Normal, Leveled, and Enhanced Steric Effects in Alkoxyamines Carrying a β-Phosphorylated Nitroxyl Fragment

Article abstract of DOI:10.1021/acs.joc.7b00541

The design of new R₁R₂NOR₃ alkoxyamines for various applications relies on the accurate prediction of two kinetic parameters, the C-ON bond homolysis rate constant (k_d) and its re-formation rate constant (k_c). Relationships to describe the steric and polar effects of the R₁R₂NO fragment ruling k_d have been developed. For all cyclic nitroxyl fragments, the steric effect is described as the sum of the bulkiness of the R₁ and R₂ groups (i.e., normal steric effect), while for the noncyclic nitroxyl fragment (except for one case), a leveled steric effect is assumed. In this work, we show that the normal steric effect also applies to noncyclic nitroxyl fragments and that for one case an enhanced steric effect is also observed, i.e., experimental k_d >5-fold larger than the predicted value.

Full text of DOI:10.1021/acs.joc.7b00541

Article
pubs.acs.org/joc
Normal, Leveled, and Enhanced Steric Effects in Alkoxyamines
Carrying a β‑Phosphorylated Nitroxyl Fragment
Gerard Audran,*,† Raphael Bikanga,‡ Paul Bremond,† Jean-Patrick Joly,† Sylvain R. A. Marque,*,†,§
́
́
and Paulin Nkolo†
†Aix Marseille Universite,
France
́
CNRS, ICR, UMR 7273, case 551, Avenue Escadrille Normandie-Niemen, 13397 Marseille Cedex 20,
‡Laboratoire de Substances Naturelles et des Syntheses Organometalliques, Universite des Sciences et Technique de Masuku, B.P.
493, Franceville, Gabon
§N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry SB RAS, Pr. Lavrentjeva 9, 630090 Novosibirsk, Russia
S
* Supporting Information
ABSTRACT: The design of new R1R2NOR3 alkoxyamines for various applications relies on
the accurate prediction of two kinetic parameters, the C−ON bond homolysis rate constant
(kd) and its re-formation rate constant (kc). Relationships to describe the steric and polar
effects of the R1R2NO fragment ruling kd have been developed. For all cyclic nitroxyl
fragments, the steric effect is described as the sum of the bulkiness of the R1 and R2 groups
(i.e., normal steric effect), while for the noncyclic nitroxyl fragment (except for one case), a
leveled steric effect is assumed. In this work, we show that the normal steric effect also applies
to noncyclic nitroxyl fragments and that for one case an enhanced steric effect is also observed,
i.e., experimental kd >5-fold larger than the predicted value.
increasing the polarity of the alkyl fragments was highlighted
using protonation,14 alkylation,14 acylation,14 complexation
with an inorganic Lewis acid,14 and complexation with metal
salts15,16 to afford an up to 30−40-fold increase in kd. In the
same way, deprotonation17,18 and decomplexation16 of the
nitroxyl fragment afforded a moderated 10-fold increase in kd.
However, we recently showed that a strong effect of polarity of
the alkyl fragment requires strong electron-widthdrawing
groups (EWGs) carried by the nitroxyl fragment.19 By contrast,
eq 120 shows that kd decreases with an increase in polarity (and
a decrease in the level of stabilization of the nitroxide).
Nevertheless, 2-based alkoxyamines seem to be promising
candidates, because of the presence of strong EWGs and a
bulky diethylphosphoryl group on the alkyl and nitroxyl
fragments.21 However, the leveling of the steric effect20,22−24
cancels all benefits because of the bulkiness and polarity of the
diethylphosphoryl group. It has been noted20,24−26 that this
leveled steric effect occurs mainly for noncyclic nitroxides
carrying a H atom at position β.
INTRODUCTION
■
For several decades,1 alkoxyamines and their fascinating
properties (Scheme 1), i.e., C−ON bond homolysis (rate
Scheme 1
constant kd) to generate an alkyl radical and a nitroxide and re-
formation via a cross-coupling reaction (rate constant kc), have
found applications in various fields such as material sciences (as
self-healing polymers,2,3 materials for photonics,4 and coding
systems5,6), polymer sciences,1,7,8 chemistry (as tin free
reagents),9,10 and biology11,12 [as theranostic agents (Figure
1)].
For the application of alkoxyamines as theranostic agents, the
concept of “smart” alkoxyamines was devised (Figure 2);12 that
is, it relies on the switch from a stable to a highly labile
alkoxyamine upon an external chemical or biochemical
triggering event. However, to circumvent the issues related to
the diffusion of alkoxyamines in tissues, a very fast homolysis is
required, i.e., a half-lifetime of a few seconds.12 In alkoxyamines,
the increasing bulkiness of both alkyl and nitroxyl fragments
and increasing the polarity in the alkyl fragment lead to an
increased kd, and conversely, in released radicals, i.e., alkyl
radicals and nitroxides, increasing their level of stabilization also
affords an increase in kd.13 At first glance, the polar effect is the
easiest effect to modify almost reversibly. On the basis of this
assumption, the activation of C−ON bond homolysis by
log[kd (s−1)] = −5.88( 0.28) − 3.07( 0.28)σI
− 0.88( 0.04)Es
(1)
As far as we know, only the synthesis of 3 has been reported
in the literature,27 which led us to design alkoxyamines 4−9
(Figure 3) and to investigate the effect of a change in both
bulkiness (3−6) and polarity (5 and 7, 6 and 8, and 9). Besides
Received: March 7, 2017
© XXXX American Chemical Society
A
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Figure 1. Concept for the use of alkoxyamines as theranostic agents based on enzymatic or metal ion activation. Reproduced with permission from
ref 12. Copyright 2014 Royal Society of Chemistry.
effect of EWGs on both the stabilization of the released
nitroxide and the change in polarity in the alkoxyamine and Es
to account for the bulkiness of the nitroxyl fragment)32 relies
on the assumption of a linear change in the steric effect, from
alkoxyamine 1 carrying a noncyclic nitroxyl fragment to
alkoxyamine 12 carrying a cyclic nitroxyl fragment. It is
Figure 2. Requirements for smart alkoxyamines. Reproduced with
assumed that the bulkiness of each of the groups attached to
permission from ref 12. Copyright 2014 Royal Society of Chemistry.
the nitroxyl moiety is given by eq 233 and that their sum (eq
3)34 accounts for the bulkiness of the alkyl fragment. However,
the development of alkoxyamines for theranostic applications,
this work has a more fundamental aspect. Indeed, the design of
among all alkoxyamines carrying noncyclic nitroxyl fragments, 1
alkoxyamines relies on the ability to predict kd and kc28
is the only one that fulfils these requirements! The results
depending on the application that is being targeted. For a
decade, both empirical20,29 and theoretical30 reactivity−
discussed hereafter highlight the fact that eqs 1−3 apply to
structure relationships have been developed. Indeed, eq 131
many types of alkoxyamines except those similar to alkoxy-
(with the σI electrical Hammett constant used to describe the
amines 2 and 14.
Figure 3. Alkoxyamines and nitroxides discussed in this work.
B
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a
b
Scheme 2. (A) Preparation of 3 , and of 4−9
a
(A) Preparation of 3: (a) t-BuNH2, HP(O)(OEt)2 neat, 0 °C, 77%; (b) mCPBA, CH2Cl2, −78 °C, 5 h, 7%; (c) PhCHBrMe, CuBr, PMEDTA,
b
Cu(0), benzene, 55−80%. (B) (d) H2NCMe2CH2COOR, TiCl4, DCM, 0 °C; (e) HP(O)(OEt)2, 40 °C, 52−90%; (f) mCPBA, CHCl3, 56−80%.
a
Table 1. Experimental C−ON Bond Homolysis Rate Constants (kd′) for Alkoxyamines 3−9 in Toluene, Activation Energies
(Ea), Re-Estimated Rate Constants (kd), Polar/Stabilization Hammett-Type Constants (σI,n), and Taft Steric Constants (Es) for
1−12
b
c
d
e
,
f
e,g,hi
T (°C)
kd′ (×10−4 s−1
)
Ea (kJ/mol)
kd (×10−3 s−1
)
σI,n
Es
refs
1
122.4
125.5
119.3
125.6
118.9
114.5
125.4
120.7
121.1
126.6
125.8
132.9
12.9
5.0
−0.06
0.28
0.27
0.27
0.27
0.27
0.60
0.60
0.60
0.28
0.28
−0.06
−4.21
−5.0
−5.0
20, 21
j
2
20, 21
3
70
79
67
55
80
80
80
1.6
0.5
1.3
1.4
6.8
3.4
2.9
33.4
4.9
this work
this work
this work
this work
this work
this work
this work
20, 21
4
−5.21
−5.81
−6.46
−5.81
−6.46
−6.46
−5.36
−5.36
−2.70
5
37.7
144.9
5.2
6
k
k
k
7
8
21.7
19.3
3.6
9
10
11
12
4.6
20, 21
0.5
20, 21
a
b
No solvent effect is considered between toluene and tert-butylbenzene, the solvent for which literature data were reported. Within 1 °C.
c
d
Estimated using values reported in the third column and using a frequency factor A of 2.4 × 1014 s−1. See ref 21. Estimated at 120 °C using values
e
reported in the fourth column and using frequency factor A of 2.4 × 1014 s−1. See ref 21. σI,n and Es values are estimated as described in ref 20.
f
g
Individual values of σI are given in ref 38: σI,H = 0, σI,Me = σI,t‑Bu = −0.01, σI,COOR = σI,COOMe = 0.32, and σI,P(O)(OEt) = 0.32. Individual steric
2
constants r are given in refs 20 and 40: r(H) = 0.32, r(Me) = 0, r[(CH2)4] = −0.04, r[(CH2)5] = −0.15, r[(CH2)6] = −0.27, r[P(O)(OEt)2] = 1.22,
h
and r(t-Bu) = −2.46. As the value of 1.04 for υ[P(O)(OEt)2] is close to the value of 1.02 for υ(sBu), assuming a value of −1.22 for r[P(O)(OEt)2]
i
is reasonable, because it is close to the r(sBu) of −1.25. See refs 39 and 40. Es values are estimated assuming that eqs 2 and 3 hold unless otherwise
j
k
mentioned. Assuming the leveled steric effect. See ref 20. It is assumed that r(COOBn) ≈ r(COOMe) ≈ r(Me) as υ(COOMe) = 0.50 and υ(Me)
= 0.52. See ref 41.
moderated to good yields (55% for 3 to 80% for 7).37 No
EsA or B = −2.104 + 3.429r(R1) + 1.978r(R2)
attempts were made to grow crystals.
+ 0.649r(R3)
(2)
Kinetic Measurements. Values of kd′ were measured by
NMR using 12• as an alkyl radical scavenger as previously
Es,n = aEsA + bEsB + ε
reported.13 Values of kd and Ea for 1−12 are listed in Table 1
(3)
along with kd′ values for 3−9. A clear decrease in Ea is observed
with the increase in ring size from 4 to 6 (Table 1). This
RESULTS
■
decrease is again observed from 7 to 9. Moreover, the size of
the ester group has no significant effect, i.e., Ea of 9 similar to Ea
of 8.
Multiparameter Relationships. Parameters σI,n
35
Preparation of 3−9. Nitroxides 3• (Scheme 2A) and
35
36
4• through 6• (Scheme 2B) were prepared as previously
reported. Nitroxides 7•−9• were prepared from the corre-
sponding cyclic ketones that were transformed into corre-
sponding imines 7′−9′, respectively, and then into phosphory-
lated amines 7″−9″, respectively, as colorless oils (Scheme 2B).
The latter were oxidized with m-chloroperbenzoic acid
(mCPBA) into nitroxides 7•−9• in rather moderate yields as
orange oils (Scheme 2B, 33% for 7•, 30% for 8•, and 37% for 9•
as overall yields). Alkoxyamines 3−9 (Scheme 2) were
prepared using Matyjaszewski’s procedure as colorless oils in
20,38
and
Es,n20 are estimated as previously reported (Table 1). Individual
steric constants r(C4), r(C5), and r(C6) are used to account
for the steric effect of the four-, five-, and six-membered rings,
respectively, attached to the nitroxyl moiety.40 The non-
significant difference in Ea between 8 (R = Me) and 9 (R =
CH2Ph) and the very close steric constants for the ester and
methyl groups, i.e., υ(COOR) = 0.50 and υ(Me) = 0.52,41
C
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support the assumption that Es(COOR) ≈ Es(Me). In previous
work, it was noticed that the leveled steric effect occurs for all
alkoxyamines carrying a diethylphosphoryl group and has to be
taken into account in estimating Es values. Moreover, it was
mentioned that the leveled effect is likely to occur for
alkoxyamines exhibiting Es values smaller than −6, which is
the case for 6, 8, and 9. Thus, when the assumption of the
leveled steric effect holds, Es for 4−9 is given as −5.0, as they
are very similar to the values of 10 and 11. When σI,n and Es,n
for 4−9 are implemented in eq 1, a scattered plot is observed
(blue empty circles in Figure 4), except for 4, which is lying
Amazingly, eqs 1−3 cannot describe the steric effect for the
very simple case of 3, which differs from 1 by one methyl group
replaced with a diethylphosphoryl group (Figure 4). Whatever
the assumption, with or without the leveled effect, the kd of 3 is
>5-fold underestimated by eq 1 (Figure 4), meaning that
r[P(O)(OEt)2] is larger than the recommended values, i.e.,
r[P(O)(Et)2] = −2.47, assuming 3 lies on the correlation line.
The r[P(O)(OEt)2] value of −1.22 was determined assuming 2
lies on the correlation line and found to be in good agreement
with those from the literature (footnote h in Table 1).
Moreover, the steric effect of 16 β-phosphorylated nitroxyl
fragments is captured by eq 4 using this value that has no
reason to vary suddenly, up to r = −2.47. From our experience,
the conformation observed around the nitroxyl moiety in a
nitroxide does not differ too much from that observed in the
corresponding alkoxyamine.44 Fortunately, the effects of the
solvent on phosphorus hyperfine coupling constant aP have
45
recently been reported for 2• through 6•35 and show striking
differences between nitroxides; that is, aP varies from alkanes to
polar solvents between 46 and 47 G, between 42 and 20 G,
between 55 and 60 G, between 52 and 53 G, and between 55
45
and 60 G for 2• through 6•, respectively.35 Obviously, 3•
experiences a solvent effect strikingly different from that for 2•
and 4•−6•. aP is due to the hyperconjugation between the
SOMO and the bonding/antibonding σC−P/σ*C−P orbital of the
C−P bond (Figure 5), meaning that the better the overlap, the
Figure 4. Plot of log[kd (s−1)] vs f(σI,n,Es) for 1−12. Bold squares are
for values listed in Table 1. Italicized numbers and empty blue circles
are for values when the leveled steric effect holds. The empty square is
for outliers. Vertical red lines are used to visualize the deviation from
the correlation.
close to the correlation line. When the leveled steric effect is
not taken into account and eqs 2 and 3 are applied
straightforwardly, a very good correlation (eq 4)42 is observed,
considering 3 as an outlier (Figure 4).43 As good statistical
outputs and very similar coefficients are observed for eq 4 as
well as for eq 1, the weight of each effect is not re-estimated. All
this is undeserving of more comment. Importantly, the
meaningfulness of the correlation is also highlighted by the
range of values covered by σI,n and Es,n, i.e., −0.06 < σI,n < 0.60,
−6.5 < Es,n < −2.1, and 1.5 < f(σI,n,Es,n) < 5.0, and the 4 order
of magnitude changes in kd.
Figure 5. Hyperconjugation effect due to the SOMO → σ*C−P
interaction in nitroxyl radicals. Blue denotes dihedral angle θ, the
angle between the C−P bond and the SOMO orbital centered on the
nitrogen atom.
more favored the syn periplanar conformation, the stronger the
interaction, and the higher the aP.35,45−48 Consequently, similar
and high values of aP for 2• and 4•−6• imply the C−P bond is
almost syn periplanar to the SOMO, as depicted in Figure 6.
Moreover, the large change in aP observed for 3•, in sharp
contrast to that observed for 2• and 4•−6•, points at a strongly
less restricted N−CP bond rotation compared to that in 2• and
4•−6•, thus affording a very different conformation for 3• and
for 2• and 4•−6• (Figure 6). As very close conformations are
expected for the corresponding alkoxyamines, a similar
bulkiness is expected for the diethylphosphoryl group in 2
and 4−6, as shown by the good observed correlation. The
enhanced steric effect observed for 3 is due to a different and
more strained conformation, in which the diethylphosphoryl
group is directed toward the alkyl fragment, providing a greater
bulkiness and thus a greater steric effect, than in 2 and 4−6,
because of a subtle interplay between the steric repulsion of the
different groups.
log[kd (s−1)] = −5.90( 0.15) − 2.79( 0.25)σI,n
− 0.88( 0.04)Es,n
(4)
DISCUSSION
■
Applying eqs 2 and 3 to describe the steric effect in 4−9 and
then eq 1 yields a very good correlation (eq 4 and Figure 4),
with almost all data lying on the correlation line, except the
value of 4, which is overestimated by a factor of 2 in the error
range, i.e., a difference of <2 kJ between predicted and
experimental data. This straightforward approach is also applied
to 10 and 11, affording data deviating by a factor of <4. These
results highlight nicely the versatility and the robustness of eqs
1−3 to describe the effects involved in changes in kd, making
only a few assumptions.20,24 They also highlight the generality
of eqs 2 and 3 which apply to cyclic and noncyclic nitroxyl
fragments.
CONCLUSION
■
This work highlights the robustness and versatility of eq 1 as
the bulkiness of each fragment attached to the nitroxyl moiety
is described by the addition of parameters used to describe the
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Figure 6. Conformations in nitroxides 2•−6•. Bold orbitals for the SOMO.
Chemical shifts (δ) in parts per million were reported using residual
steric effect (eqs 2 and 3, the so-called normal steric effect) as
well as the boundaries of this approach. That is, the normal
steric effect is replaced either by the enhanced steric effect (kd
higher than that predicted as highlighted by alkoxyamine 3 in
Figure 4) or by the leveled steric effect (kd lower than that
predicted as highlighted in previous work).20,24,49 The rules
proposed to describe the steric effect in a previous work need
to be revised and completed. Indeed, we proposed (i) if the
nitroxyl moiety shows some symmetry or pseudosymmetry, ε is
equal to zero and (ii) if the nitroxyl moiety does not show any
symmetry or pseudosymmetry, ε is equal to −bEBs . For the time
being, it seems that rule (i) applies when Es (estimated with eqs
3 and 4) does not exceed −6.
