M. F.; Neu, T.; Foubelo, F. J. Org. Chem. 1994, 59,
5038. Kaneko, T.; Takahashi, M.; Hirama, M. Tetrahedron Lett. 1999, 40,
2015. For a recent discussion, see: Semmelhack, M. F., Sarpong, R. J.
Phys. Org. Chem. 2004, 17, 807.
(11) See Supporting Information for a more elaborate kinetic analysis
including the presence of competing reactions and formation of byproducts.
(12) Frisch, M. J. et al. Gaussian 98, revision A.9; Gaussian, Inc.:
Pittsburgh, PA, 1998 (see Supporting Information for full citation).
(13) This is reminiscent of the Myers-Saito cyclization where the
benzylic radical orbital undergoes rotation to achieve coplanarity with the
π-system of the benzene ring after the cyclization TS. The additional
stabilization of the product makes this reaction effectively irreversible:
Engels, B.; Hanrath, M. J. Am. Chem. Soc. 1998, 120, 6356.
J. Org. Chem, Vol. 71, No. 3, 2006 955

Zeidan et al.
FIGURE 1. (a) Computational analysis of Bergman cyclization/intramolecular H-atom abstraction cascade of 2,3-diethynyl-1-methoxybenzene (1)
at the BS-UBLYP/6-31G** and UB3LYP/6-31G** levels (in italics). (b) Structural information for the Bergman cyclization of syn-OMe (ec): “a”
and “b” denote the C-H distances in Å and “c” and “d” correspond to the energies of σ(CH) f π*(CC)i and π(CC)inplane f σ*(CH) interactions,
respectively. All energies are in kcal/mol.
SCHEME 2. Kinetic Model for the Bergman Cyclization of 2,3-Diethynyl-1-methoxybenzene (1)
the activation energy for the Bergman cyclization is 28.8 kcal/
mol and that for the H-abstraction is 6.2 kcal/mol. Both of the
BD(T) barriers lie between the respective BLYP and B3LYP
values. To obtain more reliable computational data, we carried
out analogous calculations in monoradical where complications
due to the multiconfigurational nature of wave functions are
not present and where MP2/631-G** computations can be used
to cross-evaluate performance of the two DFT methods (Figure
2). Although the calculated barriers for intramolecular H-
abstraction in the monoradical vary from 4.8 to 7.7 kcal/mol,17
these variations do not change the general conclusion that
intramolecular H-abstraction should be able to compete ef-
ficiently with the retro-Bergman ring opening.
Interestingly, the cyclization of the eclipsed syn-conformer
of the OMe-enediyne is accompanied by noticeable weakening
of the C-H bond. This weakening resembles that in the
Schmitel cyclization/H-abstraction sequence (formal ene reac-
(14) Kraka, E.; Cremer, D. J. Am. Chem. Soc. 2000, 122, 8245 and
references therein. For the most recent discussion of the theoretical methods,
see: Schreiner, P. R.; Navarro-Vazquez, A.; Prall, M. Acc. Chem. Res. 2005,
38, 29.
(15) A recent example: Alabugin, I. V.; Manoharan, M. J. Am. Chem.
Soc. 2005, 12583.
(16) (a) Cramer, C. J. J. Am. Chem. Soc. 1998, 120, 6261. (b) Prall, M.;
Wittkopp, A.; Schreiner, P. R. J. Phys. Chem. A 2001, 105, 9265. (c)
Crawford, T. D.; Kraka, E.; Stanton, J. F.; Cremer, D. J. Chem. Phys. 2001,
114, 10638. (d) Stahl, F.; Moran, D.; Schleyer, P. v. R.; Prall, M.; Schreiner,
P. R. J. Org. Chem. 2002, 67, 1453.
FIGURE 2. Calculated energies for intramolecular H-abstraction from
the OMe-monoradical.
956 J. Org. Chem., Vol. 71, No. 3, 2006

Ortho Effect in the Bergman Cyclization
FIGURE 3. Pseudo-first-order rate constants determined using GC analysis for the disappearance of enediynes (a) 2,3-diethynyl-1-methoxybenzene
(1) (3.33 × 10-3 M) and (b) 2,3-diethynyl-1-trideuteriomethoxybenzene (3) (2.5 × 10-3 M) and the appearance of corresponding naphthalenes (a′)
1-methoxynaphthalene and (b′) 1-methoxy(OCD3)naphthalene at different temperatures; [1,4-CHD] ) 0.3 M; X is defined in eq 4.
tion) of enyne-allenes analyzed recently by Lipton, Singleton,
and co-workers,18 but the sequence of cyclization and hydrogen
transfer steps in our case is far from being concerted.
To test validity of the computational estimates, we compared
reaction rates and activation energies for the 2,3-diethynyl-1-
methoxybenzene (1), its OCD3 analogue (3), and 1,2-diethyn-
ylbenzene (2)19 using several experimental approaches: (a)
differential scanning calorimetry (DSC) of neat samples and
solutions in 1,4-cyclohexadiene (1,4-CHD) and (b) kinetic
analysis under the pseudo-first-order conditions (Figure 3 and
Table 1). Although the activation energies for the disappearance
of the three enediynes and for the formation of corresponding
naphthalene products are within experimental error, the DSC
barrier determined in 1,4-CHD is higher for the deuterated
enediyne and consumption of 2,3-diethynyl-1-methoxybenzene
proceeds on average 1.4-fold faster than that of 2,3-diethynyl-
1-trideuteriomethoxybenzene (3) at this concentration of 1,4-
CHD, vide infra. This observation can be explained by the
deuterium isotope effect on the intramolecular hydrogen ab-
straction step displayed indirectly as described in eq 2.
Apparent or effective rate constants, keff, were determined
using the method described in the Experimental Section.
Effective rate constants for the disappearance of ortho-
substituted enediynes and appearance of the corresponding
naphthalene products were measured at different temperatures.
Consumption of enediynes followed the pseudo-first-order
exponential decay dependence (eq 3), Figure 3a and b:
(17) Based on the loss of through bond (TB) interaction between the
two radical centers, reactions of diradicals should have slightly higher
barriers than analogous reactions of monoradicals. For example, Chen found
that for p-benzyne at the CASPT2N/6-31G**//CAS/3-21G level the
difference in the barriers of first and second H-abstractions from methanol
is ca. 1.6 kcal/mol. This observation suggests that UB3LYP provides a more
reliable description of these reactions than UBLYP. For more detailed
description of TB interactions, see: Hoffmann, R.; Imamura, A.; Hehre,
W. J. J. Am. Chem. Soc. 1968, 90, 1499. Hoffmann, R. Acc. Chem. Res.
1971, 4, 1. Squires, R. R.; Cramer, C. J. J. Phys. Chem. A 1998, 102, 9072.
Theoretical analysis of TB interaction in cations: Alabugin I. V.; Mano-
haran, M. J. Org. Chem. 2004, 69, 9011.
(18) Bekele, T.; Christian, C. F.; Lipton, M. A.; Singleton, D. A. J. Am.
Chem. Soc. 2005, 127, 9216.
(19) Our results are in excellent agreement with previously reported
values: Grissom, J. W.; Calkins, T. L.; McMillen, H. A.; Jiang, Y. H. J.
Org. Chem. 1994, 59, 5833.
efft
[SM] ) [SM]0 e-k
(3)
where [SM]0 is the initial concentration of enediyne, [SM] is
J. Org. Chem, Vol. 71, No. 3, 2006 957

Zeidan et al.
TABLE 1. Comparison of Activation Energies and Preexponential Factors (log A) Determined with Different Techniques and Yields of
1-Substituted Naphthalenesa
activation energies, kcal/mol
preexponential factor, log A (s-1
)
ene-
diyne
BLYP
disappear-
ance of ED
appearance of
naphthalene
disappear-
ance of ED
appearance of
naphthalene
%
(B3LYP)b
DSCc
DSCc
yieldd
1
3
2
24.7 (31.4)
24.8 (31.3)e
24.5 (31.3)
23.2 ( 0.2 (22.1 ( 0.5)
24.3 ( 0.2 (22.1 ( 0.7)
23.1 ( 0.1 (21.7 ( 0.3)
25.5 ( 0.6
24.2 ( 0.8
25.9 ( 1.1f
24.9 ( 1.4
24.4 ( 1.6
26.0 ( 1.5
10.1 ( 0.2 (11.3 ( 0.5)
10.6 ( 0.2 (11.3 ( 0.7)
10.0 ( 0.1 (10.8 ( 0.3)
9.4 ( 0.3
8.6 ( 0.4
9.4 ( 0.6
9.0 ( 0.7
8.6 ( 0.8
9.4 ( 0.8
65
62
35
a Errors are standard deviations with 90% confidence limits. b Staggered anti conformer for OCH3; 6-31G** basis set3 (see also Supporting Information).
