Hydrogen atom abstraction from C-H bonds of benzylamides by the aminoxyl radical BTNO: A kinetic study

Article abstract of DOI:10.1039/b815584d

The aminoxyl radical BTNO (benzotriazole-N-oxyl; >N-O) is generated from HBT (1-hydroxybenzotriazole; >N-OH) by oxidation with a Ce^IV salt. BTNO presents a broad absorption band with λ_max 474 nm that lends itself to investigate the kinetics of H-abstraction from H-donor substrates by spectrophotometry. Thus, rate constants (k_H) of H-abstraction by BTNO from CH₂-groups α to the nitrogen atom in X-substituted-(N-acetyl)benzylamines (X-C₆H₄CH ₂NHCOCH₃) have been determined in MeCN solution at 25 °C. Correlation of the k_H^X data with the Hammett σ⁺ parameters gives a small value for ρ (-0.65) that is compatible with a radical H-abstraction step. The sizeable value (k _H/k_D = 8.8) of the kinetic isotope effect from a suitably deuteriated amide substrate further confirms H-abstraction as rate-determining. Evidence is acquired for the relevance of stereoelectronic effects that speed up the H-abstraction whenever the scissile C-H bond is co-linear with either the nitrogen lone-pair of the amide moiety or an adjacent aromatic group. An assessment of the dissociation energy value of the benzylic C-H bond in ArCH₂NHCOMe is accordingly reported.

Full text of DOI:10.1039/b815584d

View Article Online / Journal Homepage / Table of Contents for this issue
PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Hydrogen atom abstraction from C–H bonds of benzylamides by the
aminoxyl radical BTNO: A kinetic study
Alessandra Coniglio, Carlo Galli,* Patrizia Gentili* and Raffaella Vadala`
Received 9th September 2008, Accepted 13th October 2008
First published as an Advance Article on the web 7th November 2008
DOI: 10.1039/b815584d
The aminoxyl radical BTNO (benzotriazole-N-oxyl; >N–O∑) is generated from HBT
(1-hydroxybenzotriazole; >N–OH) by oxidation with a CeIV salt. BTNO presents a broad absorption
band with lmax 474 nm that lends itself to investigate the kinetics of H-abstraction from H-donor
substrates by spectrophotometry. Thus, rate constants (kH) of H-abstraction by BTNO from
CH2-groups a to the nitrogen atom in X-substituted-(N-acetyl)benzylamines (X-C6H4CH2NHCOCH3)
have been determined in MeCN solution at 25 ◦C. Correlation of the kH data with the Hammett s
X
+
parameters gives a small value for r (-0.65) that is compatible with a radical H-abstraction step. The
sizeable value (kH/kD = 8.8) of the kinetic isotope effect from a suitably deuteriated amide substrate
further confirms H-abstraction as rate-determining. Evidence is acquired for the relevance of
stereoelectronic effects that speed up the H-abstraction whenever the scissile C–H bond is co-linear
with either the nitrogen lone-pair of the amide moiety or an adjacent aromatic group. An assessment of
the dissociation energy value of the benzylic C–H bond in ArCH2NHCOMe is accordingly reported.
alternatively been generated electrochemically.7 Kinetic studies of
Introduction
the H-abstraction reaction from substrates having C–H or O–
H bonds of appropriate energy have provided information upon
the reactivity of PINO towards alkylarenes or phenols.6a,8 The
synthetic value of the oxidation reactions induced by PINO has
stimulated us to assess the reactivity features of this, as well of
other aminoxyl radicals more closely.
The aminoxyl radicals (R2NO∑) are valuable and versatile reactive
intermediates in numerous applications.1 In particular, the syn-
thetic importance of aminoxyl radicals is highlighted by their use
as catalysts in oxidation reactions endowed with low environmen-
tal impact.1–4 Among these radicals PINO (phthalimide N-oxyl),
derived from HPI (N-hydroxyphthalimide), offers a prominent
case.5 PINO removes a hydrogen atom from a substrate (by
hydrogen atom transfer, HAT), enabling subsequent interaction
with O2 and therefore an oxidation outcome (Scheme 1).