Keeping in mind a predictive use of eqs 1−3, we propose
amended rules. (i) Equations 1−3 with ε = 0, i.e., normal steric
effect,20,24,50 hold for alkoxyamines exhibiting two tertiary
carbon atoms attached to the nitroxyl moiety.51 (ii) Equations
1−3 with ε = −bEsB, i.e., leveled steric effect,20,24,50 hold for
alkoxyamines exhibiting a tertiary carbon atom and a secondary
carbon atom attached to the nitroxyl moiety (this rule is
supported by the normal steric effect observed for 6, which
exhibits a tBu group attached to the nitroxyl moiety, whereas
the leveled steric effect20 is observed for 10, which exhibits an
iPr group attached to the nitroxyl moiety). (iii) The enhanced
steric effect might be expected for alkoxyamine exhibiting two
tertiary carbon atoms attached to the nitroxyl moiety and C−N
bonds exhibiting low rotational barriers.
1
nondeuterated solvents as an internal reference for H and 13C NMR
spectra and 85% H3PO4 for 31P NMR spectra. High-resolution mass
spectra were recorded on a SYNAPT G2 HDMS (Waters)
spectrometer equipped with a pneumatically assisted atmospheric-
pressure ionization source (API). Positive mode electrospray
ionization was used on samples: electrospray voltage (ISV), 2800 V;
opening voltage (OR), 20 V; nebulizer gas pressure (nitrogen), 800 L/
h. Low-resolution mass spectra were recorded on the ion trap AB
SCIEX 3200 QTRAP instrument equipped with an electrospray
source. Parent ion [M + H]+ is quoted.
General Procedure for the Preparation of Aminophosphory-
lated Compounds 4″−9″. To a stirred solution of cyclic ketone (1
equiv) and aminoester (5 equiv) in Et2O was added a solution of TiCl4
(0.7 equiv) in dichloromethane (DCM) at 0 °C. The resulting
suspension was stirred at room temperature overnight. The reaction
was then quenched with 0.5 M NaOH, and the product was then
extracted with Et2O. The layers were separated; the organic phase was
washed with brine and dried over MgSO4, and the solvent was
evaporated. Diethylphosphite (2 equiv) was added to crude 4′−9′, and
the reaction mixture was left overnight at 40 °C. Unreacted
diethylphosphite was evaporated, and the residual oil was purified by
flash chromatography to yield the corresponding aminophosphonates
3″−9″. NMR data of 3″−6″ are in good agreement with those from
the literature.35,36
Benzyl 2-(Diethylphosphoryl)-2-[(cyclopentyl)amino]-2-methyl-
propionate (7″). Cyclopentanone (348 mg, 4.14 mmol, 1 equiv),
benzyl aminoester (4.0 g, 20.7 mmol, 5 equiv), TiCl4 (549 mg, 2.90
mmol, 0.7 equiv), Et2O (20 mL), and diethylphosphite (1.14 g, 8.28
mmol, 2 equiv) were used. After flash chromatography [gradient,
petroleum ether (PE)/AcOEt, from 0 to 100% AcOEt], amino-
This improved description of the steric effect in the
alkoxyamine C−ON bond homolysis is important and needed
for the design of new alkoxyamines suitable for more efficient
NMP under various conditions,8 to develop smart materials3−6
or to favor new applications in biology.11
1
phosphonate 7′ was isolated (856 mg, 52%, colorless oil): H NMR
(300 MHz, CDCl3) δ 7.28 (m, 5H), 5.06 (s, 2H), 4.04 (p, J = 7.2 Hz,
4H), 2.02 (m, 2H), 1.84 (s, 1H), 1.56 (m, 6H), 1.33 (s, 6H), 1.22 (t, J
= 7.1 Hz, 6H); 31P NMR (121 MHz, CDCl3) δ 30.44; 13C NMR (75
MHz, CDCl3) δ 178.3 (d, JC−P = 2.4 Hz), 136.1, 128.6, 128.2, 66.6,
63.7 (d, JC−P = 161.1 Hz), 62.3 (d, JC−P = 7.8 Hz), 58.3 (d, JC−P = 5.4
Hz), 36.4 (d, JC−P = 5.1 Hz), 28.0, 25.2 (d, JC−P = 7.4 Hz), 16.6 (d,
JC−P = 5.5 Hz); HRMS m/z (ESI) calcd for C20H33NO5P [M + H]+
398.2091, found 398.2090.
EXPERIMENTAL SECTION
■
All solvents and reactants for the preparation of alkoxyamines were
used as received. Routine reaction monitoring was performed using
silica gel 60 F254 TLC plates; spots were visualized upon exposure to
UV light and a phosphomolybdic acid solution in EtOH as stain
revealed by heating. Purifications were performed on chromatography
columns with silica gel grade 60 (230−400 mesh) for alkoxyamines 3−
6. Purifications of 7″−9″, 7•−9•, and 7−9 were performed with a
Methyl 2-(Diethylphosphoryl)-2-[(cyclohexyl)amino]-2-methyl-
propionate (8″). Cyclohexanone (838 mg, 8.54 mmol, 1 equiv),
methyl aminoester (5.0 g, 42.68 mmol, 5 equiv), TiCl4 (1.13 g, 5.97
mmol, 0.7 equiv), Et2O (20 mL), and diethylphosphite (2.35 g, 17.07
mmol, 2 equiv) were used. After flash chromatography (gradient, PE/
AcOEt, from 0 to 100% AcOEt), aminophosphonate 8″ was isolated
(1.60 g, 56%, colorless oil): 1H NMR (400 MHz, CDCl3) δ 4.03 (p, J
= 7.2 Hz, 4H), 3.62 (s, 3H), 1.71 (m, 7H), 1.46 (m, 4H), 1.35 (s, 6H),
1.25 (t, J = 7.1 Hz, 6H); 31P NMR (162 MHz, CDCl3) δ 29.93; 13C
Reveleris X2 flash system (Buchi): a solvent delivery system equipped
̈
with high-pressure HPLC pumps, four independent channels with up
to four solvents in a single run, autoswitch lines when solvent is
depleted, normal phase and reversed phase compatible; pump flow
rate of 1−200 mL/min; maximal pressure of 200 psi; linear gradients
(the same gradient was used for all purifications, and an example of the
profile is provided in Figure S1); sample injection in liquid sample
mode; UV wavelength range of 200−500 nm; holds two racks, with
automatic rack recognition for the fraction collection; cartouches flash
Reveleris et GraceResolv of silica 40 μm. 1H, 13C, and 31P NMR
spectra were recorded in CDCl3 on a 300 or 400 MHz spectrometer.
