Organic Letters
Letter
diradical, which is attacked by nucleophile in a fast second step
followed by rapid protonation of the “naked” aryl anion
(Scheme 1).8d
The free energies of activation for the conversion of
enediynes 1−3 to their diradicals were evaluated from the
rate constants for enediyne decomposition in DMSO-d6 in the
presence of LiI and pivalic acid. The values are shown in Table
2.
According to Table S1, the rates of disappearance of
enediynes 1, 2, and 3 in the presence of LiI and pivalic acid
decrease in the order 1 > 3 > 2, and this trend remains the
same even with varying [I−] or temperature. Figure 1 shows a
Table 2. Free Energies of Activation for the Conversion of
Enediynes 1−3 to the Corresponding p-Dehydrobenzene
Diradicals
1
2
3
ΔG⧧ (kcal mol−1
lit.
)
25.3 0.0
24.8,4b 27.413
28.6 0.1
29.512
27.2 0.1
−
Figure 1. Free energy of activation (in kcal mol−1) for conversion of
enediynes 1−3 to the corresponding p-dehydrobenzene diradicals vs
C1−C6 distance (in Å).
For comparison with activation energies, calculated 1,6
distances between the two carbon atoms that form the new C−
C bond during p-dehydrobenzene formation are given in Table
3.
plot of the free energy of activation for cyclization of enediynes
1, 2, and 3 versus the calculated distance between carbon
atoms C1 and C6, between which the new bond is formed
(Tables 2 and 3). For enediyne 2, ΔG⧧ was taken as 30 kcal
mol−1 from data (Table S1) in the presence of Cl−, which is
least likely to add directly to 2. The least-squares slope is 23
kcal mol−1 Å−1, and the correlation coefficient R2 is 0.99.
Therefore, an 0.1 Å reduction in the distance between C1 and
C6 is associated with a 2.3 kcal mol−1 reduction in activation
energy.
The behavior of enediyne 2 is more complicated. According
to the data in Table S1, the rate of disappearance of 2 increases
upon doubling of the concentration of LiX, but by less than
twofold. More significantly, the rate of disappearance of
enediyne 2 is lower with the less nucleophilic LiBr and even
lower with LiCl. No such variations are seen with 1 or 3. We
attribute these deviations from zero- or first-order dependence
on halide to direct nucleophilic addition of halide to the CC
bond of 2 as well as to its p-dehydrobenzene diradical.
Moreover, 2 is slower to cyclize because cyclization produces a
dehydronaphthalene diradical, which gains less aromatic
stabilization than for 1 and 3, which produce a dehydroben-
zene from a nonaromatic precursor. Therefore, the plot in
Figure 1 is not necessarily linear because the aromatic
stabilization is not constant, and the point for 2 may be
higher if 2 reacts directly with Cl− or if capture of
dehydronaphthalene diradical by I− is competitive with its
recyclization. Nevertheless, the plot is treated as linear for
simplicity.
It is not surprising that the rate of cyclization correlates with
the C1−C6 distance. Nicolaou et al. reported that saturation of
the double bond following intramolecular thiol addition to the
α,β-unsaturated ketone in calicheamicin-γ1 shortens the
calculated distance between the alkyne carbons. Specifically,
they reported that the shorter C1−C6 distance between alkyne
carbons in the cyclic aglycone (3.16 Å) increases the chance of
spontaneous cyclization relative to the acyclic aglycone (3.35
Å).4a They also performed calculations on several other cyclic
enediynes and proposed that the critical C1−C6 distance (dc)
for room-temperature cyclization is 3.20−3.31 Å.4b Later work
suggested that this range may be extended to 2.9−3.4 Å.14
Furthermore, the synthesis of model cyclic enediynes with
Table 3. C1−C6 Distances (d) in Enediynes 1−3
1
2
3
d (Å)
lit.
3.26
3.254b
3.46
−
3.32
−
Discussion
By the use of Semmelhack’s protocol,12 macrocyclization of
1,2-diethynylcyclohexene with 1,4-diiodobutane produces
enediyne 3 as a major product (45%). The fact that enediyne
3 is solid and stable under ambient conditions allows easy
handling and accurate measurement of reactivity and kinetics.
Upon heating, the p-dehydrobenzene diradical generated
from enediyne 1 reacts with nucleophiles such as I−, SCN−,
8c
−
Br−, NC−, and N3 . Similarly, the p-dehydrobenzene
diradical generated from enediyne 2 reacts with I−, SCN−,
and Br−.10 In order to study cycloaromatization and
nucleophilic addition to the resulting p-dehydrobenzene
diradical, enediyne 3 was heated with nucleophiles. With
iodide, 3 reacts to form 9-iodo-1,2,3,4,5,6,7,8-octahydroan-
thracene 5I in >99% isolated yield. It was found to be
necessary to use a dilute solution of enediyne to reduce
polymerization, and 5 mM was found to be optimal. Heating
enediyne 3 without any nucleophile produced 1,2,3,4,5,6,7,8-
octahydroanthracene (5H) in 40% yield, whereas no 5H was
formed in the presence of I−. Consequently an excess of
nucleophile was used during the reaction to promote the
capture of the diradical. The reactions of 3 with SCN−, Br−,
NC−, and NO2 produced moderate to good yields of 5X
−
(Table 1). The lower yields of 5X compared with 5I are due to
the lower nucleophilicity of X−, leading to increased
conversion to 5H and other unidentified compounds (Figure
of disappearance of enediyne 3 is effectively independent of the
concentration of nucleophile or acid and regardless of which
nucleophile is present. Thus, the rate law can be written simply
as a first-order equation, −d[3]/dt = k[3]. It follows that the
rate-limiting step is the cycloaromatization of 3 to form the p-
dehydrobenzene diradical, which then reacts rapidly with the
nucleophile to form product 5X.
C
Org. Lett. XXXX, XXX, XXX−XXX