We have recently reported on the H-abstraction reactivity of
another aminoxyl radical, that is, BTNO (benzotriazole N-oxyl).9
This radical has been generated from oxidation of HBT (1-
hydroxybenzotriazole) with a CeIV salt (Scheme 3) and charac-
terized by UV-Vis and EPR spectra, laser flash photolysis and
cyclic voltammetry.9a Rate constants of H-abstraction (kH) from
C–H bonds of H-donor substrates, including benzyl alcohols and
alkylarenes, have been determined spectroscopically and found
to be in the 10-3 to 102 M-1 s-1 range at 25 ◦C in MeCN
solution.9b With selected substrates, activation parameters for
the H-abstraction step have been measured, and the activation
energy successfully correlated to the dissociation energy of the
C–H bond undergoing cleavage.9b Whenever comparing BTNO vs
PINO, the radical reactivity of PINO has always been found higher
than that of BTNO towards similar substrates. The explanation
provided is that PINO gives rise to a stronger NO–H bond (in
HPI) upon H-abstraction from a substrate, as compared to the
weaker NO–H bond in HBT (88 vs. ca. 85 kcal/mol, respectively),
this representing a crucial factor for a radical process where bond
cleavage and formation dominate the reactivity.1,9b
Scheme 1 Oxidation of an H-donor substrate (Sub-H) by radical PINO
in the presence of dioxygen.
In principle, aminoxyl radicals can be obtained from the parent
hydroxylamines by either H-abstraction or electron-abstraction
followed by deprotonation (Scheme 2).1
Scheme 2 Possible pathways of generation of aminoxyl radicals.
For example, PINO is generated from HPI by the action of O2
and Co(OAc)2,4,5 or else by oxidation with Pb(OAc)4;6 PINO has
Dipartimento di Chimica, Universita` ‘La Sapienza’, and IMC-CNR Sezione
Meccanismi di Reazione, P.le A. Moro 5, 00185, Roma, Italy. E-mail:
carlo.galli@uniroma1.it; Fax: +39 06 490421
Scheme 3 Kinetic study of the H-abstraction from the C–H bond a to
an amide-nitrogen by BTNO.
This journal is
The Royal Society of Chemistry 2009
Org. Biomol. Chem., 2009, 7, 155–160 | 155
©

View Article Online
The present paper deepens our understanding of the reactivity
of aminoxyl radicals in the H-abstraction reaction, a topic recently
reviewed.1 It also extends this knowledge to the oxidation of
amides, a class of substrates never explored kinetically so far. In
fact, we report on a kinetic study of the H-abstraction by BTNO
from the C–H bond a to the nitrogen atom of amides (Scheme 3), a
reaction investigated for synthetic purposes by the use of PINO.10
During our kinetic study, evidence for the important contribu-
tion from stereoelectronic effects upon the H-abstraction reactivity
has appeared. More specifically, the co-linearity between the a-C–
H bond undergoing cleavage and the nitrogen lone-pair of the
amide comes out as a key structural requirement.11 Likewise,
for substrates similarly bearing a lone-pair, such as alcohols or
ethers or amines, the H-abstraction by t-BuO. (or other radicals
as well) had been described to be more rapid than H-abstraction
from simple hydrocarbons as a result of the specific contribution
from stereoelectronic effects.11,12 We report here on our attempt
to give quantitative support to these issues. Activation parameters
for H-abstraction from the a-C–H bond in two amide substrates
have been determined, and enable to assess the contribution from
stereoelectronic effects in decreasing the energy value of the scissile
C–H bond.
the reactivity of BTNO in the H-abstraction from the CH2-
group in a to nitrogen is investigated here for a series of amides
(ArCH2NHCOMe, cf. Schemes 3 and 4). Previous synthetic
investigations had shown that the radical oxidation performed by
either PINO or BTNO in the presence of O2 gives rise to carbonyl
end-products (imide + aldehyde) from a common a-amido carbon
radical intermediate originating from cleavage of the a-C–H bond
of the amide substrate (Scheme 4).10,15
Scheme 4 Pathways of products formation in the HAT route of oxidation
of amides by an aminoxyl radical.
For kinetic purposes, the solution of the C-H bearing substrate
is employed here at initial concentrations higher than the concen-
tration of BTNO, in order to fulfil the pseudo first-order kinetic
conditions, and the drop of absorbance at 474 nm is followed. The
pseudo-first-order rate constants k¢, determined at 25 ◦C at three-
to-four initial concentrations of amide from at least duplicated
experiments, are converted into second-order H-abstraction rate
constants (kH) by determining the slope of a k¢ vs. [SubH]◦ plot,
as shown in Fig. 2 for the case of 4-chloro-N-benzylacetamide.
Typical uncertainty of the kinetic data ranges from 3 to 6%.
Results and discussion
H-abstraction reactivity
Addition of a stoichiometric amount of the monoelectronic
oxidant cerium(IV) ammonium nitrate (NH4)2Ce(NO3)6 (i.e.,
CAN; E◦ 1.3 V vs the normal hydrogen electrode, NHE)13 to
HBT (E◦ 1.08 V vs NHE)14 in MeCN solution at 25 ◦C, both
compounds being at 0.5 mM initial concentration, gives rise to a
broad absorption band in the 350–600 nm range (Fig. 1)9 having
lmax at 474 nm and e 1840 M-1 cm-1.
Fig. 1 UV-Vis spectrum of a 0.5 mM solution of HBT in MeCN: (●)
before the addition of CAN; after the addition of CAN (0.5 mM): (᭢)
15 ms after the addition, (ꢀ) 110 s after the addition.
Fig. 2 Determination of the second order rate constant kH for reaction of
BTNO with 4-chloro-N-benzylacetamide in MeCN at 25 ◦C, from the plot
of the pseudo-first-order rate constants k¢ at various initial concentration
of the substrate.
The band pertains to the formation of the BTNO species:
electron transfer from HBT to CAN is in fact exoergonic and
occurs quantitatively (cf. Scheme 3).9 The spectrum of BTNO
is not stable but decays according to an almost first-order
exponential curve (kdecay = 5.1 ¥ 10-3 s-1 in MeCN at 25 ◦C),
with a half life of 140 s at 0.5 mM.9b The spontaneous decay of
BTNO is strongly accelerated in the presence of purposely added
H-donor substrates. By following the progress of the reaction at
474 nm through stopped-flow or conventional spectrophotometry,
The k¢ constants are faster than the spontaneous decay of
BTNO in all cases investigated, as the linearity of the plot and the
minor y-intercept in Fig. 2 demonstrates, and exhibit first-order
dependence on the excess substrate concentration. The second-
order rate constants (kH) are given in Table 1 for the substrates of
this study, which includes the a,a-bisdeuterio-N-benzylacetamide
purposely synthesized (vide infra).
156 | Org. Biomol. Chem., 2009, 7, 155–160
This journal is
The Royal Society of Chemistry 2009
©

View Article Online
Table 1 Summary of the rate constants kH (M-1 s-1) obtained spectropho-
tometrically at 25 ◦C in MeCN solution from reaction of BTNO with amide
substratesa
make the H-abstraction faster whereas electron-withdrawing ones
slow it down.17 This is tantamount to saying that the C–H bond
undergoing cleavage in the two series of substrates is made weaker
or stronger by the X-substituents, causing a faster or slower H-
abstraction, respectively. Earlier and strictly related studies of the
reactivity of the radical PINO with benzylic substrates such as 4-
X-C6H4CH2OH had provided r values of -0.68 in MeCN and of
Substrate
kH (M-1 s-1)
PhCH2NHCOMe
PhCD2NHCOMe
0.49
0.056
2.54
1.17
0.43
0.26
0.33
0.11
4-MeO-C6H4CH2NHCOMe
4-Me-C6H4CH2NHCOMe
4-Cl-C6H4CH2NHCOMe
4-CF3-C6H4CH2NHCOMe
4-NO2-C6H4CH2NHCOMe
PhCH(Me)NHCOMe
+
-0.41 in AcOH, once again giving better correlation with s .1,6a,8b
The consistency of these r values stresses the uniform pattern
of selectivity of the electrophilic >N–O∑ species (either PINO or
BTNO) in the HAT reaction. Finally, the relative reactivity from
competitive oxidations for a series of X-N-benzylacetamides in
3
reaction with alkylperoxy-l -iodane, i.e., a radical HAT agent,
had been reported in the literature,18 and a r value (i.e., -0.56)
very close to our finding given. This supports the same extent
of stabilization/destabilization offered by X-substituents to an
incipient benzyl radical a to nitrogen in the rate-determining
H-abstraction step.
N-Acetyl-tetrahydroisoquinoline
26
a Initial conditions: [BTNO] 0.5 mM, [SubH] 5–40 mM. Determinations
in triplicate; typical errors 3–6%.
Hammett correlation
Kinetic isotope effect
The effect of the substituents upon reactivity is reckoned by cor-
relating the kH data for reaction of the 4-X-N-benzylacetamides
The ratio of the rate constants for reaction of BTNO with
PhCH2NHCOMe and PhCD2NHCOMe (in Table 1) gives
kH/kD = 8.8. This sizeable value is consistent with a rate-
determining H-abstraction step, and supports the contribution
from tunnelling already commented on for reaction of either
PINO or BTNO with various H-donors (kH/kD values in the 11–27
range).6a,8b,9
Both the r and kH/kD data (-0.65 and 8.8) obtained here with
the CAN/HBT oxidizing system compare favourably with the
corresponding ones (i.e., -0.64 and 6.4, respectively) obtained
in the oxidation of X-substituted benzyl alcohols by the copper
enzyme laccase as the oxidant in the presence of HBT.19 The close
agreement provides clear-cut support to the involvement of the
very >N–O∑ radical BTNO as the reactive intermediate in that
kind of chemo-enzymatic oxidation, in keeping with the necessary
monoelectronic oxidation of mediator HBT by laccase as outlined
in Scheme 5.14
X
with BTNO (in Table 1) vs the s constants of the X-substituents
according to the Hammett equation (log kX/kH = rs). A slightly
+
better linearity is obtained in the plot (Fig. 3) when using the s
parameters, which take into account the resonance contribution
from electron-donor substituents more effectively.16 The correla-
tion parameter r, obtained from the slope of the plot, is -0.65.
This is a small value, as expected for a radical process, and its
+
negative sign besides the better fit to the s parameters confirms
the polar character of the aminoxyl radical.8b,9,10 The present r
value compares very well with the one previously determined
+
(i.e., -0.55 vs s ) for reaction of BTNO with another series of
benzylic substrates, that is, the 4-X-substituted benzyl alcohols (4-
X-C6H4CH2OH).9a A common selectivity trend for H-abstraction
by BTNO from benzylic C–H bonds in the two series of substrates
emerges.1 This is likely to be due to the analogous stabilization
offered by the X-substituents of the aromatic ring to an incipient
benzylic radical in the transition state: electron-donor groups
Scheme 5 The aerobic chemo-enzymatic oxidation of an H-donor
substrate (Sub-H) by laccase with a >NO-H mediator.
Therefore, the present kinetic study corroborates our trust in
the mechanism of the chemo-enzymatic oxidation by laccase and
mediator compounds having the >NO-H functionality.14
Evaluation of the BDE(C-H) for the benzylic CH2-group in
ArCH2NHCOMe
In the radical HAT route investigated here, the dissociation energy
of the C–H bond undergoing cleavage, i.e. BDE(C-H), embodies
a crucial reactivity feature.1 Accordingly, the weaker the C–H
bond the faster is expected the HAT route, either with BTNO
or other radical species. We had corroborated this expectation
by correlating the energies of activation of the BTNO-induced
HAT route with an homologous series of benzylic substrates
Fig. 3 Hammett plot for the reaction of 4-X-substituted N-benzyl-
acetamides with BTNO in MeCN at 25 ◦C.
This journal is
The Royal Society of Chemistry 2009
Org. Biomol. Chem., 2009, 7, 155–160 | 157
©

View Article Online
(alkylarenes and benzyl alcohols) vs the corresponding BDE(C-H)
data according to the Evans-Polanyi equation (Ea = a BDE(C-
H) + const).9b Unfortunately, not always are thermochemical data
available in order to attempt a similar correlation and the ensuing
rationalization of the reactivity trend. This in part is the case of
the present study because BDE(C-H) data for amide substrates
are scarce.20
What energy value could the benzylic C–H bond of
PhCH2NHCOMe have? The kH rate constant determined here
(Table 1) for reaction of BTNO with PhCH2NHCOMe is
0.49 M-1 s-1; the kH determined under the same conditions
for reaction of BTNO with PhCH2OH is very close in value
(i.e., 0.94 M-1 s-1).9b Because we extrapolated a BDE(C-H) of
79 kcal/mol for PhCH2OH,9b the corresponding BDE(C-H) of
PhCH2NHCOMe ought to be pretty close in value. Strangely
enough, the reactivity of BTNO with the benzylic C–H bond of
the amine PhCH2NEt2, despite a reported BDE(C-H) of 89 kcal/
mol,20 was too fast to measure (> 100 M-1 s-1) with our kinetic
device.9b The BDE(C-H) of the latter compound is 10 kcal/mol
larger than the extrapolated BDE(C–H) of PhCH2OH, the kH
of which was slow enough to measure.9b Either our extrapolated
BDE(C-H) of PhCH2OH is too low, or the literature value of
BDE(C-H) for PhCH2NEt2 is too high!
Fig. 4 Evans-Polanyi plot for reaction of BTNO with benzylic substrates
(from ref. 9b), and extrapolation of the BDE(C-H) of PhCH2NHCOMe
from the Ea value obtained (see text).
solvent when comparing kinetic data vs. BDE data. Hydrogen
bonding between our solvent (MeCN) and substrates such as
PhCH2NHCOMe or PhCH2OH can certainly affect the rate
constants. However, the Evans-Polanyi plot of Fig. 4 shows good
linearity for five substrates encompassing alkylarenes and benzylic
alcohols, regardless their apolar or polar nature. Therefore, the
hydrogen bonding issue provides only a partial explanation for
the discrepancy between rate constants and BDE values stressed
above. Secondly, we can not exclude that the high rate constant
obtained9b for reaction of BTNO with PhCH2NEt2 is rather due
to the incursion of a mechanism different from the HAT one.
For example, the abstraction of electron (ET) by BTNO from
the electron-rich PhCH2NEt2 could be alternatively envisioned.
A similar ET route is documented for reaction of the aminoxyl
radical PINO (0.92 V/NHE for the PINO/PINO- redox couple)
with 4-X-substituted-N,N-dimethylanilines (redox potentials in
the 0.5–1.1 V/NHE range), as reported recently.1,21 Benzyl amines
are however more difficult to remove an electron from (redox
potentials > 1 V/NHE)22 than anilines, and an ET route between
BTNO and PhCH2NEt2 could be thought as less favoured. For
sure, an ET route between BTNO and the present series of amides
can be disregarded in view of redox potential considerations, as
the one-electron oxidation of PhNHCOCH3 has a redox potential
>1.8 V/NHE.23 Anyhow, we take the ET point as a sound
suggestion, and work has already been planned in order to better
investigate the boundaries of the ET/HAT dichotomy for reaction
of aminoxyl radicals with benzylamines.
In the attempt to settle this point, we have determined the acti-
vation parameters for reaction of BTNO with PhCH2NHCOMe.
The rate constants, measured in the temperature range of 12.5 to
49.8 ◦C according to the experimental procedure described above,
are given in Table 2. From use of the Arrhenius equation (lnkH =
lnA - Ea/RT),16 an Ea of 4.1 0.2 kcal/mol is obtained. An
analogous determination yields an Ea value of 3.1 0.3 kcal/mol
for reaction of BTNO with 4-MeO-C6H4CH2NHCOMe (Table 2).
By entering the newly acquired Ea value (i.e., 4.1 kcal/mol)
of PhCH2NHCOMe in the Evans-Polanyi plot already obtained
for reaction of BTNO with a few benzylic substrates (Fig. 4),9b
a
BDE(C-H) of 71 kcal/mol can be extrapolated; analogously, for
4-MeO-C6H4CH2NHCOMe (Ea of 3.1 kcal/mol) a BDE(C–H)
of 68 kcal/mol is extrapolated. On averaging these two numbers,
one gets 70 ( 2) kcal/mol for the dissociation energy of these
particular C–H bonds: this certainly represents a small BDE value,
particularly when compared to the archetypal benzylic BDE(C-H)
of 88.5 kcal/mol of toluene.20 Such a conspicuous drop of C–H
bond energy on going from PhCH3 to ArCH2NHCOMe, whatever
the precision of our determinations is, is likely to be ascribed to
the operation of stereoelectronic effects upon the amide substrate,
as we comment on in the next section.
Actually, the issue could be even more complex than this, as a
referee has correctly pointed out. First, we neglet the effect of the
Table 2 Rate constants of H-abstraction for reaction of BTNO with two
amides at various temperatures in MeCN solution. Typical errors are in
the 3–5% range
Stereoelectronic effects
Griller et al.11 have convincingly demonstrated that hyperconju-
gation from the lone-pair of a heteroatom weakens an adjacent
C–H bond, and stabilizes an intervening C-radical generated by
H-abstraction. The contribution from this weakening effect on the
energy of an adjacent C–H bond is the greater the more co-linear
are the C–H bond and the lone-pair,11 as shown in Fig. 5 for the
case of an amine.
PhCH2NHCOMe
4-MeO-C6H4-CH2NHCOMe
kH (M-1 s-1)
T (◦C)
kH (M-1 s-1)
T (◦C)
0.364
0.393
0.490
0.680
0.832
12.5
18.1
25.0
41.3
49.8
0.72
—
0.80
1.13
—
12.7
—
25.5
38.5
—
This interaction reportedly accounts for a 7–9 kcal/mol weak-
ening of the C–H bond.12 For torsion angles (q) wider than
158 | Org. Biomol. Chem., 2009, 7, 155–160
This journal is
The Royal Society of Chemistry 2009
©

View Article Online
cleavage of its secondary C–H bond, and accounts for an overall
depression of the H-abstraction rate by ca. 9 fold (i.e., 4.2/0.46).
A plausible explanation for this unfavourable effect would be that
PhCH(Me)NHCOMe is conformationally more stable (Fig. 7,
left structure) whenever the larger groups in a, either Me- or–
NHCOMe, are co-linear with the aromatic p-orbitals in order to
lessen clash with the aromatic ortho C–H bonds.
Fig. 5 Stereoelectronic interaction between the lone-pair of an amine
and a C–H bond. Reprinted with permission from Griller et al. (ref. 11).
Copyright (1981) American Chemical Society.
30◦, the effect drastically fades away.11 Our above finding of a
substantial reduction of BDE(C-H) when passing from PhCH3
(88.5 kcal/mol) to PhCH2NHCOMe (71 kcal/mol) is likely due
to the stereoelectronic interaction from the nitrogen lone-pair of
the amide with the scissile C–H bond.
Fig. 7 Limiting conformations of PhCH(Me)NHCOMe and PhCH2-
NHCOMe. The section of the aromatic ring is represented as a rectangle.
Consequently, the benzylic C–H bond is preferentially directed
in the ring plane, where any incipient a-amido carbon radical
resulting from H-abstraction would not experience p-stabilisation.
This is going to slow down the oxidation with respect to
PhCH2NHCOMe (Fig. 7, right structure), where co-linearity of
one a-C–H bond with respect to the plane of the aromatic ring is
always feasible.
In order to support this conformational issue, the hydrogen
abstraction rate constants by BTNO from a series of benzyl
alcohols have been determined in MeCN at 25 ◦C, and are reported
in Scheme 6.
Additional data obtained from specific substrates enable us to
further address the stereoelectronic issue. In a previous synthetic
investigation,15 the oxidation of N-acetyl-tetrahydroisoquinoline
by BTNO gave evidence for exclusive functionalization at C1, i.e.,
at the C–H bonds a to nitrogen, to produce an imide compound (cf.
Scheme 4 and Fig. 6. Our present kinetic data (Table 1) point out
that H-abstraction from N-acetyl-tetrahydroisoquinoline is indeed
much faster (ca. 20–40 fold) than from the structurally comparable
but acyclic C6H5CH2NHCOMe or 4-Me-C6H4CH2NHCOMe.
Simple modelling with Hyperchem shows that in N-acetyl-
tetrahydroisoquinoline the benzylic C–H bond of C1 is almost
co-linear with both the p-orbitals of the aromatic ring and with
the nitrogen lone pair (Fig. 6), being kept in this profitable
conformation by steric restrictions caused by the heterocyclic
system. This double beneficial effect is likely to weaken that C–
H bond, as well as to stabilize the intermediate benzyl radical at
C1 (Fig. 6). In the acyclic counterparts, instead, free rotation of the
chain partially disrupts a similarly profitable conformation of the
corresponding C–H bond, and lessens the extent of stabilisation
of the intermediate radical ArCH(∑)NHCOMe.
Scheme
6 Absolute (normalised) and relative rate constants of
H-abstraction by BTNO.
Once again, whereas abstraction of a secondary H-atom is
1.9 fold faster than that of a primary one, in keeping with the
corresponding BDE values,20 co-linearity of the t-Bu-group with
the aromatic p-orbitals in the tertiary alcohol is preferred because
lessens steric hindrance (cf. Fig. 7, left structure), thereby pushing
the scissile C–H bond in the ring-plane where no p-stabilization
is experienced, and resulting in a depression of reactivity
(krel = 0.74).
Fig. 6 Stabilising interaction from both the p-system and the nitrogen
lone-pair to the C1 radical resulting from H-abstraction in N-acetyl-
tetrahydroisoquinoline by BTNO.
Conclusions
The reciprocal orientation between a C–H bond undergoing
cleavage and the lone pair of an adjacent heteroatom, or else
an adjacent aromatic ring, emerges as an important structural
feature upon the reactivity of an homolytic C–H cleavage, and is
responsible for substantial weakening of the C–H bond energy.
We have attempted to highlight these structural features upon the
HAT reactivity of the aminoxyl radical BTNO with a few examples
of amide substrates.
As another example, the kH rate constants of PhCH(Me)-
NHCOMe and PhCH2NHCOMe with BTNO (Table 1), when
normalized for the number of equivalent H-atoms, are 0.11 and
0.24 M-1 s-1 respectively (or 0.46:1 in relative terms), thereby indi-
cating an unfavourable contribution from the a-Me-substitution
upon reactivity. In principle, H-abstraction from the secondary
benzylic C–H bond of PhCH(Me)NHCOMe ought to be easier
and faster than for the primary C–H bond of PhCH2NHCOMe.
This is consistent with the relative reactivity of H-abstraction
from ArCH2CH3 and ArCH3 (normalised for the number of
equivalent H-atoms)9b by BTNO, that is 4.2:1 (see also below),
as well as with the BDE trend of a secondary vs primary
benzylic C–H bond.20 The specific unfavourable effect from a-Me
substitution in PhCH(Me)NHCOMe offsets the expected easier
Experimental
Reagents
HBT (Aldrich) was used as received; most of the substrates were
obtained commercially and used without further purification. A
This journal is
The Royal Society of Chemistry 2009
Org. Biomol. Chem., 2009, 7, 155–160 | 159
©

View Article Online
few starting amides were synthesized from the parent amines by
conventional acetylation with Ac2O in pyridine,24 and charac-
terised by NMR and GC-MS.15 Cerium(IV) ammonium nitrate
(CAN; Erba RPE) was oven-dried before use. Reagent grade
acetonitrile (Erba RPE) was used as the solvent. N-Acetyl-a,a-
bisdeuteriated benzylamine was obtained from LiAlD4 reduction
of PhCONH2 to PhCD2NH2 in a 1:2 THF:diethyl ether mixed
solvent, followed by acetylation.24 The purity was checked by
GC-MS.
References
1 C. Galli, P. Gentili and O. Lanzalunga, Angew. Chem. Int. Ed., 2008,
47, 4790–4796.
2 I. W. C. E. Arends, and R. A. Sheldon, Modern Oxidations of Alcohols
using Environmentally Benign Oxidants, Chapter 4, p. 83 in Mod-
ern Oxidation Methods, J.-E. Ba¨ckvall, Ed., Wiley-VCH, Weinheim,
2004.
3 W. Adam, C. R. Saha-Mo¨ller and P. A. Ganeshpure, Chem. Rev., 2001,
101, 3499–3538.
4 F. Minisci, C. Punta and F. Recupero, J. Mol. Catal. A:Chem., 2006,
251, 129–149.
5 Y. Ishii, S. Sakaguchi and T. Iwahama, Adv. Synth. Catal., 2001, 343,
393–427.
Instrumentation
6 (a) K. Nobuyoshi, B. Saha and J. H. Espenson, J. Org. Chem., 2003,
68, 9364–9370; (b) P. J. Figiel and J. M. Sobczak, New J. Chem., 2007,
31, 1668–1673.
7 C. Ueda, M. Noyama, H. Ohmori and M. Masui, Chem. Pharm. Bull.,
1987, 35, 1372–1377.
8 (a) N. Koshino, Y. Cai and J. H. Espenson, J. Phys. Chem. A, 2003,
107, 4262–4267; (b) C. Annunziatini, M. F. Gerini, O. Lanzalunga
and M. Lucarini, J. Org. Chem., 2004, 69, 3431–3438; (c) R. Amorati,
M. Lucarini, V. Mugnaini, G. F. Pedulli, F. Minisci, F. Recupero, F.
Fontana, P. Astolfi and L. Greci, J. Org. Chem., 2003, 68, 1747–1754;
(d) E. Baciocchi, O. Lanzalunga and M. F. Gerini, J. Org. Chem., 2004,
69, 8963–8966.
The kinetic study was carried out with a Hi-Tech SFA-12
stopped flow instruments, interfaced to a HP 8453 diode array
spectrophotometer, and having a thermostated cuvette holder. A
conventional UV-Vis spectrophotometer (Perkin Elmer Lambda
18) was alternatively used. A thermocouple was employed for
reading the temperature in the cuvette.
Kinetic Procedure
The BTNO species was generated in MeCN in a thermostated
quartz cuvette, by adding a 0.5 mM solution of CAN to a
0.5 mM solution of HBT. A broad absorption band developed
almost immediately (15 ms) in the 350–600 nm region (lmax at
474 nm, e 1840 M-1 cm-1).9 The A474 reading was not stable,
but decayed with a half-life of ca. 140 s. The rate of decay was
unaffected by the use of deareated MeCN. Rate constants of
H-abstraction from H-donor substrates were determined at 25 ◦C
in MeCN (Table 1), by following the decrease of the A474 band
of BTNO. The initial concentration of the substrate was in the
0.5- to -4 ¥ 10-2 M range, so to enable a pseudo-first-order
treatment of the kinetic data. Plots of (At-A•) vs time were well
fitted by a first-order exponential over more than three half-lives
and pseudo-first-order rate constant (k¢) reckoned. From a plot
of three-to five k¢ vs [subst]◦ data pairs, the second-order rate
constant of H-abstraction (kH) was obtained. Determination of
H-abstraction rate constants was analogously carried out at dif-
ferent temperatures (in the 13–50 ◦C range) for PhCH2NHCOMe
and 4-MeO-C6H4CH2NHCOMe (Table 2), for the calculation of
the activation parameters from the Arrhenius plot.
9 (a) C. Galli, P. Gentili, O. Lanzalunga, M. Lucarini and G. F. Pedulli,
Chem. Commun., 2004, 2356–2357; (b) P. Brandi, C. Galli and P. Gentili,
J. Org. Chem., 2005, 70, 9521–9528.
10 F. Minisci, C. Punta, F. Recupero, F. Fontana and G. F. Pedulli, J. Org.
Chem., 2002, 67, 2671–2676.
11 D. Griller, J. A. Howard, P. R. Marriott and J. C. Scaiano, J. Am. Chem.
Soc., 1981, 103, 619–623.
12 V. Malatesta and K. U. Ingold, J. Am. Chem. Soc., 1981, 103, 609–
614.
13 G. Prabhakar Rao and A. R. Vasudeva Murthy, J. Phys. Chem., 1964,
68, 1573–1576.
14 P. Astolfi, P. Brandi, C. Galli, P. Gentili, M. F. Gerini, L.
Greci and O. Lanzalunga, New J. Chem., 2005, 29, 1308–
1317.
15 A. Coniglio, C. Galli, P. Gentili and R. Vadala`, J. Mol. Catal. B:Enzym.,
2008, 50, 40–49.
16 T. H. Lowry, and K. S. Richardson, Mechanism and Theory
in Organic Chemistry, 2nd ed., Harper
1981.
& Row, New York,
17 For recent and detailed considerations on substituent effects on
radical stabilization energy, see: D. A. Pratt, G. A. DiLabio,
P. Mulder and K. U. Ingold, Acc. Chem. Res., 2004, 37, 334–
340.
18 T. Sueda, D. Kajishima and S. Goto, J. Org. Chem., 2003, 68, 3307–
3310.
19 P. Baiocco, A. M. Barreca, M. Fabbrini, C. Galli and P. Gentili, Org.
Biomol Chem., 2003, 1, 191–197.
Semiempirical calculations
20 Y.-R. Luo, Comprehensive Handbook of Chemical Bond Energies, CRC
Press, Boca Raton, Florida, USA, 2007.
21 E. Baciocchi, M. Bietti, M. F. Gerini and O. Lanzalunga, J. Org. Chem.,
2005, 70, 5144–5149.
The structure of a few substrates has been optimized by a semi-
empirical method (PM3 level) on using the Hyperchem program.
22 A. Cuppoletti, C. Dagostin, C. Florea, C. Galli, P. Gentili, O.
Lanzalunga, A. Petride and H. Petride, Chem. Eur. J., 1999, 5, 2993–
2999.
Acknowledgements
23 M. Aweke Tadesse, A. D’Annibale, C. Galli, P. Gentili and F. Sergi,
Org. Biomol. Chem., 2008, 6, 868–878.
24 Vogel’s Textbook of Practical Organic Chemistry, IV edn, Longman,
London, chapter VII, 1978.
This work was supported by grants from the Italian MIUR
(COFIN and FIRB projects) and from the University of Roma
‘La Sapienza’.
160 | Org. Biomol. Chem., 2009, 7, 155–160
This journal is
The Royal Society of Chemistry 2009
©