c In neat 1,4-CHD, using ASTM E-698 thermal stability procedure; values in parentheses are for neat enediynes. d Determined by GC. e The isotope calculations
have been done at 298 K and 1 atm. f This value is in good agreement with the earlier report of Grissom et al.19
FIGURE 4. Dependence of the effective rate constant on the 1,4-CHD concentration for (a) the consumption of 2,3-diethynyl-1-methoxybenzene
(1) (filled circles) and 2,3-diethynyl-1-trideuteriomethoxybenzene (3) (red crosses) and formation of 1-methoxynaphthalene (open circles) at 170
°C and (b) trends in keff at different k-1:k2 ratios predicted by eq 1 when k1 ) 2.4 × 10-3 M vs the experimental dependence of the rate of
consumption for 1,2-diethynylbenzene (2) solution (3.9×10-3 M) at 188 °C, shown in red triangles. At infinite concentration of 1,4-CHD the
apparent rate constant will approach asymptotically the value of k1 ) 2.4 × 10-3 M.
the concentration of enediyne at time t, and keff is the effective
rate concentration of the reaction.
intermediate being funneled down the reaction path and the
retro-Bergman step effectively shut-off. On the other hand,
formation of 1-methoxynaphthalene requires the presence of a
H-atom donor, and thus the respective effective rate constant
is dependent on the concentration of 1,4-CHD (Figure 4a).
Similarly, the appearance of naphthalene products followed
pseudo-first-order kinetic behavior, Figure 3a′ and b′. The
effective rate constants, keff, for the formation of the Bergman
products were determined by fitting the data to eq 4, which
normalizes formation of the product to the observed reaction
yield:
In contrast, the rate of consumption of 1,2-diethynylbenzene
(2) depends on 1,4-CHD concentration.8,10 Comparison of the
experimental curve with theoretical predictions at different k2/
k-1 ratios based on eq 1 suggests that the ratio of experimental
rate constants for H-atom abstraction and retro-Bergman reaction
is ca. 5 M-1 (Figure 4b). An important consequence from the
dependence of experimental curves from the k2/k-1 ratios is that
only the absolute concentration of H-donor is important, whereas
the excess of H-donor relative to enediyne is not. For instance,
experiments with 100-fold excess of 1,4-CHD relative to 1 mM
and 0.01 mM concentration ratio of enediyne are not compa-
rable. Since the 1,4-CHD excess per se is irrelevant, we suggest
that only the absolute concentrations of H-donors should be
reported in kinetic studies of Bergman cyclization and related
reactions. Moreover, since k2/k-1 ratios are different for different
enediynes, the pseudo-first-order plateau will be reached at
different 1,4-CHD concentrations. Thus, kinetic studies relying
on the pseudo-first-order approximations should carefully
examine the effect of H-atom concentration for each new
substrate.20
[P]inf
ln(X) ) ln
) kefft
(4)
(
)
[P]inf - [P]
where [P] and [P]inf are concentrations of the corresponding
naphthalene product at time t and infinity, respectively, and keff
is the effective rate constant for the appearance of the Bergman
product. Activation energies and preexponential factors were
determined by fitting the effective rate constants at different
temperatures to the Arrhenius plot. The results are given in Table
1.