NMR (101 MHz, CDCl3) δ 178.3 (d, JC−P = 3.7 Hz), 61.9 (d, JC−P
=
7.9 Hz), 58.7 (d, JC−P = 3.8 Hz), 57.1 (d, JC−P = 146.8 Hz), 51.8, 32.6
(d, JC−P = 3.2 Hz), 28.2, 26.0, 20.6 (d, JC−P = 7.9 Hz), 16.7 (d, JC−P
=
5.6 Hz); HRMS m/z (ESI) calcd for C15H31NO5P [M + H]+
336.1934, found 336.1934.
Benzyl 2-(Diethylphosphoryl)-2-[(cyclohexyl)amino]-2-methyl-
propionate (9″). Cyclohexanone (416 mg, 4.24 mmol, 1 equiv),
E
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benzyl aminoester (4.1 g, 21.22 mmol, 5 equiv), TiCl4 (563 mg, 2.97
mmol, 0.7 equiv), Et2O (20 mL), and diethylphosphite (1.17 g, 8.48
mmol, 2 equiv) were used. After flash chromatography (gradient, PE/
AcOEt, from 0 to 100% AcOEt), aminophosphonate 9″ was isolated
(925 mg, 53%, colorless oil): 1H NMR (400 MHz, CDCl3) δ 7.35 (m,
5H), 5.14 (s, 2H), 4.09 (p, J = 7.2 Hz, 4H), 1.60 (m, 10H), 1.44 (s,
6H), 1.29 (t, J = 7.0 Hz, 6H); 31P NMR (162 MHz, CDCl3) δ 29.51;
13C NMR (101 MHz, CDCl3) δ 174.5 (d, JC−P = 3.3 Hz), 133.4, 125.8,
125.5, 125.1, 125.1, 63.4, 58.9 (d, JC−P = 8.0 Hz), 55.7 (d, JC−P = 4.0
Hz), 54.1 (d, JC−P = 148.0 Hz), 29.6 (d, JC−P = 3.2 Hz), 25.2, 22.8, 17.7
(d, JC−P = 7.5 Hz), 13.6 (d, JC−P = 5.5 Hz); HRMS m/z (ESI) calcd for
C21H35NO5P [M + H]+ 412.2247, found 412.2245.
δ 30.56, 29.90; 13C NMR (101 MHz, CDCl3) δ 144.8, 144.3, 128.1,
128.0, 127.4, 127.0, 126.8, 82.6, 80.1, 66.2, 65.8, 64.7, 64.3, 63.0, 62.9,
62.3, 62.2, 62.1 (d, JC−P = 7.6 Hz), 61.6 (d, JC−P = 7.4 Hz), 30.4, 29.7,
27.6, 26.9, 25.5, 24.8, 22.0, 16.6 (t, J = 5.8 Hz); HRMS m/z (ESI)
calcd for C19H35NO4P [M + H]+ 372.2298, found 372.2298.
Diethyl {1-[tert-Butyl(1-phenylethoxy)amino]cyclobutyl}-
phosphonate (4). CuBr (139.14 mg, 0.97 mmol, 0.55 equiv), Cu
powder (123.92 mg, 1.95 mmol, 1.1 equiv), benzene (2 × 3 mL),
N,N,N′,N′,N″-pentamethyldiethylenetriamine (0.2 mL, 0.97 mmol,
0.55 equiv), 4• (495 mg, 1.77 mmol, 1 equiv), and bromoethylbenzene
(360.9 mg, 1.95 mmol, 1.1 equiv) were used. After flash
chromatography (gradient, PE/AcOEt, from 0 to 60% AcOEt by 5%
1
General Procedure for Oxidation of 4″−9″ to 4•−9•. To a
stirred solution of aminophosphonates 4″−9″ (1 equiv) in chloroform
was added a solution of mCPBA (1.5 equiv) in chloroform. The
reaction mixture was strirred at room temperature for 3 h and then the
reaction quenched with 10% Na2SO3 in water. Nitroxides 4•−9• were
extracted with DCM. The layers were separated; the organic phase was
washed with saturated NaHCO3 and brine and dried over MgSO4. The
solvents were evaporated, and the product was purified by flash
chromatography to yield the corresponding nitroxides 4•−9•. EPR and
HRMS data of 3•−6• are in good agreement with those from the
literature.35,36
N,N-(1-Methyl-1-benzylcarboxyethyl)(1-diethylphosphorylcyclo-
pentyl)amino-N-oxyl Radical (7•). Aminophosphonate 7″ (500 mg,
1.26 mmol, 1 equiv), 77% mCPBA (422 mg, 1.89 mmol, 1.5 equiv),
and chloroform (10 mL) were used. The solvents were evaporated,
and the product was purified by flash chromatography (gradient, PE/
AcOEt, from 0 to 100% AcOEt) to afford nitroxide 7• (330 mg, 64%,
orange oil): HRMS m/z (ESI) calcd for C20H32NO6P [M + H]+
413.1962, found 413.1961.
N,N-(1-Methyl-1-methylcarboxyethyl)(1-diethylphosphorylcyclo-
hexyl)amino-N-oxyl Radical (8•). Aminophosphonate 8″ (415 mg,
1.24 mmol, 1 equiv), 77% mCPBA (416 mg, 1.86 mmol, 1.5 equiv),
and chloroform (10 mL) were used. The solvents were evaporated,
and the product was purified by flash chromatography (gradient, PE/
AcOEt, from 0 to 100% AcOEt) to afford the corresponding nitroxides
8• (228 mg, 53%, orange oil): HRMS m/z (ESI) calcd for
C15H30NO6P• [M + H]+ 351.1805, found 351.1805.
N,N-(1-Methyl-1-benzylcarboxyethyl)(1-diethylphosphorylcyclo-
hexyl)amino-N-oxyl Radical (9•). Aminophosphonate 9″ (475 mg,
1.15 mmol, 1 equiv), 77% mCPBA (388 mg, 1.73 mmol, 1.5 equiv),
and chloroform (10 mL) were used. The solvents were evaporated,
and the product was purified by flash chromatography (gradient, PE/
AcOEt, from 0 to 100% AcOEt) to afford the corresponding nitroxides
9• (333 mg, 68%, orange oil): HRMS m/z (ESI) calcd for
C21H34NO6P [M + H]+ 427.2118, found 427.2118.
