meta-arylated phenols ( 9 and 10 ) (fig. S2).
Synthesis ofmeta-substituted phenols is not
trivial, and there are no efficient direct methods
to selectivelymeta-functionalize phenols, a
typical trap question for undergraduate or-
ganic chemistry students. To date, the most
used gateway to these products has been a
meta-halogenated phenol such as 6 , which
in turn cannot be directly synthesized from
phenol and requires indirect, often tedious,
synthetic routes.
Density functional theory calculations using
tolueneasthesubstrateandasimplifiedligand
model bearing one Bpin substituent revealed
that this ligand indeed favors themetatran-
sition state [DG‡(TSmeta) = 28.0 kcal/mol]
over theparatransition state [DG‡(TSpara)=
30.8 kcal/mol] by 2.8 kcal/mol in Gibbs free
energy (Fig. 4). To investigate the reasons for
this difference, we performed a distortion/
interaction analysis ( 34 , 35 )(Fig.4B)inwhich
the activation energy (DE‡)oftheC–H bond
cleavage was partitioned into the energy to
distort the catalyst and substrate to the tran-
sition state geometry (DE‡dist) and the energy of
interaction between the distorted fragments
(DE‡int). The analysis suggests that the observed
selectivity can be ascribed to the larger in-
teraction energy in themetatransition state
[DDE‡int(meta−para)=–1.8 kcal/mol], which
results from the larger steric hindrance between
the substrate and the catalyst in theparatran-
sition state, tilting the arene substrate away
from the ligand (∠IrCmetaCortho= 165.5° versus
∠IrCparaCipso= 170.1°;∠CbpyIrCmeta= 83.0° versus
∠CbpyIrCpara= 87.4°).
This remote steric control strategy has the
potential to be applied to a variety of tran-
sition metal–catalyzed C–H functionalization
reactions ( 36 , 37 ), and the ligand design can
be tuned on demand to fit a substrate in dif-
ferent orientations to achieve different selec-
tivities. Considering the prevalence of bipyridine
ligands in transition metal catalysis, we expect
that the spirobipyridine scaffold will also enable
reactivity and selectivity in various other cata-
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662 11 FEBRUARY 2022•VOL 375 ISSUE 6581 science.orgSCIENCE
Fig. 4. Computational study.(A) Relative Gibbs energies (DG‡), enthalpies (DH‡), and electronic energies (DE‡) calculated at the M06/SDD:6-311+G(d,p)1,4-dioxane(SMD)//
B3LYP-D3/SDD:6-31+G(d,p)1,4-dioxane(SMD)level of theory are given (in kcal/mol) for the reaction of toluene with a simplified ligand model. (B) Distortion/interaction analysis at
the B3LYP-D3/SDD:6-31+G(d,p)1,4-dioxane(SMD)level of theory.
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