The key evidence for the intramolecular p-benzyne intercep-
tion is provided by the response of experimental reaction rates
to variations in the H-atom concentration. The experimentally
measured trend in Figure 4a clearly follows eq 2, where the
consumption of 2,3-diethynyl-1-methoxybenzene (1) is inde-
pendent from the concentration of the external hydrogen donor,
1,4-CHD. As a result, the Bergman cycloaromatization step in
this case can be considered irreVersible, with the p-benzyne
Both the intramolecular hydrogen abstraction and the rela-
tively long lifetime of the intermediate R-aryloxy radical are
958 J. Org. Chem., Vol. 71, No. 3, 2006

Ortho Effect in the Bergman Cyclization
30 min. After the reaction mixture turned yellow, the solvent was
evaporated under vacuo. The residue was dissolved in CH2Cl2,
washed with H2O (2 × 20 mL), and dried over Na2SO4. The solvent
was removed under vacuum. Recrystallization from hexanes
afforded 0.45 g (85%) of the desired product as yellow crystals:
further supported by formation of the product of the cyclohexa-
dienyl radical recombination with OCH2 moiety derived from
the methoxy group (see Supporting Information, Figure S1c).
Finally, we observed D-incorporation at the C8 of the naph-
thalene ring with the concomitant H-incorporation at the
1
mp 93-95 °C; H NMR (300 MHz, CDCl3) δ 7.4 (dd, 1H, J )
1
methoxy group in the OCD3 substrate. The H NMR signal of
8.4, 7.8 Hz), 7.3 (dd, 1H, J ) 8.4, 1.2 Hz), 6.9 (dd, 1H, J ) 8.1,
1.2 Hz); 13C NMR (75.5 MHz, CDCl3) δ 159.7, 155.7, 130.0, 119.8,
113.4, 79.9; UV-vis (CH3CN) λmax (lg ꢀ) ) 317 nm (3.81), 272
(3.46), 222 (4.13); IR (neat) 3074, 1522, 1448, 1348, 1285, 1098
cm-1; HRMS (EI+) calcd for C7H3D3NO3I 281.95810, found
281.95873.
the methoxy moiety in the naphthalene product derived from
the deuterated anisole 3 (see Supporting Information, Figure
S1b) is a quintet at 3.9 ppm due to proton coupling with the
two deuterium atoms in the OCHD2 moiety. Furthermore, the
integral intensity (0.8) of the proton at C8 in 1-methoxynaph-
thalene is decreased in proportion to the intensity of the OCHD2
signal. The extent of D-incorporation provides an insight into
the relative rates of intramolecular and intermolecular H-atom
abstraction. At the 0.33 M concentration of 1,4-CHD, about
20% of D is transferred, indicating the k2[CHD]/k3 ratio of 4:1
(see Supporting Information, Figure S1b).
Although direct determination of the extent of D-incorporation
at lower concentration of 1,4-CHD is complicated by low yields
of naphthalene products under these conditions, these data
suggest the dominance of the intramolecular H-atom transfer
(>96%) at equal concentrations (0.0033 M) of the enediyne
and the H-atom donor when k2[CHD]/k3 ratio is as low as 0.04:
1. Most interestingly, these observations also suggest that the
D-effect on k3 is significant and intramolecular interception
becomes less competitive with H-abstraction from the external
donor and retro-Bergman ring opening. Indeed, the rate of
disappearance of OCD3-labeled enediyne (red crosses in Figure
3a) becomes sensitive to [1,4-CHD] concentration.
Synthesis of 2-Iodo-3-trideuteriomethoxy-1-aminobenzene (5).
SnCl2 (2.5 g, 12.9 mmol) was added to 2-iodo-1-trideuteriomethoxy-
3-nitrobenzene (4) (0.73 g, 2.59 mmol) in 5 mL of EtOH. The
reaction was stirred at room temperature for 32 h. The solvent was
evaporated under vacuum and the residue was rendered alkaline
by adding NaOH (1N). The mixture was extracted with CH2Cl2
(3 × 10 mL) and the organic mixture was washed with H2O (2 ×
10 mL) and dried over Na2SO4. The solvent was removed under
vacuum. The reaction mixture was purified by chromatography on
silica gel (hexanes) to afford 0.49 g (75%) of the desired product
as a yellow solid: mp 42 °C; 1H NMR (300 MHz, CDCl3) δ 7.08
(d, 1H, J ) 8.1, 7.8 Hz), 6.39 (dd, 1H, J ) 8.1, 1.2 Hz), 6.20 (dd,
1H, J ) 8.1, 1.2 Hz), 4.25 (bs, 2H); 13C NMR (75.5 MHz, CDCl3)
δ 185.8, 148.4, 129.6, 107.8, 100.4, 75.8, 55.4 (septet, J ) 21.7
Hz); UV-vis (CH3CN) λmax (lg ꢀ) ) 293 nm (3.36), 238 (3.93),
214 (4.54); IR (neat) 3348, 1608, 1454, 1266, 1101, 761 cm-1
;
HRMS (EI+) calcd for C7H5D3NOI 251.98392, found 251.98476.
