Angewandte
Chemie
In all cases, significant amounts of the 4-iodoanisole
were generated during the thermal decomposition
reactions of 4, even when 2-functionalized thio-
phenes are not observed. These data support the
assessment of Carroll et al.[32] and the original
observations by Yamada and Okawara[33] that the
directing-group ability of the 2-thienyl and 4-
methoxyphenyl substituents are similar.
Though the data in Table 1 are limited, it
appears that for oxygen or sulfur nucleophiles the
directing-group ability of the cyclophane ligand
diminishes as nucleophile basicity and the driving
force for functionalizing the more electron-poor
ring increases. Such a trend is consistent with
Hammondꢀs postulate and a concerted, reductive
elimination mechanism in which less steric strain is
developed at the cyclophane ipso carbon atom as
the reaction becomes more exergonic.
The kinetics of aryl azide formation from N3
salts of 1–3 were investigated to probe the relative
steric and electronic contributions to the observed
regioselectivity. The observed rate constants for
xylyl azide formation (CD3CN, 458C) were 4.2 ꢁ
10À4 sÀ1, 5.5 ꢁ 10À5 sÀ1, and 3.3 ꢁ 10À6 sÀ1, corre-
Scheme 4. Functionalization of diaryliodonium salts. (Reductively eliminated aryl
iodides are omitted for clarity.)
corresponds to a difference in the Gibbs energies of activation
(DDG°) of at least 2.8 kcalmolÀ1. Thus, the validity of the
computational model is confirmed.
sponding to Gibbs energies of activation of 21.7, 22.9, and
24.6 kcalmolÀ1 for the reactions of 1, 2, and 3, respectively.
The fact that the rate constant for xylyl azide formation is
To provide context for the SECURE results, arene
functionalization by various nucleophiles X in the 4-methoxy-
phenyl-substituted compound 2 was investigated and revealed
a regioselectivity that mirrors that of the cyclophanyl-
substituted diaryliodonium salt 1 (Table 1). The 4-methox-
yphenyl moiety is the most effective commonly employed
directing group in diaryliodonium chemistry,[10,29,30] however
perfect regioselectivity for arene functionalization is not
observed with this directing group: for the redox-active
thiophenoxide and phenoxide nucleophiles, some loss of
regiocontrol is evident and functionalized anisoles are
formed.
To test the relative directing-group abilities of 4-methox-
yphenyl and [2.2]paracyclophan-4-yl substituents, we pre-
pared the unsymmetrical IIII derivative 3 from 4-methoxy-
(diacetoxyiodo)benzene (38% yield) and examined its ther-
mal decomposition chemistry. More vigorous reaction con-
ditions (808C, CD3CN) were necessary to promote speedy
carbon–heteroatom bond formation with acetate and thio-
cyanate from 3 in comparison to 1 or 2. As can be seen from
inspection of Table 1, the directing-group ability of the
[2.2]paracyclophanyl ligand is comparable or slightly superior
to that of the 4-methoxyphenyl substituent on IIII.
greater for
1
than for
2
indicates that 4-iodo-
[2.2]paracyclophane is a significantly better leaving group
than 4-iodoanisole. Because leaving-group ability is corre-
lated with the electron density on the iodine atom in the aryl
iodide that is being reductively eliminated, these kinetic data
show experimentally that the [2.2]paracyclophane ligand is a
significantly more electron-poor aryl substituent than the 4-
methoxyphenyl ligand and that steric destabilization of the
transition state is responsible for the enhanced directing-
group ability of the [2.2]paracyclophane ligand.
These initial results validated the SECURE concept, but
perfect regiochemical control was still not achievable for
functionalizing very electron-rich rings. To address this issue
we prepared compound 5, which features an electron-
donating methoxy substituent para to the IIII center
(Scheme 5). The methoxy substituent enhances the solubility
of the cyclophanylzinc chloride reagent, leading to improved
yield in the IIII transfer reaction. We were gratified to find that
5 provided excellent regiochemical control for arene func-
tionalization across the range of nucleophiles investigated.
Only anisole substitution was observed after the thermal
decomposition of the azide, acetate, phenoxide, thiocyanate,
and thiophenoxide salts (Scheme 6). However, a mixture of
cyclophane- (30%) and anisole-substituted (60%) products
was obtained from the reductive elimination of the 2,2,2-
trifluoroethoxide salt of 5. The reason for the breakdown in
regioselectivity is clear from the product analysis, which
shows roughly equal amounts of 3- and 4-(2,2,2-trifluoroe-
thoxy)anisole, as well as roughly equal amounts of the two
CF3CH2O-substituted cyclophane regioisomers. This lack of
selectivity and distribution of regioisomers is consistent with a
change in mechanism to one involving benzyne intermediates.
The 2-thienyl substituent has been reported to deliver
high regioselectivities for the radiofluorination of various
electron-rich arenes.[31] We synthesized 4 to examine the
relative directing-group abilities of the 2-thienyl and 4-
methoxyphenyl substituents under stoichiometric conditions.
Inspection of the data in Table 1 indicates that, for the
nucleophiles examined here, the directing-group ability of the
2-thienyl moiety is roughly comparable to that of the 4-
methoxyphenyl and the [2.2]paracyclophanyl ligands on IIII.
Angew. Chem. Int. Ed. 2010, 49, 4079 –4083
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim