Fine Control over Site and Substrate Selectivity in Hydrogen Atom Transfer-Based Functionalization of Aliphatic C-H Bonds

Article abstract of DOI:10.1021/acs.joc.6b01842

The selective functionalization of unactivated aliphatic C-H bonds over intrinsically more reactive ones represents an ongoing challenge of synthetic chemistry. Here we show that in hydrogen atom transfer (HAT) from the aliphatic C-H bonds of alkane, ether, alcohol, amide, and amine substrates to the cumyloxyl radical (CumO^?) fine control over site and substrate selectivity is achieved by means of acid-base interactions. Protonation of the amines and metal ion binding to amines and amides strongly deactivates the C-H bonds of these substrates toward HAT to CumO^?, providing a powerful method for selective functionalization of unactivated or intrinsically less reactive C-H bonds. With 5-amino-1-pentanol, site-selectivity has been drastically changed through protonation of the strongly activating NH₂ group, with HAT that shifts to the C-H bonds that are adjacent to the OH group. In the intermolecular selectivity studies, trifluoroacetic acid, Mg(ClO₄)₂, and LiClO₄ have been employed in a orthogonal fashion for selective functionalization of alkane, ether, alcohol, and amide (or amine) substrates in the presence of an amine (or amide) one. Ca(ClO₄)₂, that promotes deactivation of amines and amides by Ca²⁺ binding, offers, moreover, the opportunity to selectively functionalize the C-H bonds of alkane, ether, and alcohol substrates in the presence of both amines and amides.

Full text of DOI:10.1021/acs.joc.6b01842

Article
pubs.acs.org/joc
Fine Control over Site and Substrate Selectivity in Hydrogen Atom
Transfer-Based Functionalization of Aliphatic C−H Bonds
Michela Salamone, Giulia Carboni, and Massimo Bietti*
Dipartimento di Scienze e Tecnologie Chimiche, Universita
S Supporting Information
̀
“Tor Vergata”, Via della Ricerca Scientifica, 1 I-00133 Rome, Italy
*
ABSTRACT: The selective functionalization of unactivated aliphatic C−
H bonds over intrinsically more reactive ones represents an ongoing
challenge of synthetic chemistry. Here we show that in hydrogen atom
transfer (HAT) from the aliphatic C−H bonds of alkane, ether, alcohol,
•
amide, and amine substrates to the cumyloxyl radical (CumO ) fine
control over site and substrate selectivity is achieved by means of acid−
base interactions. Protonation of the amines and metal ion binding to
amines and amides strongly deactivates the C−H bonds of these
•
substrates toward HAT to CumO , providing a powerful method for
selective functionalization of unactivated or intrinsically less reactive C−H
bonds. With 5-amino-1-pentanol, site-selectivity has been drastically changed through protonation of the strongly activating NH
2
group, with HAT that shifts to the C−H bonds that are adjacent to the OH group. In the intermolecular selectivity studies,
trifluoroacetic acid, Mg(ClO ) , and LiClO have been employed in a orthogonal fashion for selective functionalization of alkane,
4
2
4
ether, alcohol, and amide (or amine) substrates in the presence of an amine (or amide) one. Ca(ClO ) , that promotes
4
2
2
+
deactivation of amines and amides by Ca binding, offers, moreover, the opportunity to selectively functionalize the C−H bonds
of alkane, ether, and alcohol substrates in the presence of both amines and amides.
INTRODUCTION
and metal-based catalysts limit, however, the applicability of this
approach.
■
C−H bond functionalization is currently a mainstream topic of
synthetic chemistry and one of the most investigated
approaches to develop new synthetic methodology.
Deactivating polar effects can be also employed to control
site-selectivity. In aliphatic C−H bond functionalization
procedures based on hydrogen atom transfer (HAT) to radical
or radical-like species, the main factor that governs HAT
reactivity is represented by bond strengths, but other factors
such as steric, stereoelectronic, strain release, and polar effects
1
−4
Functionalization of aliphatic C−H bonds generally proceeds
at the most reactive center of an organic substrate. Accordingly,
the development of selective functionalization procedures that
are able to overcome the inherent or innate reactivity of
different C−H bonds, i.e., procedures that occur selectively at
an unactivated aliphatic C−H bond over a functional group or a
C−H bond that is activated by an adjacent functional group,
represents one of the major challenges of modern synthetic
organic chemistry. Among the available procedures, the use of
bulky transition-metal-based catalysts that are able to
discriminate between different C−H bonds on the basis of
sterical accessibility is emerging as a convenient strategy for
selective functionalization of primary and secondary unac-
2
1−23
have also been shown to play an important role.
consequence of the electrophilic nature of the majority of the
As a
24
hydrogen atom abstraction reagents employed, functionaliza-
tion generally occurs at the more electron-rich C−H bonds
(
i.e., the C−H bonds that are α to a heteroatom in substrates
such as amines, amides, alcohols, and ethers or C−H bonds
that are remote from an electron-withdrawing
group).
3,17c,19c,25−28
Along this line, remote, undirected
aliphatic C−H functionalization of amine substrates has been
successfully achieved following deactivation of the proximal C−
5
,6
tivated aliphatic C−H bonds and of methane over alkane and
7
,8
cycloalkane substrates. Great interest has been also attracted
by directing group strategies, where site-selectivity is achieved
through binding of a transition-metal catalyst or an organic
H bonds via protonation or Lewis acid complexation at the
29−32
nitrogen center.
These acid−base interactions convert an
9
−11
activating electron-donating group into a strong electron-
withdrawing and deactivating group, inverting the polarity of
the adjacent C−H bonds and decreasing their reactivity toward
activator group to a substrate functionality.
The need for
covalent installation and removal of the directing group
generally represents, however, a major drawback of this
strategy. An alternative approach is provided by enzymatic
and biomimetic C−H bond oxidations, where substrate
positioning via specific noncovalent interactions and steric
21,28
electrophilic hydrogen atom abstracting reagents.
Most
importantly, in these reactions site-selectivity is achieved by
1
2−20
effects can promote site-selective C−H functionalization.
Availability, stability, and substrate specificity of the enzymes
Received: July 29, 2016
Published: September 12, 2016
©
2016 American Chemical Society
9269
DOI: 10.1021/acs.joc.6b01842
J. Org. Chem. 2016, 81, 9269−9278

The Journal of Organic Chemistry
Article
means of cheap and easily available Brønsted and Lewis acidic
additives.
protonation or proper selection of the added alkali or alkaline
earth-metal ion. Most importantly, these results suggest that
this approach can provide a method for site-selective C−H
bond functionalization of substrates bearing functionalities
characterized by different basicities (intramolecular selectivity,
Scheme 2) or for selective functionalization of an aliphatic or a
Within this framework, recent studies have provided a
quantitative evaluation of the α-C−H bond deactivation of
basic substrates toward a genuine and electrophilic HAT
•
•
reagent such as the cumyloxyl radical (PhC(CH ) O , CumO )
3
2
determined by acid−base interactions. Transient kinetic and
computational studies have shown that in acetonitrile solution
Scheme 2
2
+
protonation or Mg complexation leads to a >4-order of
magnitude decrease in the rate constant for HAT (k ) from the
H
•
33−35
α-C−H bonds of aliphatic amines to CumO .
Strong
deactivating effects have been also observed in the presence of
2+
36
Ca , whereas significantly weaker effects have been observed
when the same reactions have been carried out in the presence
+
33
of Li , quantified on the basis of a ∼2-fold decrease in k .
H
C−H bond deactivation has been also observed in the
reactions of CumO• with tertiary alkanamides following
37
addition of alkali and alkaline earth-metal ions. Strong C−
H deactivation has been observed in acetonitrile solution after
addition of Li and Ca , where in particular the latter metal ion
has been observed to promote deactivation of up to four
substrate equivalents. A significantly weaker deactivation has
+
2+
2
+
been instead observed in the presence of Mg , quantified on
the basis of a ∼3-fold decrease in k .
H
With aliphatic ethers, no significant effect on k for HAT to
weakly basic substrate (alkane, ether, alcohol) in the presence
of a more basic and intrinsically more reactive amine and/or
amide substrate (intermolecular selectivity, Scheme 3). These
possibilities appear of great interest in the framework of the
development of synthetically useful selective C−H functional-
ization procedures based on HAT to electrophilic hydrogen
atom abstracting species.
H
•
CumO has been observed after addition of a Brønsted acid
34b
such as trifluoroacetic acid (TFA). A ≤3-fold decrease in kH
has been instead measured when the corresponding reactions
+
2+ 33
have been carried out in the presence of Li or Mg , in line
with the relatively weaker Lewis basicity of ethers as compared
to amines and amides.
This behavior has been explained in terms of protonation or
metal ion (M ) binding to the basic center of these substrates.
Within this framework, in order to address these issues and
to obtain information on the effect of Brønsted and Lewis acids
on the intermolecular HAT selectivity, detailed transient kinetic
n+
These interactions increase the bond dissociation enthalpy of
3
5,38
•
the α-C−H bonds,
decreasing the electron density of these
studies on the reactions of CumO with a variety of selected
bonds and of the product radical, leading to a destabilization of
substrate couples and triads have been carried out. The
following substrates have been chosen for this purpose:
cyclooctane (COT), dibenzylether (DBE), tetrahydrofuran
(THF), cyclohexanol (CHXOH), N,N-dimethylacetamide
the HAT transition state and to an overall α-C−H bond
•
deactivation toward CumO (Scheme 1, showing the effect of
metal ion binding on HAT from a tertiary alkylamine to
•
21,33,34
CumO ).
(DMA), cyclohexylamine (CHXNH ), triethylamine (TEA),
2
and 1,2,2,6,6-pentamethylpiperidine (PMP).
Scheme 1
RESULTS AND DISCUSSION
In these studies, CumO has been generated by 355 nm laser
flash photolysis of acetonitrile solutions containing the parent
■
•
dicumyl peroxide, and the second-order HAT rate constants
(
kH) have been obtained from the slope of the observed rate
constant (k ) vs [substrate] plots, where in turn the k values
have been measured following the decay of the CumO visible
obs
obs
•
39
absorption band (λmax = 485 nm) at the different substrate
concentrations. Most importantly, this laser flash photolysis
approach can provide direct and reliable information on the
HAT process, without complications generally associated with
indirect information extracted from catalytic procedures, where
multiple steps are involved and overfunctionalization can be
observed, often leading to mass balance problems, and partially
masking the intrinsic HAT selectivity.
Taken together, these results clearly show that C−H
deactivation can be modulated varying the Brønsted or Lewis
basicity of the substrate as well as the nature and strength of the
acid, allowing for careful control over the HAT reactivity of
basic substrates toward alkoxyl (and, more generally, electro-
philic) radicals. Comparison between the results obtained with
the different substrates shows that deactivation of C−H bonds
that are proximal to amine or amide functionalities toward
HAT to electrophilic radicals can be achieved through
It is well-established that with the chosen substrates, HAT to
alkoxyl radicals predominantly occurs from the α-C−H bonds
40
of ethers, alcohols, and amines and from the N-methyl groups
4
1
of DMA. The k values measured in acetonitrile solution at T
H
•
= 25 °C, for reaction of CumO with the hydrogen atom donor
substrates employed in this study are collected in Table 1.
9
270
DOI: 10.1021/acs.joc.6b01842
J. Org. Chem. 2016, 81, 9269−9278

The Journal of Organic Chemistry
Article
Scheme 3
Table 1. Second-Order Rate Constants (k ) for Reaction of
CumO with Different Hydrogen Atom Donor Substrates
Measured in Acetonitrile at T = 25 °C
been studied exclusively in the presence of Ca(ClO ) , and the
triads have been chosen in such a way as to determine selective
deactivation of two substrates via metal ion complexation
4 2
H
•
(
amine and amide), over a third hydrocarbon or ether
kH (M− s−1
)
1
a
substrate
cyclooctane (COT)
substrate.
(3.2 ± 0.1) × 106
b
c
Kinetic studies have been complemented by product analysis
tetrahydrofuran (THF)
dibenzyl ether (DBE)
(5.8 ± 0.1) × 106
•
of the reactions of CumO with COT and DBE, where the
(5.62 ± 0.02) × 106
(2.66 ± 0.05) × 106
b
b
b
intermolecular selectivity has been studied carrying out the
reactions in the presence of an amine substrate such as PMP
and of a stoichiometric amount of TFA. In these studies,
cyclohexanol (CHXOH)
N,N-dimethylacetamide (DMA)
cyclohexylamine (CHXNH2)
triethylamine (TEA)
6
(1.47 ± 0.02) × 10
(2.1 ± 0.1) × 107
b
•
CumO has been generated by visible light irradiation of
8
d
(2.0 ± 0.1) × 10
(1.70 ± 0.02) × 108
dichloromethane solutions containing cumyl alcohol
d
1,2,2,6,6-pentamethylpiperidine (PMP)
43
(
CumOH), (diacetoxyiodo)benzene (DIB), and iodine (I2).
a
The given values are the average of at least two independent kinetic
Information on the effect of TFA on the intramolecular HAT
b
c
d
experiments. This work. Ref 42. Ref 40d.
selectivity has been obtained through a detailed transient
•
kinetic study in acetonitrile solution on the reactions of CumO
TFA has been used as Brønsted acid for quantitative
protonation of the amine substrates, while LiClO , Mg(ClO ) ,
with 5-amino-1-pentanol (APOH), with comparison to the
corresponding reactions with pentane (PentH), 1-pentanol
(PentOH), and 1-aminopentane (PentNH2).