General Procedure for the Preparation of Alkoxyamines 3−
9. To a suspension of CuBr (0.55 equiv) and Cu powder (1.1 equiv)
in degassed benzene (3 mL) under argon was added N,N,N′,N′,N″-
pentamethyldiethylenetriamine (0.55 equiv). After being stirred for 10
min, a solution of nitroxides 3•−9• (1 equiv) and bromoethylbenzene
(1.1 equiv) in degassed benzene (argon bubble in benzene for 1 h) (3
mL) was transferred to the first solution. The mixture was allowed to
stir for 12 h. The solution was diluted with EtOAc, the reaction
quenched with saturated NH4Cl, and the mixture washed with water
and brine and dried over MgSO4. The solvents were evaporated under
reduced pressure. The crude product was purified by automatic flash
chromatography to yield the corresponding alkoxyamines 3−9.
Diethyl {2-[tert-Butyl(1-phenylethoxy)amino]propan-2-yl}-
phosphonate (3). CuBr (50.2 mg, 0.35 mmol, 0.55 equiv), Cu
powder (44.48 mg, 0.7 mmol, 1.1 equiv), benzene (2 × 3 mL),
N,N,N′,N′,N″-pentamethyldiethylenetriamine (0.073 mL, 0.35 mmol,
0.55 equiv), 3• (170 mg, 0.64 mmol, 1 equiv), and bromoethylbenzene
(130 mg, 0.7 mmol, 1.1 equiv) were used. After purification by column
chromatography [dichloromethane (DCM)/MeOH, from 0 to 10%
MeOH by 1% step], 3 was obtained in 55% yield (130 mg, colorless
oil): 1H NMR (400 MHz, CDCl3) δ 7.20 (m, 5H), 5.24 (q, J = 5.9 Hz,
0.56H), 4.99 (J = 6.2 Hz, 0.41H), 4.06 (m, 4H), 1.43 (d, J = 6.6 Hz,
3H), 1.40−1.13 (m, 18H), 1.01 (s, 3H); 31P NMR (162 MHz, CDCl3)
step), 4 was obtained in 71% yield as a colorless oil (479 mg): H
NMR (300 MHz, CDCl3) δ 7.42−7.14 (m, 5H), 4.88 (q, J = 6.4 Hz,
1H), 4.32−4.08 (m, 4H), 2.88−2.60 (m, 2H), 2.42−2.23 (m, 2H),
1.98 (dd, J = 19.3, 9.6 Hz, 1H), 1.64 (dd, J = 21.8, 11.4 Hz, 1H), 1.45
(d, J = 6.5 Hz, 3H), 1.36 (q, J = 7.6 Hz, 6H), 1.19 (s, 9 H); 31P NMR
(121 MHz, CDCl3) δ 29.14; 13C NMR (75 MHz, CDCl3) δ 144.8,
128.1, 127.0, 126.6, 67.5, 65.4, 62.0 (m), 61.3 (d, JC−P = 6.2 Hz), 28.7,
22.8, 16.6 (m), 14.9; HRMS m/z (ESI) calcd for C20H35NO4P [M +
H]+ 384.2298, found 384.2297.
Diethyl {1-[tert-Butyl(1-phenylethoxy)amino]cyclopentyl}-
phosphonate (5). CuBr (117.63 mg, 0.82 mmol, 0.55 equiv), Cu
powder (104.22 mg, 1.64 mmol, 1.1 equiv), benzene (2 × 3 mL),
N,N,N′,N′,N″-pentamethyldiethylenetriamine (0.17 mL, 0.82 mmol,
0.55 equiv), 5• (436 mg, 1.49 mmol, 1 equiv), and bromoethylbenzene
(309.49 mg, 1.64 mmol, 1.1 equiv) were used. After flash
chromatography (gradient, PE/AcOEt, from 0 to 50% AcOEtby 5%
1
step), 5 was obtained in 63% yield as a colorless oil (377 mg): H
NMR (300 MHz, CDCl3) δ 7.31−7.14 (m, 5H), 5.04 (s, 1H), 4.27−
3.91 (m, 4H), 2.12 (s, 4H), 1.60 (s, 4H), 1.47 (d, J = 6.6 Hz, 3H),
1.31−1.13 (m, 15H); 31P NMR (121 MHz, CDCl3) δ 31.49, 30.64;
13C NMR (75 MHz, CDCl3) δ 144.3, 127.8, 126.8, 126.6, 81.5 (d, JC−P
= 175.5 Hz), 75.8, 73.7, 61.7 (d, JC−P = 57.4 Hz), 37.6, 36.4 (d, JC−P
=
4.4 Hz), 35.1, 29.8, 24.6, 22.2, 16.3 (t, J = 6.5 Hz); HRMS m/z (ESI)
calcd for C21H37NO4P [M + H]+ 398.2455, found 398.2452.
Diethyl {1-[tert-Butyl(1-phenylethoxy)amino]cyclohexyl}-
phosphonate (6). CuBr (111.9 mg, 0.78 mmol, 0.55 equiv), Cu
powder (99.1 mg, 1.56 mmol, 1.1 equiv), benzene (2 × 3 mL),
N,N,N′,N′,N″-pentamethyldiethylenetriamine (0.16 mL, 0.78 mmol,
0.55 equiv), 6• (435 mg, 1.42 mmol, 1 equiv), and bromoethylbenzene
(288.7 mg, 1.56 mmol, 1.1 equiv) were used. After flash
chromatography (gradient, PE/AcOEt, from 0 to 20% AcOEt by 3%
1
step), 6 was obtained in 68% yield as a colorless oil (401 mg): H
NMR (400 MHz, CDCl3) δ 7.28−7.16 (m, 5H), 4.87 (q, J = 6.5 Hz,
1H), 4.18−4.01 (m, 4H), 2.68−1.46 (m, 10H), 1.39 (d, J = 10.6 Hz,
3H), 1.33 (t, J = 7.0 Hz, 6H), 1.18 (s, 9H); 31P NMR (162 MHz,
CDCl3) δ 31.03; 13C NMR (101 MHz, CDCl3) δ 146.6, 145.4, 127.9
(d, JC−P = 33.4 Hz), 126.7, 126.2, 85.3 (d, JC−P = 38.2 Hz), 68.1, 66.8,
64.0 (d, JC−P = 52.1 Hz), 61.2 (d, JC−P = 7.6 Hz), 33.9 (d, JC−P = 54.5
Hz), 32.6 (d, JC−P = 19.1 Hz), 30.2, 26.7, 25.1 (d, JC−P = 57.8 Hz),
21.3, 16.5 (d, JC−P = 6.0 Hz); HRMS m/z (ESI) calcd for C22H39NO4P
[M + H]+ 412.2611, found 412.2607.