Synthesis of 2,3-Diiodo-1-trideuteriomethoxybenzene (6).
Dropwise addition of a solution of sodium nitrite (0.21 g, 3.06
mmol) in 6 mL of water to a solution of 2-iodo-3-deuteriomethoxy-
1-aminobenzene (5) (0.70 g, 2.78 mmol) in 11 mL of HCl (prepared
from 5 mL of concentrated HCl and 6 mL of H2O solution) at
5 °C was carried out over 30 min. After the mixture was stirred
for additional 20 min at 5 °C, a solution of potassium iodide (3.1
g, 19.2 mmol) in H2O (4 mL) was added dropwise. The solution
was then heated at 80 °C for 2 h, cooled, and extracted with CH2Cl2
(3 × 10 mL). The combined extracts were washed with 5% aqueous
sodium bisulfite and dried over Na2SO4. The solvent was removed
under vacuum. The reaction mixture was purified by chromatog-
raphy on silica gel (hexanes) to afford 0.71 g (70%) of the desired
Conclusion
In conclusion, the OMe group in 2,3-diethynyl-1-methoxy-
benzene (1) intercepts the p-benzyne diradical through intramo-
lecular H-atom abstraction. This step renders cyclization
effectively irreversible and provides a route to diradicals with
new topologies that are likely to be longer living than p-benzyne.
The question of whether the same mechanism operates in
calicheamicins and esperamicins as well as further implications
for DNA damage and triggering of cascade radical reactions21
are under investigation.
1
product as a white solid: mp 71-72 °C; H NMR (300 MHz,
CDCl3) δ 7.5 (d, 1H, J ) 8.1, 1.5 Hz), 7.0 (dd, 1H, J ) 8.1, 8.1
Hz), 6.7 (d, 1H, J ) 7.2 Hz); 13C NMR (75.5 MHz, CDCl3) δ
159.8, 131.7, 130.5, 109.7, 109.4, 100.4; UV-vis (CH3CN) λmax
(lg ꢀ) ) 291 nm (3.36), 283 (3.43), 217 (4.40); IR (neat) 3054,
2255, 2228, 2068, 1558, 1335, 1267, 1102, 989, 764 cm-1; HRMS
(EI+) calcd for C7H3D3OI2 362.86970, found 362.86909.
Experimental Section
2-Iodo-3-nitrophenol22 and 2,3-diethynyl-1-methoxybenzene (1)3
were prepared according to literature procedures. Capillaries (300
mm length, 1.5-1.8 mm outer diameter, 0.2 mm wall) used in
kinetic studies were purchased from Freidrick and Dimmock Inc.
Synthetic Procedures. Synthesis of 2-Iodo-1-trideuterio-
methoxy-3-nitrobenzene (4). KOH pellets (0.11 g, 1.96 mmol)
were added to a solution of 2-iodo-3-nitrophenol (0.50 g, 1.89
mmol) in MeOH (10 mL) and stirred for 20 h. The red precipitate
of potassium 2-iodo-3-nitrophenolate (0.50 g, 1.65 mmol) was
filtered, dissolved in dry acetonitrile, and placed in an Ace pressure
tube. CD3I was added and the reaction was heated to 80 °C for
Synthesis of 2,3-Bis(trimethylsilylethynyl)-1-trideuteriometh-
oxybenzene (7). A suspension of 2,3-diiodo-1-trideuteriomethoxy-
benzene (6) (2.10 g, 5.78 mmol), PdCl2(PPh3)2 (203 mg, 0.29
mmol), and Cu(I) iodide (55.0 mg, 0.29 mmol) in 40 mL of (i-
Pr)2NH was degassed three times by the freeze/pump/thaw tech-
nique in a flame-dried screw-cap Ace pressure tube. Trimethylsilyl
(TMS) acetylene (1.36 g, 13.8 mmol) was added using a syringe.