4
4 2
and Ca(ClO ) have been used for metal-ion binding to the
4
2
amine and/or amide substrates. Substrate couples and acid
additives have been chosen in such a way as to determine
selective C−H bond deactivation of one substrate via
protonation (amine) or metal ion complexation (amine or
amide) over a second hydrocarbon, ether, alcohol, amide, or
amine substrate. The HAT reactivity of substrate triads has
Intermolecular Selectivity. Starting from the study of the
reactions of CumO with COT, a representative saturated
hydrocarbon substrate, the following kH value has been
•
measured in acetonitrile, from the slope of the k vs [COT]
obs
6
−1 −1
plot: kH = (3.2 ± 0.1) × 10 M
s
(Figure 1a,b, black
circles). The intercept of this plot mostly reflects the
•
Figure 1. Plots of kobs vs [cyclooctane] for reaction with the cumyloxyl radical (CumO ). (a) In acetonitrile (black circles) and in acetonitrile
containing: (i) 0.1 M CHXNH (white circles); (ii) 0.01 M PMP (red circles); (iii) 0.01 M PMP and 0.2 M DMA (green circles). (b) In acetonitrile
2
(
black circles) and in acetonitrile containing: (i) 0.1 M CHXNH and 0.1 M TFA (white circles); (ii) 0.01 M PMP and 0.01 M Mg(ClO ) (red
2
4
2
circles); (iii) 0.01 M PMP, 0.2 M DMA, and 0.2 M Ca(ClO ) (green circles). From the linear regression analysis: in acetonitrile, k = (3.2 ± 0.1) ×
4
2
H
6
−1 −1
6
−1 −1
6
−1 −1
6
−1 −1
1
±
0 M s . (a) (i) k = (3.05 ± 0.06) × 10 M s ; (ii) k = (3.2 ± 0.1) × 10 M s ; (iii) k = (3.30 ± 0.05) × 10 M s . (b) (i) k = (3.19
H
H
H
H
6
−1 −1
6
−1 −1
6
−1 −1
0.05) × 10 M s ; (ii) k = (3.1 ± 0.1) × 10 M s ; (iii) k = (3.40 ± 0.04) × 10 M s . The different intercepts observed in graph (b)
H H
33,37a
•
reflect the effect of the acid additive on the CumO β-scission rate constant.
9
271
DOI: 10.1021/acs.joc.6b01842
J. Org. Chem. 2016, 81, 9269−9278

The Journal of Organic Chemistry
Article
•
39a
contribution from C−CH β-scission in CumO . Negligible
different substrates (points 1−2 and points 1−3 in Figure 2a,b,
respectively). Successive addition of the Brønsted or Lewis acid
(marked with # in Figure 2a,b, and indicative of the addition of
Mg(ClO ) and Ca(ClO ) , respectively) deactivates the basic
amine and/or amide substrates by protonation or metal ion
binding, as clearly shown by the sharp decrease in kobs observed
following addition. The increase in reactivity observed in the
3
effects on k have been observed after addition of 0.1 M TFA,
.6 M LiClO , or 0.2 M Ca(ClO ) (Supporting Information
SI), Figure S1). No significant effect on kH has been also
observed when the reaction has been studied in the presence of
i) 0.1 M CHXNH (Figure 1a, white circles), (ii) 0.01 M PMP
red circles), and (iii) 0.01 M PMP and 0.2 M DMA (green
H
0
4 4 2
(
4 2
4 2
(
2
(
circles). As compared to acetonitrile, the significantly higher
values of the intercepts for the kobs vs [COT] plots reflect the
kinetic contribution of HAT from the α-C−H bonds of the
last concentration range reflects selective HAT from COT to
•
CumO , as evidenced by the very similar slopes (i.e., k values)
H
measured in the first and last region of the kobs vs [substrate]
plots (points 3 and 4 in Figure 2a,b, respectively). A
representative example is shown in Scheme 5, where, according
to the plots displayed in Figure 2a, the effect of sequential
addition of COT, PMP, Mg(ClO ) , and COT on the reaction
added amines (CHXNH and PMP) and from the N-methyl
2
groups of DMA, clearly indicating that under these conditions,
competitive HAT from COT and from the added amine and
amide substrates occurs.
Almost identical kH values have been measured when the
same reactions have been carried out in the presence of
Brønsted and Lewis acid additives, namely (i) 0.1 M CHXNH2
and 0.1 M TFA (Figure 1b, white circles), (ii) 0.01 M PMP and
4
2
•
with CumO is shown.
•
Product studies on the reaction of CumO with COT have
been also carried out following visible light irradiation (30−120
min) of argon saturated dichloromethane solutions containing
0
.01 Mg(ClO ) (red circles), and (iii) 0.01 M PMP, 0.2 M
4 2
COT (0.4−1.0 M), CumOH (0.10 M), DIB (0.22 M), and I
2
DMA and 0.2 M Ca(ClO ) (green circles), where, however, a
4
2
(
0.11 M). Formation of cyclooctyl acetate (COTOAc) and
sharp decrease in the intercepts of the k vs [COT] plots has
obs
acetophenone (AcPh) as the exclusive reaction products has
been observed. Both COTOAc and AcPh increase with
increasing irradiation time, whereas an increase in substrate
concentration from 0.4 to 1.0 M leads to a 3-fold increase in the
COTOAc/AcPh ratio. These results can be accounted for on
the basis of the competitive pathways described in Scheme 6,
4
4
been observed. In particular, the different intercepts observed
in Figure 1b reflect the effect of the acidic additive on the
CumO β-scission rate constant (see for comparison the
•
33,37a
pertinent kobs vs [COT] plots displayed in Figure S1).
The almost identical slopes observed for the kobs vs [COT]
plots under these diverse experimental conditions and, most
importantly, the sharp decrease in intercept clearly show that
where AcPh derives from C−CH β-scission in the first formed
3
•
39a
2
+
CumO (path a), whereas the formation of COTOAc can be
explained in terms of the acetolysis of cyclooctyl iodide, formed
following HAT from COT to CumO (path b) and reaction of
protonation of CHXNH by TFA, Mg binding to PMP, and
2
2
+
Ca binding to PMP, and DMA can promote strong
•
deactivation of the C−H bonds of these substrates, with
•
the cyclooctyl radical thus formed with I (path c), clearly
2
HAT to CumO that now exclusively occurs from COT,
indicating that COTOAc represents the exclusive product
deriving from the HAT pathway. On the basis of this picture, an
increase in [COT] will increase the relative importance of the
bimolecular HAT pathway over the unimolecular β-scission
one.
despite of the fact that the α-C−H bonds of CHXNH and
2
•
PMP are significantly more reactive toward CumO (k = 2.1 ×
H
7
8
−1 −1
1
0 and 1.7 × 10 M s , respectively), while the α-C−H
6
bonds of DMA display a comparable reactivity (k = 1.47 × 10
H
−
1
−1
M
s ). A representative example is displayed in Scheme 4,
By carrying out the reaction in the presence of PMP (0.05−
.10 M) and of a stoichiometric amount of TFA, the same
0
Scheme 4
product distribution has been observed, and quantitative
recovery of PMP has been obtained after workup. This result
is again indicative of the strong deactivation toward HAT of the
α-C−H bonds of PMP determined by protonation, in full
agreement with the mechanistic picture discussed above.
Moving to representative ether substrates such as THF and
DBE, the following kH values have been measured in
•
acetonitrile after reaction with CumO : k = (5.8 ± 0.1) ×
1
H
6
6
−1 −1
0 and (5.62 ± 0.02) × 10 M s , respectively. Negligible
effects on k have been observed after addition of 0.1 M
H
34b
TFA or 0.2 M Ca(ClO ) (Figure S5), whereas a ≤3-fold
where, according to the plot displayed in Figure 1a,b (red
4 2
•
decrease in kH has been measured after addition of 1.0 M
circles) for the reaction of CumO with COT and PMP, the
33
2
+
LiClO or Mg(ClO ) . No significant effect on k has been
effect of added Mg on the intermolecular HAT selectivity is
shown.
4 4 2 H
also observed when the reaction with THF has been studied in
the presence of (a) 0.1 M CHXNH and TFA, (b) 0.2 M PMP
Additional experiments where the concentration of COT has
been initially varied, followed by a concentration variation of
other hydrogen atom donor substrates [(i) PMP, (ii) DMA and
2
and TFA, (c) 0.2 M TEA and TFA, and (d) 0.01 M PMP and
Mg(ClO ) (Figure S6) and when the reaction with DBE has
4 2
PMP, (iii) DMA, (iv) CHXNH ], by addition of a Lewis or
been studied in the presence of (a) 0.2 M PMP and TFA, (b)
0.2 M TEA and TFA, (c) 0.5 M TEA and TFA, and (d) 0.01 M
2
Brønsted acid [(i) Mg(ClO ) , (ii) Ca(ClO ) , (iii) LiClO ,
4
2
4 2
4
(
iv) TFA], and by a second variation in [COT], fully support
PMP, 0.2 M DMA, and 0.2 M Ca(ClO
) (Figure S7). These
4 2
this mechanistic picture (Figures 2a,b, S3, and S4, respectively).
Competitive HAT from the C−H bonds of the different
substrates is initially observed, evidenced by the change in slope
of the kobs vs [substrate] plots that accompanies addition of the
results clearly indicate that also under these conditions,
protonation of the amine substrates (CHXNH
, PMP and
2
TEA) by TFA, Mg2+ binding to PMP, and Ca binding to
2+
PMP, and DMA promotes strong deactivation of the C−H
9
272
DOI: 10.1021/acs.joc.6b01842
J. Org. Chem. 2016, 81, 9269−9278

The Journal of Organic Chemistry
Article
•
Figure 2. Plots of kobs vs [substrate] for reaction with the cumyloxyl radical (CumO ) in acetonitrile, following sequential addition of: (a) COT
black circles), PMP (red circles), Mg(ClO ) and COT (black circles); (b) COT (black circles), DMA (red circles), PMP (green circles),
(
4
2
6
−1 −1
8
−1 −1
6
Ca(ClO ) and COT (black circles). From the linear regression analysis: (a) k = 3.51 × 10 M s , k = 1.36 × 10 M s , k = 3.38 × 10
M
of the first and fourth plot (black circles) reflects the effect of Ca(ClO ) on the CumO β-scission rate constant.
4
2
H1
H2
H3
−1
−1
6
−1 −1
6
−1 −1
8
−1 −1
6
−1 −1
s . (b) k = 3.30 × 10 M s , k = 1.92 × 10 M s , k = 1.87 × 10 M s , k = 4.64 × 10 M s . In (b), the shift in the intercept
H1 H2 H3 H4
37a
•
4
2
Scheme 5
Scheme 6
•
bonds of these substrates, with HAT to CumO that selectively
occurs from THF or DBE.
containing the Lewis acid, the concentration of the ether
substrate has been initially varied, followed by a concentration
variation of other hydrogen atom donor substrates and by a
second variation in the concentration of the ether substrate (for
THF, starting from an acetonitrile solution containing 0.6 M
The same reactivity pattern has been observed in experi-
ments where the concentration of THF or DBE has been
initially varied, followed by a sequential concentration variation
of other hydrogen atom donor substrates, by addition of a
Brønsted or Lewis acid, and by a second variation in the
concentration of the ether substrate (for THF: (i) TEA and
TFA (Figure 3a); for DBE: (i) DMA, PMP and Ca(ClO4)2
LiClO : DMA (Figure S9); for DBE, starting from an
4
acetonitrile solution containing 0.2 M Ca(ClO ) : DMA and
4
2
PMP (Figure S10).
When the sequential concentration variation of the hydrogen
atom donors (points 1−2 and 1−3 in Figure 3a,b, respectively)
has been followed by addition of the Brønsted or Lewis acid
(
Figure 3b); (ii) PMP and TFA (Figure S8)) and in
experiments where, starting from an acetonitrile solution
9
273
DOI: 10.1021/acs.joc.6b01842
J. Org. Chem. 2016, 81, 9269−9278

The Journal of Organic Chemistry
Article
•
Figure 3. Plots of kobs vs [substrate] for reaction with the cumyloxyl radical (CumO ) in acetonitrile, following sequential addition of: (a) THF
black circles), TEA (red circles), TFA and THF (black circles); (b) DBE (black circles), DMA (red circles), PMP (green circles), Ca(ClO ) and
(
4
2
6
−1 −1
8
−1 −1
6
−1 −1
DBE (black circles). From the linear regression analysis: (a) k = 6.08 × 10 M s ; k = 2.10 × 10 M s ; k = 6.48 × 10 M s . (b) k =
6
fourth plot (black circles) reflects the effect of Ca(ClO ) on the CumO β-scission rate constant.
H1
H2
H3
H1
6
−1 −1
6
−1 −1
8
−1 −1
6
−1 −1
.50 × 10 M s ; k = 1.72 × 10 M s ; k = 1.80 × 10 M s ; k = 6.01 × 10 M s . In (b), the shift in the intercept of the first and
H2 H3 H4
37a
•
4
2
Scheme 7
(
marked with # in Figure 3a,b, and indicative of the addition of
indicative of the strong C−H bond deactivation of these
TFA and Ca(ClO ) , respectively), competitive HAT from the
C−H bonds of the different substrates has been initially
observed. Protonation deactivates the amine substrates while
Ca binding deactivates both the amine and amide substrates,
as clearly shown by the sharp decrease in kobs observed
following addition of TFA and Ca(ClO ) . The increase in
reactivity observed in the last concentration range (points 3 and
4
HAT from THF or DBE to CumO . A representative example
is shown in Scheme 7, where, according to the plots displayed
in Figure 3b, the effect of sequential addition of DBE, DMA,
PMP, Ca(ClO ) , and DBE on the reaction with CumO is
shown.
When the sequential concentration variation of the hydrogen
atom donors has been carried out on an acetonitrile solution
containing the Lewis acid, the linear increase in reactivity
observed in the first and last concentration range reflects
substrates determined by metal ion binding.
4
2
•
Product studies on the reaction of CumO with DBE (for
details see the SI) have shown the formation of benzaldehyde
and benzyl alcohol as the exclusive products deriving from
HAT from the benzylic C−H bonds of this substrate,
accompanied by acetophenone (AcPh) formed following
2+
4
2
•
•
CumO β-scission. When the reaction with CumO has been
carried out in the presence of 0.10 M PMP and 0.10 M TFA,
formation of the same products and quantitative recovery of
PMP has been observed, providing an additional example of the
selective deactivation toward HAT of the C−H bonds of a
more basic and intrinsically more reactive amine substrate over
an ether substrate determined by protonation.
in Figure 3a,b, respectively) reflects in both cases selective
•
•
4
2
•
Additional experiments on the reactions of CumO with
selected substrate couples have shown moreover that selective
C−H bond deactivation of an amine (TEA or PMP) or amide
(
DMA) substrate over an alcohol (CHXOH), amide (DMA),
or amine (PMP) one can be successfully achieved following
•
selective HAT from the ether substrate to CumO , as
addition of TFA, Mg(ClO ) , or LiClO . The k vs [substrate]
4
2
4
obs
evidenced by the very similar slopes measured in these regions
for the kobs vs [substrate] plots (Figures S9 and S10). The
negligible effect on reactivity observed after addition of DMA
plots showing selective deactivation of DMA over CHXOH and
of DMA over PMP by LiClO addition; of PMP over DMA,
4
TEA over DMA, and TEA over CHXOH by TFA addition; of
PMP over DMA, and PMP over CHXOH by Mg(ClO4)2
addition, are displayed in Figures S11−S17, respectively. The
results obtained in the present study on the effect of Brønsted
(in the reaction carried out in the presence of LiClO : Figure
4
S9) or after addition of DMA and PMP (in the reaction carried
out in the presence of Ca(ClO ) : Figure S10) is instead
4
2
9
274
DOI: 10.1021/acs.joc.6b01842
J. Org. Chem. 2016, 81, 9269−9278

The Journal of Organic Chemistry
Article
and Lewis acidic additives on the intermolecular HAT
•
selectivity for reactions of CumO with hydrogen atom donor
substrate couples and triads are summarized in Table 2.
Table 2. Effect of Brønsted and Lewis Acidic Additives on
the Intermolecular HAT Selectivity for Reactions of CumO
•
with Hydrogen Atom Donor Substrate Couples and Triads
strong C−H bond deactivation
additive
for
selective HAT from
H+
amine
amine
amide
alkane, ether (alcohol), amide
alkane, ether (alcohol), amide
alkane, ether (alcohol), amine
alkane, ether (alcohol)
Mg2+
Li+
Ca2+
amine and amide
Intramolecular Selectivity. In order to obtain information
on the role of acid−base interactions on the intramolecular
•
HAT selectivity, the effect of TFA on the reaction of CumO
with 5-amino-1-pentanol (APOH) has been investigated by
•
laser flash photolysis. As a matter of comparison the
Figure 4. Plot of kobs vs [pentylamine] for reaction with CumO in
•
corresponding reactions of CumO with pentane (PentH), 1-
MeCN containing 0.10 M TFA. From the linear regression analysis:
pentanol (PentOH), and 1-aminopentane (PentNH ) have
for [PentNH
2
] ≤ [TFA] (black circles), by taking into account that for
2
[
[
TFA] = 0.1−1.0 M, no effect on k has been observed up to
been also studied. The k values thus obtained are collected in
obs
−1 −1
H
4
PentNH ] = [TFA], k < 10 M s ; for [PentNH ] > [TFA] (red
Table 3. The pertinent kobs vs [substrate] plots are displayed in
Figure S18.
2
H1
2
7
−1 −1
circles) kH2 = 1.22 × 10 M s .
−
1
−1
Clearly, under these conditions protonation of the amine
Table 3. Second-Order Rate Constants (k , M s ) for
H
•
functionality strongly deactivates the α-C−H bonds (Scheme
Reaction of CumO with Pentane Derivatives Measured in
8
), leading to a decrease in reactivity that exceeds 3 orders of
Acetonitrile at T = 25 °C
3
magnitude (k /k (TFA) > 10 ).
H
H
Scheme 8
By taking into account that the C−H bonds of unactivated
methyl groups display an extremely low reactivity toward
4
−1 −1
alkoxyl radicals (k (CH ) ≤ 1.3 × 10 M
s
per methyl
H
3
4
5
group), it can be reasonably concluded that the k value5
H
•
measured for reaction of CumO with PentH (k = 3.1 × 10
H
−
1 −1
M
s ) mostly reflects HAT from the methylene groups. On
the basis of this observation, the ∼5-fold increase in kH
measured on going from PentH to PentOH clearly indicates
that with the latter substrate HAT predominantly occurs from
the CH that is α to the OH group. Along the same line, the
2
∼
50-fold increase in kH measured on going from PentH to
PentNH2 and APOH indicates that with the latter two
Most interestingly, comparison of this upper limit with the
5
k value measured in acetonitrile for PentH (k = 3.1 × 10
H
H
−
1
−1
substrates HAT almost exclusively occurs from the CH that
M
s ) shows that with PentNH , the strong deactivating
2
2
is α to the NH group, in full agreement with the results of
polar effect determined by protonation extends up to the δ-
2
4
−1 −1
previous studies on the reactions of alkylamines with alkoxyl
methylene group, for which k (CH ) < 10 M s .
H 2
4
0c−e,46
radicals.
For [PentNH ] > [TFA] a linear increase in k with
2 obs
As compared to acetonitrile, when the reactions of CumO•
with the same substrates have been studied in acetonitrile
increasing [PentNH ] has been observed (Figure 4, region 2:
2
7
red circles), leading to a rate constant value (k = 1.22 × 10
H2
−1
−1
containing 0.2 M TFA, no significant effect on k has been
M
s ) that is very similar to the value measured in
H
observed for PentH, and a slight decrease in kH has been
acetonitrile in the absence of TFA, indicating that in this
concentration range HAT occurs from the α-C−H bonds of the
nonprotonated amine (Scheme 8).
5
−1 −1
measured for PentOH (k = (1.08 ± 0.03) × 10 M s ,
H
Figure S19), quantified on the basis of the rate constant ratio
k /k (TFA) = 1.35. On the other hand, when the reaction of
With APOH, in order to obtain information on the effect of
TFA, the time-resolved kinetic study has been carried out by
successive dilutions of an acetonitrile solution containing
equimolar amounts of APOH and TFA (0.50 M).
H
H
•
CumO with PentNH has been studied in the presence of
2
TFA (0.1−1.0 M), no significant effect on reactivity has been
observed up to [PentNH ] = [TFA] (Figure 4, region 1: black
2
•
circles), indicating that in this concentration range, only an
The kobs vs [substrate] plot for reaction of CumO with
4
−1 −1
upper limit to k can be determined as k < 10 M s .
APOH in the presence of TFA is displayed in Figure S20, from
H
H1
9
275
DOI: 10.1021/acs.joc.6b01842
J. Org. Chem. 2016, 81, 9269−9278

The Journal of Organic Chemistry
Article
Scheme 9
which k = (5.6 ± 0.1) × 10 M s−1 has been obtained. This
5
−1
EXPERIMENTAL SECTION
H
■
value is 28 times lower than the value measured in acetonitrile
in the absence of TFA, but, on the other hand, is at least 56
times higher than the upper limit determined for HAT from
PentNH3 to CumO• (Scheme 8). In keeping with the
discussion outlined above, this behavior can be rationalized
on the basis of Scheme 9, where protonation of the APOH
amino group strongly deactivates the proximal and remote
methylene groups toward HAT to CumO .
However, differently than for PentNH , where C−H
deactivation has been shown to extend up to the δ-methylene
Materials. Spectroscopic grade acetonitrile was used in the kinetic
experiments. The following substrates were of the highest commercial
quality available and were used as received: cyclooctane (COT),
dibenzylether (DBE), tetrahydrofuran (THF), cyclohexanol
+
(
(
(
(
CHXOH), N,N-dimethylacetamide (DMA), cyclohexylamine
CHXNH ), triethylamine (TEA), 1,2,2,6,6-pentamethylpiperidine
2
PMP), pentane (PentH), 1-pentanol (PentOH), 1-aminopentane
PentNH ), and 5-amino-1-pentanol (APOH).
•
2
Commercial samples of cumyl alcohol (CumOH), diacetoxyiodo-
+
3
benzene (DIB), and I were used in the product studies. The reaction
2
products observed in these studies were commercially available and
were used as received (cyclooctylacetate (COTOAc), acetophenone
group, the measured k value indicates that the presence of an
OH group on the ε-carbon promotes selective HAT to CumO
H
•
(PhCOCH ), benzaldehyde (PhCHO), and benzyl alcohol
3
(
PhCH OH)).
2
from the C−H bonds that are adjacent to this functional group.
Dicumyl peroxide, trifluoroacetic acid (TFA), lithium perchlorate
The ∼3-fold decrease in k measured on going from PentOH
H
(
LiClO ), magnesium perchlorate (Mg(ClO ) ), and calcium
4
4 2
to protonated APOH points nevertheless toward a deactivating
perchlorate (Ca(ClO ) ) were of the highest commercial quality
4
2
+
polar effect of the remote NH3 group on HAT from the C−H
bonds that are α to the OH group.
available and were used as received. Previous studies have shown the
stability of dicumyl peroxide to TFA and to these perchlorate salts
under the experimental conditions employed.
3
3,34,37
Laser Flash Photolysis (LFP) Studies. LFP experiments were
carried out with a laser kinetic spectrometer using the third harmonic
(355 nm) of a Q-switched Nd:YAG laser, delivering 8 ns pulses. The
laser energy was adjusted to ≤10 mJ/pulse by the use of the
appropriate filter. A 3.5 mL Suprasil quartz cell (10 mm × 10 mm) was
used in all experiments. Argon saturated acetonitrile solutions
containing dicumyl peroxide (1.0 M) were employed. All the
experiments were carried out at T = 25 ± 0.5 °C under magnetic
stirring. The observed rate constants (kobs) were obtained by averaging
2−5 individual values and were reproducible to within 5%.
CONCLUSIONS
■
Taken together, the results obtained in this study have clearly
shown that in HAT reactions from the aliphatic C−H bonds of
substrates bearing different functionalities or from the C−H
bonds of substrates couples or triads characterized by different
basicities, careful control over the site (intramolecular) and
substrate (intermolecular) selectivity can be achieved through
Brønsted and Lewis acid−base interactions, providing useful
guidelines for the development of selective HAT-based C−H
functionalization procedures. When dealing with bifunctional
substrates, the results presented above indicate that site-
selectivity can be drastically changed through protonation of a
Second-order rate constant for the reactions of the cumyloxyl
radical with the different substrates were obtained from the slopes of
the kobs (measured following the decay of the cumyloxyl radical visible
absorption band at 490 nm) vs [substrate] plots. Transient kinetic
•
studies on the reactions of CumO with substrate couples and triads in
basic and strong activating NH functionality over an OH one,
2
the presence of [TFA] (between 0.10 and 1.00 M) or metal ion salts
with the latter group that directs HAT to the adjacent C−H
bonds. In the intermolecular selectivity studies, the results for
which are summarized in Table 2, the similar reactivity patterns
observed after addition of TFA and Mg(ClO ) , where
(
LiClO , Mg(ClO ) or Ca(ClO ) : between 0.01 and 0.60 M) were
4 4 2 4 2
carried out following different procedures: (a) addition of one
substrate (hydrocarbon, ether, or alcohol) to an acetonitrile solution
containing dicumyl peroxide, the Lewis or Brønsted acidic additive,
and an amine, amide, or an amine + amide substrate couple; (b)
sequential addition to an acetonitrile solution containing dicumyl
peroxide of a first substrate (hydrocarbon, ether or alcohol), a second
one (amine or amide), or a second and a third one (amine and amide),
the acidic additive, and a second amount of the first substrate; (c)
sequential addition to an acetonitrile solution containing dicumyl
peroxide and the acidic additive of a first substrate (hydrocarbon,
ether, or alcohol), a second one (amine or amide), or a second and a
third one (amine and amide), and a second amount of the first
substrate.
4
2
2
+
protonation or Mg binding strongly deactivates the C−H
•
bonds of amine substrates toward HAT to CumO , together
with the observation that LiClO promotes selective C−H
4
bond deactivation of amide substrates, indicate that these
additives can be employed in a orthogonal fashion for selective
functionalization of hydrocarbon, ether, alcohol, and amide (or
amine) substrates in the presence of an amine (or amide) one.
These selectivity patterns are complemented by Ca(ClO4)2
that, by promoting, contemporarily, strong C−H bond
deactivation for intrinsically activated amine and amide
substrates, offers the opportunity to selectively functionalize
alkane, ether, and alcohol substrates in the presence of the
former ones.
•
Product Studies. Product studies on the reactions of CumO with
COT and DBE were carried out following visible light irradiation (λirr
=
480 nm, irradiation time = 30−120 min) of argon saturated
dichloromethane solutions containing the substrate (0.2−1.0 M),
cumyl alcohol (CumOH, 0.10 M), DIB (0.22 M), and I (0.11 M).
43
2
9
276
DOI: 10.1021/acs.joc.6b01842
J. Org. Chem. 2016, 81, 9269−9278

The Journal of Organic Chemistry
Article
In a typical experiment, 5 mL of an argon saturated dichloromethane
A. I.; Barnard, J. H.; Marder, T. B.; Murphy, J. M.; Hartwig, J. F. Chem.
Rev. 2010, 110, 890−931.
solution containing the substrate, CumOH, DIB, and I , was
2
introduced into a pyrex glass vessel equipped with an external jacket
for water circulation. The reaction mixture was then irradiated with
visible light at T = 20 °C employing a photochemical reactor equipped
with 8 × 15 W lamps. At the end of the irradiation, the solution was
(6) (a) Liao, K.; Negretti, S.; Musaev, D. G.; Bacsa, J.; Davies, H. M.
L. Nature 2016, 533, 230−234. (b) Fu, L.; Guptill, D. M.; Davies, H.
M. L. J. Am. Chem. Soc. 2016, 138, 5761−5764.
(7) Cook, A. K.; Schimler, S. D.; Matzger, A. J.; Sanford, M. S. Science
2016, 351, 1421−1424.
added to 10 mL of H O and then extracted with dichloromethane (3
2
×
10 mL). The organic extracts were washed with a 10% sodium
(
́
8) Smith, K. T.; Berritt, S.; Gonzalez-Moreias, M.; Ahn, S.; Smith,
thiosulfate solution and dried over Na SO . All the preparation and
2
4
M. R., III; Baik, M.-H.; Mindiola, D. J. Science 2016, 351, 1424−1427.
workup procedures were carried out limiting exposure of the solution
to light. Reaction products were identified by GC and GC-MS by
comparison with authentic samples and quantified by GC employing
(9) (a) Zhang, F.-L.; Hong, K.; Li, T.-J.; Park, H.; Yu, J.-Q. Science
2
016, 351, 252−256. (b) Li, S.; Zhu, R.-Y.; Xiao, K.-J.; Yu, J.-Q. Angew.
Chem., Int. Ed. 2016, 55, 4317−4321. (c) Jiang, H.; He, J.; Liu, T.; Yu,
J.-Q. J. Am. Chem. Soc. 2016, 138, 2055−2059.
(
1,2-diphenylethane (bibenzyl) as internal standard. With both COT
and DBE, no product formation was observed in the absence of
irradiation by leaving the reaction mixtures in the dark for at least 1 h.
Reaction of CumO• with COT. When COT (5.0 mmol) and
CumOH (0.50 mmol) were irradiated for 30 min in the presence of
10) (a) Topczewski, J. J.; Cabrera, P. J.; Saper, N. I.; Sanford, M. S.
Nature 2016, 531, 220−224. (b) Neufeldt, S. R.; Sanford, M. S. Acc.