Benzyl 2-{[1-(Diethoxyphosphoryl)cyclopentyl](1-phenylethoxy)-
amino}-2-methylpropanoate (7). CuBr (57 mg, 0.40 mmol, 0.55
equiv), Cu powder (51 mg, 0.80 mmol, 1.1 equiv) N,N,N′,N′,N″-
pentamethyldiethylenetriamine (83 μL, 0.40 mmol, 0.55 equiv), 7•
(300 mg, 0.73 mmol, 1 equiv), bromoethylbenzene (148 mg, 0.80
mmol, 1.1 equiv), and benzene (2 × 3 mL) were used. After flash
chromatography (gradient, PE/AcOEt, from 0 to 100% AcOEt), 7 was
1
obtained in 80% as a colorless oil (301 mg): H NMR (300 MHz,
CDCl3) δ 7.22 (m, 10H), 5.03 (m, 3H), 4.02 (m, 4H), 2.06 (m, 4H),
1.39 (d, J = 6.5 Hz, 3H), 1.29 (m, 10H), 1.19 (m, 6H); 31P NMR (121
MHz, CDCl3) δ 30.38; 13C NMR (75 MHz, CDCl3) δ 176.5, 143.6,
136.1, 128.6, 128.2, 128.0, 127.3, 74.6, 68.3 (m), 66.5, 61.8 (m), 26.3,
25.1 (m), 21.7 (m), 16.6 (d, JC−P = 3.8 Hz), 16.5 (d, JC−P = 3.9 Hz);
HRMS m/z (ESI) calcd for C28H41NO6P [M + H]+ 518.2666, found
518.2665.
Methyl 2-{[1-(Diethoxyphosphoryl)cyclohexyl](1-phenylethoxy)-
amino}-2-methylpropanoate (8). CuBr (193 mg, 1.35 mmol, 0.55
F
DOI: 10.1021/acs.joc.7b00541
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
equiv), Cu powder (172 mg, 2.70 mmol, 1.1 equiv), N,N,N′,N′,N″-
pentamethyldiethylenetriamine (282 μL, 1.35 mmol, 0.55 equiv),
nitroxide 8• (860 mg, 2.45 mmol, 1 equiv), bromoethylbenzene (499
mg, 2.7 mmol, 1.1 equiv), and benzene (2 × 3 mL) were used. After
flash chromatography (gradient, PE/AcOEt, from 0 to 100% AcOEt),
8 was obtained in 72% yield as a colorless oil (791 mg): 1H NMR (400
MHz, CDCl3) δ 7.16 (m, 5H), 5.00 (q, J = 6.6 Hz, 1H), 4.07 (m, 4H),
3.61 (m, 3H), 2.47−0.92 (m, 22H), 1.27 (t, J = 7.1 Hz, 3H); 31P NMR
(162 MHz, CDCl3) δ 29.49; 13C NMR (101 MHz, CDCl3) δ 177.9,
144.7, 127.8, 126.9, 126.3, 82.9, 70.4, 68.1 (d, JC−P = 136.3 Hz), 61.5
(d, JC−P = 7.7 Hz), 61.4 (d, JC−P = 7.7 Hz), 51.9, 32.8, 31.7, 26.32,
24.09, 21.34, 16.51 (d, JC−P = 6.0 Hz); HRMS m/z (ESI) calcd for
C23H39NO6P [M + H]+ 456.2510, found 456.2513.
Benzyl 2-{[1-(Diethoxyphosphoryl)cyclohexyl](1-phenylethoxy)-
amino}-2-methylpropanoate (9). CuBr (67 mg, 0.46 mmol, 0.55
equiv), Cu powder (59 mg, 0.93 mmol, 1.1 equiv), N,N,N′,N′,N″-
pentamethyldiethylenetriamine (80 mg, 0.46 mmol, 0.55 equiv),
nitroxide 9• (360 mg, 0.84 mmol, 1 equiv), bromoethylbenzene (172
mg, 0.93 mmol, 1.1 equiv), and benzene (2 × 3 mL) were used. After
flash chromatography (gradient, PE/AcOEt, from 0 to 100% AcOEt),
9 was obtained in 56% yield as a colorless oil (250 mg): 1H NMR (300
MHz, CDCl3) δ 7.16 (m, 10H), 4.96 (m, 3H), 4.03 (m, 4H), 2.48−
0.98 (m, 19H), 1.25 (t, J = 7.0 Hz, 3H), 1.20 (t, J = 7.0 Hz, 3H); 31P
NMR (121 MHz, CDCl3) δ 29.51; 13C NMR (75 MHz, CDCl3) δ
177.2, 144.7, 136.0, 128.6, 128.5, 128.1, 128.0, 127.8, 126.8, 126.2,
83.0, 70.6, 68.8, 67.2 (d, JC−P = 5.7 Hz), 66.7, 61.4 (m), 26.5, 21.2,
16.5 (d, JC−P = 5.9 Hz); HRMS m/z (ESI) calcd for C29H43NO6P [M
+ H]+ 532.2823, found 532.2824.
REFERENCES
■
(1) Nitroxide Mediated Polymerization: From Fundamentals to
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[C]0
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ln
= −kdt
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Theranostic agents against cancer. Mol. Pharmaceutics 2014, 11, 2412−
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⎟
Ea
RT
kd = 2.4 × 1014 × exp −
2419.
⎜
⎝
⎠
́
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Massot, P.; Mellet, P.; Parzy, E.; Thiaudiere, E. Alkoxyamines: a new
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.7b00541.
■
(13) Bagryanskaya, E. G.; Marque, S. R. A. In Nitroxide Mediated
Polymerization: From Fundamentals to Applications in Materials Sciences;
Gigmes, D., Ed.; RSC Polymer Chemistry Series 19; Royal Society of
Chemistry: London, 2016; Chapter 2, p 45, and references cited
therein.
S
Physical characterizations of 7″−9″ and 3−9 (PDF)
́
(14) Bremond, P.; Koïta, A.; Marque, S. R. A.; Pesce, V.; Roubaud,
V.; Siri, D. Chemically Triggered C−ON Bond Homolysis of
Alkoxyamines. Quaternization of the Alkyl Fragment. Org. Lett.