The tube was sealed and the mixture was heated at 100 °C for 3 h
in an oil bath. Reaction was monitored by TLC. After total
consumption of the aryl halide, the reaction mixture was filtered
through Celite and washed with methylene chloride (3 × 30 mL).
The organic layer was washed with a saturated solution of
ammonium chloride (2 × 30 mL) and water (2 × 30 mL) and dried
over anhydrous Na2SO4. Solvent was removed under vacuum. The
reaction mixture was purified by flash chromatography on silica
gel (hexanes) to afford 1.40 g (80%) of the desired product as
(20) A thorough kinetic study on the effect of H-atom donor for different
ortho-substituted benzannelated enediynes is described in a separate
manuscript: Zeidan, T. A.; Kovalenko, S. V.; Manoharan, M.; Alabugin,
I. V. J. Org. Chem. In press.
(21) Although intramolecular trapping of p-benzynes by reactions with
π-bonds is known (Grissom, J. W.; Calkins, T. L. J. Org. Chem. 1993, 58,
5422; Grissom, J. W.; Calkins, T. L.; Egan, M. J. Am. Chem. Soc. 1993,
115, 11744), its atom transfer counterpart is virtually unexplored.
(22) Hine, J.; Hahn, S.; Miles, D. E.; Ahn, K. J. Org. Chem. 1985, 50,
5092.
1
yellow needles: mp 65 °C; H NMR (300 MHz, CDCl3) δ 7.12
(dd, 1H, J ) 8.1, 7.8 Hz), 7.04 (d, 1H, J ) 7.8 Hz), 6.74 (d, 1H,
J ) 8.2 Hz), 0.27 (s, 9H), 0.25 (s, 9H); 13C NMR (75.5 MHz,
CDCl3) δ 160.2, 128.9, 127.7, 124.5, 114.9 110.6, 103.1, 102.8,
J. Org. Chem, Vol. 71, No. 3, 2006 959

Zeidan et al.
99.2, 89.1, -0.2, -0.3; UV-vis (CH3CN) λmax (lg ꢀ) ) 328 nm
(3.14), 315 (3.10), 283 (3.98), 243 (4.44); IR (neat) 2960, 2156,
1562, 1460, 1249, 1110, 844, 760 cm-1; HRMS (EI+) calcd for
C17H21D3OSi2 303.15541, found 303.15549.
2,3-Diethynyl-1-methoxybenzene (1)/Trideuteriomethoxyben-
zene (3). A 10 mL volumetric flask was charged with 2,3-diethynyl-
1-methoxybenzene (1) (5.2 mg, 3.3 × 10-3 M), 1,2,3,4-tetraphen-
ylnaphthalene (5.6 mg), and 1,4-cyclohexadiene (0.3 mL, 0.3 M).
The solution was analyzed with GC and HPLC to determine the
initial enediyne concentration (3.33 × 10-3 M). The GC time
program had the following parameters: initial temperature )
70 °C for 5 min, 20 °C/min until 220 °C and hold for 5 min, then
30 °C/min until 250 °C and hold for 20 min. Retention times:
tED ) 8.8 min, tnaphth ) 9.4 min, and tstd ) 28.5 min. The following
conditions were used for kinetic analysis using HPLC: A:B
8.5:1.5 solvent system (A ) hexanes; B ) hexanes/ethyl acetate
120/1), 1 mL/min flow rate, 265 nm detector wavelength. Retention
times: tstd ) 13.0 min and tED ) 41.5 min.
Kinetic Studies under Different Concentrations of 1,4-
Cyclohexadiene. 1,2-Diethynylbenzene (1). A 10 mL volumetric
flask was charged with 1,2-diethynylbenzene (25.0 mg, 19.8 × 10-3
M) and 1,2,3,4-tetraphenylnaphthalene (25.0 mg). Five master
solutions (3.96 × 10-3 M each) were prepared with different
concentrations of 1,4-cyclohexadiene, [1,4-CHD] ) 0.04, 0.10, 0.20,
0.40, 0.60, and 0.80 M. The enediynes initial concentration for every
stock solution was determined by GC and HPLC as 3.9 × 10-3 M.