Chem. Res. 2012, 45, 936−946. (c) Lyons, T. W.; Sanford, M. S. Chem.
Rev. 2010, 110, 1147−1169.
DIB (1.10 mmol) and I (0.55 mmol), formation of COTOAc (0.09
2
(
11) (a) Huang, Z.; Wang, C.; Dong, G. Angew. Chem., Int. Ed. 2016,
5, 5299−5303. (b) Ozawa, J.; Tashiro, M.; Ni, J.; Oisaki, K.; Kanai,
M. Chem. Sci. 2016, 7, 1904−1909.
12) Lewis, J. C.; Coelho, P. S.; Arnold, F. H. Chem. Soc. Rev. 2011,
0, 2003−2021.
13) (a) Narayan, A. R. H.; Jimen
mmol) and PhCOCH (0.06 mmol) was observed. When the reaction
3
5
of COT (2.0 mmol) was carried out under identical conditions in the
presence of TFA (0.28 mmol) and PMP (0.27 mmol), formation of
(
4
COTOAc (0.05 mmol) and PhCOCH (0.12 mmol) was observed.
3
PMP was recovered quantitatively (0.27 mmol) from the irradiated
(
́ ́
ez-Oses, G.; Liu, P.; Negretti, S.;
reaction mixture.
Reaction of CumO• with DBE. When DBE (1.0 mmol) and
Zhao, W.; Gilbert, M. M.; Ramabhadran, R. O.; Yang, Y.-F.; Furan, L.
R.; Li, Z.; Podust, L. M.; Montgomery, J.; Houk, K. N.; Sherman, D.
H. Nat. Chem. 2015, 7, 653−660. (b) Negretti, S.; Narayan, A. R. H.;
Chiou, K. C.; Kells, P. M.; Stachowski, J. L.; Hansen, D. A.; Podust, L.
M.; Montgomery, J.; Sherman, D. H. J. Am. Chem. Soc. 2014, 136,
4901−4904.
CumOH (0.50 mmol) were irradiated for 30 min in the presence of
DIB (1.10 mmol) and I (0.55 mmol), formation of PhCHO (0.34
2
mmol), PhCH OH (0.08 mmol) and PhCOCH (0.14 mmol) was
2
3
observed. When the same reaction was carried out in the presence of
TFA (0.55 mmol) and PMP (0.50 mmol), formation of PhCHO (0.22
mmol), PhCH OH (0.06 mmol), and PhCOCH (0.15 mmol) was
(14) (a) Roiban, G.-D.; Reetz, M. T. Chem. Commun. 2015, 51,
2208−2224. (b) Roiban, G.-D.; Agudo, R.; Reetz, M. T. Angew. Chem.,
Int. Ed. 2014, 53, 8659−8663. (c) Kille, S.; Zilly, F. E.; Acevedo, J. P.;
Reetz, M. T. Nat. Chem. 2011, 3, 738−743.
(15) Rydzik, A. M.; Leung, I. K. H.; Kochan, G. T.; McDonough, M.
A.; Claridge, T. D. W.; Schofield, C. J. Angew. Chem., Int. Ed. 2014, 53,
2
3
observed. PMP was recovered quantitatively (0.49 mmol) from the
irradiated reaction mixture.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.6b01842.
■
*
S
1
0925−10927.
16) (a) Font, D.; Canta, M.; Milan, M.; Cusso,
Gebbink, R. J. M.; Costas, M. Angew. Chem., Int. Ed. 2016, 55, 5776−
5779. (b) Canta, M.; Font, D.; Gomez, L.; Ribas, X.; Costas, M. Adv.
(
́
O.; Ribas, X.; Klein
Plots of k vs substrate concentration for the reactions
obs
́
•
of CumO (PDF)
́
Synth. Catal. 2014, 356, 818−830. (c) Gomez, L.; Garcia-Bosch, I.;
Company, A.; Benet-Buchholz, J.; Polo, A.; Sala, X.; Ribas, X.; Costas,
M. Angew. Chem., Int. Ed. 2009, 48, 5720−5723.
AUTHOR INFORMATION
Corresponding Author
E-mail: bietti@uniroma2.it.
■
(17) (a) Liu, W.; Groves, J. T. Acc. Chem. Res. 2015, 48, 1727−1735.
(b) Huang, X.; Cheng, M.-J.; Nielsen, R. J.; Goddard, W. A., III;
*
Groves, J. T. J. Am. Chem. Soc. 2015, 137, 5300−5303. (c) Liu, W.;
Huang, X.; Cheng, M.-J.; Nielsen, R. J.; Goddard, W. A.; Groves, J. T.
Science 2012, 337, 1322−1325.
Notes
The authors declare no competing financial interest.
(
18) Ottenbacher, R. V.; Talsi, E. P.; Bryliakov, K. P. ACS Catal.
015, 5, 39−44.
19) (a) Gormisky, P. E.; White, M. C. J. Am. Chem. Soc. 2013, 135,
4052−14055. (b) Bigi, M. A.; Reed, S. A.; White, M. C. J. Am. Chem.
Soc. 2012, 134, 9721−9726. (c) Chen, M. S.; White, M. C. Science
007, 318, 783−787.
20) Das, S.; Incarvito, C. D.; Crabtree, R. H.; Brudvig, G. W. Science
2006, 312, 1941−1943.
2
(
1
ACKNOWLEDGMENTS
Financial support from the Ministero dell’Istruzione dell’Uni-
■
versita
̀
e della Ricerca (MIUR) project 2010PFLRJR (PRIN
2
010-2011) is gratefully acknowledged. We thank Prof. Miquel
2
(
Costas for helpful discussion and Prof. Lorenzo Stella for the
use of a LFP equipment.
(
21) Salamone, M.; Bietti, M. Acc. Chem. Res. 2015, 48, 2895−2903.
REFERENCES
(22) (a) Zou, L.; Paton, R. S.; Eschenmoser, A.; Newhouse, T. R.;
■
Baran, P. S.; Houk, K. N. J. Org. Chem. 2013, 78, 4037−4048.
(
1) (a) Hartwig, J. F.; Larsen, M. A. ACS Cent. Sci. 2016, 2, 281−292.
(b) Chen, K.; Eschenmoser, A.; Baran, P. S. Angew. Chem., Int. Ed.
(
b) Hartwig, J. F. J. Am. Chem. Soc. 2016, 138, 2−24.
2
009, 48, 9705−9708. (c) Chen, K.; Baran, P. S. Nature 2009, 459,
(
(
(
2) Davies, H. M. L.; Morton, D. J. Org. Chem. 2016, 81, 343−350.
3) White, M. C. Science 2012, 335, 807−809.
824−828.
4) (a) Bru
̈
ckl, T.; Baxter, R. D.; Ishihara, Y.; Baran, P. S. Acc. Chem.
(23) Moteki, S. A.; Usui, A.; Zhang, T.; Solorio Alvarado, C. R.;
Maruoka, K. Angew. Chem., Int. Ed. 2013, 52, 8657−8660.
(24) Newhouse, T.; Baran, P. S. Angew. Chem., Int. Ed. 2011, 50,
3362−3374.
Res. 2012, 45, 826−839. (b) Gutekunst, W. R.; Baran, P. S. Chem. Soc.
Rev. 2011, 40, 1976−1991.
(
2
5) (a) Larsen, M. A.; Cho, S. H.; Hartwig, J. F. J. Am. Chem. Soc.