2012, 14, 358−361.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: g.audran@univ-amu.fr.
*E-mail: sylvain.marque@univ-amu.fr.
■
́
(15) Audran, G.; Bagryanskaya, E.; Bagryanskaya, I.; Bremond, P.;
Edeleva, M.; Marque, S. R. A.; Parkhomenko, D.; Tretyakov, E.;
Zhivetyeva, S. CON Bond Homolysis of Alkoxyamines Triggered by
Paramagnetic Copper(II) Salts. Inorg. Chem. Front. 2016, 3 (11),
1464−1472.
ORCID
Sylvain R. A. Marque: 0000-0002-3050-8468
Notes
The authors declare no competing financial interest.
(16) Audran, G.; Bagryanskaya, E.; Bagryanskaya, I.; Edeleva, M.;
Marque, S. R. A.; Parkhomenko, D.; Tretyakov, E.; Zhivetyeva, S.
Zinc(II) Hexafluoroacetylacetonate complexes of alkoxyamines: NMR
and kinetic investigations. First step for a new way to prepare hybrid
materials. ChemistrySelect 2017, 2, 3584−3593.
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A.; Tsentalovich, Y. P.; Bagryanskaya, E. G. pH-Sensitive C−ON bond
homolysis of alkoxyamines of imidazoline series with multiple
ionizable groups as an approach for control of Nitroxide Mediated
Polymerization. J. Org. Chem. 2011, 76, 5558−5573.
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Nitroxide Mediated radical Polymerization of styrene. J. Polym. Sci.,
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ACKNOWLEDGMENTS
■
The authors thank Aix-Marseille University and CNRS for
financial support. ANR provided funding for this project (ANR-
14-CE16-0023-01) and the A*MIDEX project (ANR-11-IDEX-
0001-02) funded by the “Investissements d’Avenir” French
Government program, managed by the French National
Research Agency (ANR). P.N. thanks the Ministere de la
Recherche du Gabon and campus France for the Ph.D. grant.
The authors thank Dr. Monnier for help with HRMS.
G
DOI: 10.1021/acs.joc.7b00541
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Article
(19) Audran, G.; Nkolo, P.; Bikanga, R.; Marque, S. R. A.; Roubaud,
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(43) Only data reported in refs 20 and 24 are used. Data reported in
other articles concern mainly cyclic nitroxides and do not significantly
change the coefficients of eq 1.
(44) Because of the shift from sp2 hybridization in the nitroxide to
sp3 hybridization in the alkoxyamine at the N atom, which is the major
geometrical change occurring in the nitroxyl fragment, the angles
change but the general arrangement around the nitroxyl moiety is not
modified.
́
(45) Audran, G.; Bosco, L.; Nkolo, P.; Bikanga, R.; Bremond, P.;
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Macromol. Chem. Phys. 2004, 205, 973−978.
(46) The occurrence of this interaction, and consequently the
magnitude of the hyperfine coupling constant, depends both on the
spin population on the nitrogen atom (ρNπ) and on dihedral angle θ
(25) Studer, A.; Harms, K.; Knoop, C.; Muller, C.; Schulte, T. New
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sterically hindered nitroxides for the Living Free Radical Polymer-
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between the C−P bond and the singly occupied molecular orbital
π
(SOMO) (Figure 5) on the nitrogen atom of the nitroxyl moiety. ρN
,
(26) Lagrille, O.; Cameron, N. R.; Lovell, P. A.; Blanchard, R.; Goeta,
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the spin population on the nitrogen atom of the nitroxyl moiety, is
proportional to aN. B0 is the transfer of the spin population through
the spin polarization process, and B1 is the transfer of the spin
population through the hyperconjugation process. In general, B0 is
very small and can be neglected (see ref 47). Values of B1 are
dependent on the atom or on the function at position β (see refs 47
and 48).
(47) Janzen, E. G.; Coulter, G. A.; Oehler, U. M.; Bergsma, J. P.
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(27) In this Ph.D. work, 3• was prepared using the spin-trapping
approach affording a very low yield, and the crude was used for the
preparation of 3 in low yields: Acerbis, S. Ph.D. Thesis, Synthes
etude de nouveaux nitroxides et alcoxyamines. Application en
Polymerisation Radicalaire Controlee. Universite de Provence,
Marseille, France, 2003.
̀
e et
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́
́
(28) Bagryanskaya, E. G.; Marque, S. R. A. Scavenging of organic C-
centered radicals by nitroxides. Chem. Rev. 2014, 114, 5011−5056.
(29) Bertin, D.; Gigmes, D.; Marque, S. R. A.; Tordo, P. Polar, steric,
and stabilization effects in alkoxyamines C−ON bond homolysis: A
multiparameter analysis. Macromolecules 2005, 38, 2638−2650.
(30) Lin, C. Y.; Marque, S. R. A.; Matyjaszewski, K.; Coote, M. L.
Linear-free energy relationships for modeling structure−reactivity
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(48) Gerson, F.; Huber, W. In Electron Spin Resonance Spectroscopy of
Organic Radicals; Wiley-VCH: Weinheim, Germany, 2003.
(49) The most upward-deviating data in refs 20 and 24 are due to the
intramolecular hydrogen bonding effect, and the other data are due to
a configuration effect.
(50) Fischer, H.; Kramer, A.; Marque, S. R. A.; Nesvadba, P. Steric
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(51) The leveled steric effect is also observed for alkoxyamines
complying with item (i). In that case, Es must be smaller than −6 and
the nitroxyl fragment is either a large ring affording an easy change in
conformation or a substituent that can change the steric fingerprint
(Janus group). See refs 20, 24, and 50.
(31) N = 239; R2 = 0.95; t = 99.99%; F0.01 = 210. See ref 20.
(32) This relationship was developed only for the released phenethyl
radical.
(33) ri(X) is the individual steric constant for group X, with i being
the rank related to the value of r(X), i.e., its size [the more negative
r(X) is, the larger X is].
(34) It is assumed that a = b = 1 and ε = 0 for the conventional steric
effect and a = b = 1 and ε = −EBs when the leveled steric effect occurs.
Fragment A is in general ascribed to the fragment carrying either the
largest group or the H atom at position β.
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(38) Charton, M. Electrical effect substituent constants for
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H
DOI: 10.1021/acs.joc.7b00541
J. Org. Chem. XXXX, XXX, XXX−XXX