Kinetic experiments were performed at 188 °C. The GC time
program had the following parameters: initial temperature ) 70
°C for 5 min, 20 °C/min until 220 °C and hold for 5 min, then 30
Synthesis of 2,3-Diethynyl-1-trideuteriomethoxybenzene (3).
NaOH (1 N, 5 mL) was added to a methanol solution (50 mL) of
2,3-bis(trimethylsilylethynyl)-1-trideuteriomethoxybenzene (7) (1.10
g, 3.63 mmol). The mixture was stirred at room temperature for
15 min. The progress of reaction was monitored by TLC. After
total consumption of the TMS acetylenes, the solvent was removed
in vacuo. Aqueous HCl (1 N, 10 mL) was added to the crude
mixture. The acidic mixture was extracted by dichloromethane
(3 × 20 mL). The organic layer was washed with water (2 × 30
mL) and dried over anhydrous Na2SO4. Solvent was removed under
vacuum. The reaction mixture was purified by flash chromatography
on silica gel (hexanes) to afford 0.50 g (86%) of the desired product
1
as a white solid: mp 52 °C; H NMR (300 MHz, CDCl3) δ 7.2
(dd, 1H, J ) 8.1, 7.8 Hz), 7.1 (d, 1H, J ) 7.5 Hz), 6.8 (dd, 1H,
J ) 9.3), 3.6 (s, 1H), 3.3 (s, 1H); 13C NMR (75.5 MHz, CDCl3) δ
160.6, 129.4, 126.5, 124.6, 113.9, 110.9, 85.4, 81.6, 81.2, 78.0, 55
(septet, J ) 22.3 Hz); UV-vis (CH3CN) λmax (lg ꢀ) ) 321 nm
(3.61), 267 (3.99), 258 (3.94), 254 (3.93), 235 (4.57); IR (neat)
3280, 2230, 2073, 1565, 1458, 1294, 1104, 789, 633 cm-1; HRMS
(EI+) calcd for C11H5D3O 159.07635, found 159.07608.
Representative Procedure for Preparative Scale of Bergman
Cyclizations. 2,3-Diethynyl-1-methoxybenzene (1) (75 mg, 0.48
mmol) was dissolved in anhydrous chlorobenzene (9 mL). 1,4-
Cyclohexadiene (4.5 mL, 48 mmol) was added and the mixture
was placed in a Pyrex glass tube equipped with a joint. The tube
was attached through the joint to a vacuum line and the mixture
was degassed three times by the freeze/pump/thaw technique. The
tube was sealed under argon, placed in an oil bath, and heated to
150 °C for 5 h. After cooling, chlorobenzene was distilled under
vacuum and the products were isolated and purified by HPLC using
hexanes HPLC grade as solvent with 4 mL/min flow rate, 265 nm
detection wavelength, and 500 µL loop.
Differential Scanning Calorimetry Studies. Temperature and
enthalpy calibrations were performed using indium standard. The
heat capacity was calibrated using a 25 mg sapphire standard. About
8-10 mg of enediyne was used for each experiment. For neat
samples, enediynes were sealed in aluminum hermetic pans. The
samples were equilibrated in the purge gas (argon) for about 15
min prior to each run. For solution samples, stock solutions of
enediynes (5.0 mg) in 1,4-CHD (0.5 mL) were prepared and 50
µL of the stock solutions was sealed in high volume aluminum
pans with O-rings in a glovebox under argon.
°C/min until 250 °C and hold for 20 min. Retention times: tED
)
5.5 min, tnaphth ) 7.0 min, and tstd ) 28.5 min. For kinetic analysis
using HPLC the following conditions were used: A:B 9.5:0.5
solvent system (A ) hexanes; B ) hexanes/ethyl acetate 100/1), 1
mL/min flow rate, 250 nm detector wavelength. Retention times:
tstd ) 7.7 min and tED ) 23.6 min.