016, 138, 762−765. (b) Larsen, M. A.; Wilson, C. V.; Hartwig, J. F. J.
(25) (a) Shaw, M. H.; Shurtleff, V. W.; Terrett, J. A.; Cuthbertson, J.
D.; MacMillan, D. W. C. Science 2016, 352, 1304−1308. (b) Jeffrey, J.
L.; Terrett, J. A.; MacMillan, D. W. C. Science 2015, 349, 1532−1536.
Am. Chem. Soc. 2015, 137, 8633−8643. (c) Li, Q.; Liskey, C. W.;
Hartwig, J. F. J. Am. Chem. Soc. 2014, 136, 8755−8765. (d) Mkhalid, I.
9
277
DOI: 10.1021/acs.joc.6b01842
J. Org. Chem. 2016, 81, 9269−9278

The Journal of Organic Chemistry
Article
(
26) (a) Quinn, R. K.; Ko
̈
nst, Z. A.; Michalak, S. E.; Schmidt, Y.;
the former bonds as compared to the C−H bonds that are α to the
OH and NH groups and of the significantly lower k values measured
previously for HAT from the OH group of alcohols and the NH2
group of alkylamines to tertiary alkoxyl radicals (refs 40d, 40e, and 47).
(47) Griller, D.; Ingold, K. U. J. Am. Chem. Soc. 1974, 96, 630−632.
Szklarski, A. R.; Flores, A. R.; Nam, S.; Horne, D. A.; Vanderwal, C. D.;
Alexanian, E. J. J. Am. Chem. Soc. 2016, 138, 696−702. (b) Schmidt, V.
A.; Quinn, R. K.; Brusoe, A. T.; Alexanian, E. J. J. Am. Chem. Soc. 2014,
2
H
1
(
36, 14389−14392.
27) Sharma, A.; Hartwig, J. F. Nature 2015, 517, 600−604.
(
(
28) Roberts, B. P. Chem. Soc. Rev. 1999, 28, 25−35.
29) Howell, J. M.; Feng, K.; Clark, J. R.; Trzepkowski, L. J.; White,
M. C. J. Am. Chem. Soc. 2015, 137, 14590−14593.
30) Adams, A. M.; Du Bois, J.; Malik, H. A. Org. Lett. 2015, 17,
066−6069.
31) Asensio, G.; Gonzal
R.; Adam, W. J. Am. Chem. Soc. 1993, 115, 7250−7253.
32) An analogous selectivity has been also observed in the Fe-
(
6
(
́
́
̃
ez-Nunez, M. E.; Bernardini, C. B.; Mello,
(
catalyzed oxyfunctionalization and Pt-catalyzed oxidation of aliphatic
amines following substrate protonation, see: (a) Mbofana, C. T.;
Chong, E.; Lawniczak, J.; Sanford, M. S. Org. Lett. 2016, 18, 4258−
4
1
261. (b) Lee, M.; Sanford, M. S. J. Am. Chem. Soc. 2015, 137, 12796−
2799.
(
33) Salamone, M.; Mangiacapra, L.; DiLabio, G. A.; Bietti, M. J. Am.
Chem. Soc. 2013, 135, 415−423.
34) (a) Milan, M.; Salamone, M.; Bietti, M. J. Org. Chem. 2014, 79,
(
5
2
(
(
710−5716. (b) Salamone, M.; Giammarioli, I.; Bietti, M. Chem. Sci.
013, 4, 3255−3262.
35) Nova, A.; Balcells, D. Chem. Commun. 2014, 50, 614−616.
•
36) Transient kinetic studies have shown that in HAT to CumO ,
the addition of Ca(ClO ) leads to strong C−H bond deactivation for
4
2
tertiary amine substrates such as triethylamine (TEA) and 1,2,2,6,6-
2+
pentamethylpiperidine (PMP) up to [Ca ] ≤ [substrate]. See, for
example, Figure S21 showing the effect of Ca(ClO ) on the reaction
4
2
•
of CumO with PMP.
37) (a) Salamone, M.; Carboni, G.; Mangiacapra, L.; Bietti, M. J.
(
Org. Chem. 2015, 80, 9214−9223. (b) Salamone, M.; Mangiacapra, L.;
Carboni, G.; Bietti, M. Tetrahedron ASAP. DOI: 10.1016/
j.tet.2016.05.047.
(
38) For a critical discussion and a quantitative evaluation of the role
of polar effects on the kinetics and thermodynamics of HAT from
aliphatic C−H bonds, see: (a) Chan, B.; Easton, C. J.; Radom, L. J.
Phys. Chem. A 2015, 119, 3843−3847. (b) Amos, R. I. J.; Chan, B.;
Easton, C. J.; Radom, L. J. Phys. Chem. B 2015, 119, 783−788.
(
c) O’Reilly, R. J.; Chan, B.; Taylor, M. S.; Ivanic, S.; Bacskay, G. B.;
Easton, C. J.; Radom, L. J. Am. Chem. Soc. 2011, 133, 16553−16559.
39) (a) Baciocchi, E.; Bietti, M.; Salamone, M.; Steenken, S. J. Org.
(
Chem. 2002, 67, 2266−2270. (b) Avila, D. V.; Ingold, K. U.; Di Nardo,
A. A.; Zerbetto, F.; Zgierski, M. Z.; Lusztyk, J. J. Am. Chem. Soc. 1995,
1
(
1
1
17, 2711−2718.
40) (a) Malatesta, V.; Scaiano, J. C. J. Org. Chem. 1982, 47, 1455−
459. (b) Paul, H.; Small, R. D., Jr.; Scaiano, J. C. J. Am. Chem. Soc.
978, 100, 4520−4527. (c) Finn, M.; Friedline, R.; Suleman, N. K.;
Wohl, C. J.; Tanko, J. M. J. Am. Chem. Soc. 2004, 126, 7578−7584.
(
d) Salamone, M.; DiLabio, G. A.; Bietti, M. J. Am. Chem. Soc. 2011,
1
2
(
33, 16625−16634. (e) Pischel, U.; Nau, W. M. J. Am. Chem. Soc.
001, 123, 9727−9737.
41) Salamone, M.; Milan, M.; DiLabio, G. A.; Bietti, M. J. Org.
Chem. 2013, 78, 5909−5917.
42) Bietti, M.; Martella, R.; Salamone, M. Org. Lett. 2011, 13, 6110−
113.
43) Suar
Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim, 2001; Vol. 2, pp
40−454.
44) The time course of the decay of absorbance at 490 nm for the
(
6
(
́
ez, E.; Rodriguez, M. S. In Radicals in Organic Synthesis;
4
(
•
reaction of CumO with COT in MeCN and in MeCN containing
0
.01 M PMP, 0.2 M DMA, and 0.2 M Ca(ClO ) is displayed in Figure
4 2
S2.
(
45) (a) Weber, M.; Fischer, H. J. Am. Chem. Soc. 1999, 121, 7381−
388. (b) Salamone, M.; Basili, F.; Mele, R.; Cianfanelli, M.; Bietti, M.
Org. Lett. 2014, 16, 6444−6447.
46) HAT from the O−H and N−H bonds of PentOH, PentNH ,
7
(
2
and APOH can be ruled on the basis of the significantly higher BDE of
9
278
DOI: 10.1021/acs.joc.6b01842
J. Org. Chem. 2016, 81, 9269−9278