2,3-Diethynyl-1-methoxybenzene (1). A 10 mL volumetric flask
was charged with 2,3-diethynyl-1-methoxybenzene (1) (12.5 mg,
8.1 × 10-3 M) and 1,2,3,4-tetraphenylnaphthalene (25.0 mg). Five
master solutions (1.6 × 10-3 M each) were prepared with different
concentrations of 1,4-cyclohexadiene, [1,4-CHD] ) 0.00, 0.02, 0.04,
0.08, 0.16, 0.24, 0.32, and 0.40 M. The enediynes initial concentra-
tion for every stock solution was determined by GC as 1.4 × 10-3
M. Kinetic experiments were performed at 170 °C. The GC time
program had the following parameters: initial temperature ) 70
°C for 5 min, 20 °C/min until 220 °C and hold for 5 min, then 30
°C/min until 250 °C and hold for 20 min. Retention times: tED
8.8 min, tnaphth ) 9.4 min, and tstd ) 28.5 min.
)
Kinetic Studies of 2,3-Diethynyl-1-trideuteriomethoxybenzene
(3) in the Absence of 1,4-CHD. A 10 mL volumetric flask was
charged with 2,3-diethynyl-1-trideuteriomethoxybenzene (3) (7.8
mg, 8.1 × 10-3 M) and 1,2,3,4-tetraphenylnaphthalene (7.2 mg).
The volumetric flask was filled to the mark with chlorobenzene.
The solution was mixed and analyzed with GC to determine their
initial enediynes concentration (5.3 × 10-3 M). Fifteen capillary
melting-point tubes were filled with 75 µL of the solution. The
capillary tubes were frozen by liquid nitrogen, degassed under high
vacuum, and sealed with only enough space for liquid expansion.
The capillary tubes were placed in an oil bath heated at 170 °C
and monitored for 2-3 half-lives. The GC time program had the
following parameters: initial temperature ) 70 °C for 5 min, 20
°C/min until 220 °C and hold for 5 min, then 30 °C/min until 250
Conventional DSC was used to determine the reaction kinetics
using the ASTM E-698 thermal stability protocol.23 This protocol
is used to determine Arrhenius activation energies and preexpo-
nential factors.
Kinetic Studies. 1,2-Diethynylbenzene (1). A 10 mL volumetric
flask was charged with 1,2-diethynylbenzene (7.1 mg, 5.6 × 10-3
M), 1,2,3,4-tetraphenylnaphthalene (5.3 mg), and 1,4-cyclohexa-
diene (0.4 mL, 0.6 M). The solution was analyzed with GC and
HPLC to determine the initial concentration of enediynes (5.6 ×
10-3 M). The GC time program had the following parameters:
initial temperature ) 70 °C for 5 min, 20 °C/min until 220 °C and
hold for 5 min, then 30 °C/min until 250 °C and hold for 20 min.
Retention times: tED ) 5.5 min, tnaphth ) 7.0 min, and tstd ) 28.5
min. The following conditions were used for kinetic analysis using
HPLC: A:B 9.5:0.5 solvent system (A ) hexanes; B ) hexanes/
ethyl acetate 100/1), 1 mL/min flow rate, 250 nm detector
wavelength. Retention times: tstd ) 7.7 min and tED ) 23.6 min.
°C and hold for 20 min. Retention times: tED ) 8.8 min and tstd
28.5 min.
)
Acknowledgment. The authors are grateful to the National
Science Foundation (CHE-0316598) and to the Material Re-
search and Technology (MARTECH) Center at Florida State
University for partial support of this research, to the 3M
Company for an Untenured Faculty Award, and to Professor
Jack Saltiel and Dr. Serguei Kovalenko for helpful discussions.
The authors thank Dr. U. Goli and Mr. H. Henricks of the
Biochemical Analysis and Synthesis Services laboratory (BASS
(23) Standard Test Method for Arrhenius Kinetic Constants for Thermally
Unstable Materials (ANSI/ASTM E698-99). ASTM Book of Standards;
ASTM: Philadelphia, PA, 1999; pp 299-305.
960 J. Org. Chem., Vol. 71, No. 3, 2006

Ortho Effect in the Bergman Cyclization
and characterization details, kinetic procedures and derivation of
kinetic equations. This material is available free of charge via the
Internet at http://pubs.acs.org.
Lab) and Dr. J. Vaughn, Dr. T. Gedris and Dr. S. Freitag of the
NMR facility at the Department of Chemistry and Biochemistry
at Florida State University.
Supporting Information Available: Additional information
including experimental and computational details such as synthesis
JO051857N
J. Org. Chem, Vol. 71, No. 3, 2006 961