Effect of the tether length upon Truce-Smiles rearrangement reactions

Article abstract of DOI:10.1002/poc.3742

This report examines the effect of substrate design upon the Truce-Smiles rearrangement, an intramolecular nucleophilic aromatic substitution reaction. The length of the molecular spacer that tethers the carbanion nucleophile to the substituted benzene ri

Full text of DOI:10.1002/poc.3742

Received: 5 April 2017
DOI: 10.1002/poc.3742
Revised: 3 June 2017
Accepted: 8 June 2017
R E S E A R C H A R T I C L E
Effect of the tether length upon Truce‐Smiles rearrangement
reactions
David Fuss | Yu Qi Wu | Michael R. Grossi | Joshua W. Hollett
| Tabitha E. Wood
Department of Chemistry, The University of
Abstract
Winnipeg, Winnipeg, Manitoba, Canada
This report examines the effect of substrate design upon the Truce‐Smiles rearrange-
ment, an intramolecular nucleophilic aromatic substitution reaction. The length of
the molecular spacer that tethers the carbanion nucleophile to the substituted
benzene ring was found to have a strong influence on the ability of the substrate
to undergo the reaction successfully. Our experimental results show highest yield
of desired aryl migration product for substrates designed with a 3‐atom tether, which
proceed through a 5‐membered spirocyclic intermediate. The results are interpreted
in comparison with a survey of Truce‐Smiles rearrangements described in the
literature and found to be consistent. Computational studies support the observed
reactivity trend and suggest an explanation of a favorable combination of ring strain
and electrostatic repulsion leading to optimal reactivity of the substrate designed
with a 3‐atom tether. Comparison of our results with trends for related ring‐closing
reactions illustrate the unique electrostatic features of the system studied herein.
Correspondence
Tabitha E. Wood, Department of Chemistry,
The University of Winnipeg, 515 Portage
Avenue, Winnipeg, Manitoba, Canada R3B
2E9.
Email: te.wood@uwinnipeg.ca
Funding information
Natural Sciences and Engineering Research
Council of Canada, Grant/Award Number:
402608‐2011‐RGPIN and 435374‐2013‐
RGPIN
KEYWORDS
aromatic substitution, cyclization, nucleophilic substitution, rearrangement, synthetic methods
1 | INTRODUCTION
further defining this reaction and transforming it into a syn-
thetically reliable method.[4] Our previous paper reported
results supporting the SNAr mechanism for this reaction
and specified the substrate scope with respect to electron‐
withdrawing substituents on the phenyl ring.[4d] Herein, we
examine the variable of the molecular spacer that links the
carbanion nucleophile to the aryl ring. Due to the spirocyclic
nature of the intermediate, wherein the size of the transient
ring is determined by the length of the spacer, this variable
would be predicted to have great influence on the reaction.
The Truce‐Smiles rearrangement is a relatively unknown and
unexploited intramolecular nucleophilic aromatic substitu-
tion reaction (Scheme 1). The reaction has great synthetic
potential due to its ability to efficiently form a sp2‐sp3
carbon‐carbon bond at the expense of an easily installed
carbon‐heteroatom bond, while simultaneously revealing a
heteroatom‐containing functional group. There is some
discrepancy between the modern definition[1] of the Truce‐
Smiles rearrangement and the definition originally intro-
duced by Truce,[2] with respect to mechanism and substrate
structure. The reaction is now recognized as a carbanion
variation of the Smiles rearrangement, and it is accepted that
it should therefore normally proceed through a SNAr
mechanism.[1]
2 | RESULTS AND DISCUSSION
The experimental substrates 1a‐e (Scheme 2) were designed
based upon a molecular structure that has been found to read-
ily undergo the proposed aryl migration reaction.[4d] The
inclusion of a strongly electron‐withdrawing nitro substituent
at the 4‐position of the phenyl ring provides requisite
A review of the literature indicates that the substrate
scope of the Truce‐Smiles rearrangement is versatile, and
not entirely defined.[3] There has been renewed interest in
J Phys Org Chem. 2017;e3742.
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Copyright © 2017 John Wiley & Sons, Ltd.
1 of 11
https://doi.org/10.1002/poc.3742

2 of 11
FUSS ET AL.
SCHEME 1 General reaction for the
Truce‐Smiles rearrangement
SCHEME 2 Substrates and products examined in this study
stabilization of the delocalized hexadienyl anion σ‐adduct,
known as a Meisenheimer adduct. The substrates incorporate
a nitrile functional group to lend stabilization to the proposed
α‐carbanion,[5] such that the nucleophile can be generated
using standard bases in an organic solvent. The ether
linkage provides an easily installed tether between the
intended α‐cyano carbanion nucleophile and the aryl ring
ipso‐carbon electrophile. Compounds 1a, 1c,[4d] 1d, and 1e
were prepared using the standard Williamson ether
synthesis method using 4‐nitrophenol and the corresponding
ω‐haloalkylnitrile. Compound 1b was prepared using
the alternate strategy of conjugate addition of 4‐nitrophenol
to acrylonitrile because attempted synthesis using 3‐
bromopropanenitrile resulted exclusively in elimination
products.
using organolithium reagents,[6] we returned to further inves-
tigate our previous experiments[4d] involving the addition of
lithium bis(trimethylsilyl)amide (LiHMDS) as a base to a
50 mM solution of 1c in anhydrous tetrahydrofuran (THF)
cooled at 0°C under inert atmosphere followed by passive
warming to 20°C for 4 hours. The reaction is quenched
through the addition of dilute aqueous acid. It became appar-
ent that our previous efforts with these conditions had failed
to optimize the reaction conditions with respect to equiva-
lents of LiHMDS (Table 1, entries 1‐5) and that we had
naively used a substoichiometric amount of base.[4d] The
optimal stoichiometry was found to be 2.5 equivalents of
LiHMDS relative to substrate 1c (Table 1, entry 4). An opti-
mal conversion and isolated yield of 87% 2c was achieved by
increasing the reaction time to 20 hours (Table 1, entry 6).
These newly optimized conditions of addition of 2.5
equivalents of LiHMDS to a 50 mM solution of aryl ether
substrate in anhydrous THF cooled at 0°C under inert atmo-
sphere followed by passive warming to 20°C for 20 hours
were tried with each of the other substrates 1a, 1b, 1d, and
Conditions to promote Truce‐Smiles rearrangement of
substrates 1a‐e were investigated using compound 1c as a
model substrate. We have previously shown that 1c is an
excellent substrate for this aryl migration reaction.[4d]
Inspired by the success of related aryl migration reactions
TABLE 1 Optimization of Truce‐Smiles rearrangement of substrate 1c using LiHMDS as a base in tetrahydrofuran
Entry
Equivalents
Time, h
Ratio of 1c:2ca
% yield 2
1
1.0
4
95:<5
0
2
3
4
5
6
1.5
2.0
2.5
3.0
2.5
4
4
48:52
46:54
14:86
11:89
<5:95
43
n.d.
80
4
4
n.d.
87
20
adetermined by 1H NMR spectrum integrations of crude reaction mixtures

FUSS ET AL.
3 of 11
1e, yet failed to yield the rearranged products. Further, the
rearrangement of these substrates was attempted using
similar reaction conditions except for increasing temperatures
to 40°C and 60°C. Increased temperature failed to yield prod-
ucts 2a, 2b, or 2e (Table 2, entries 1, 3, and 9) but did
however afford rearrangement product 2d in 48% yield
(Table 2, entry 7) at 40°C. The crude reaction mixtures of
1a and 1e were composed of recovered substrate. The crude
reaction mixture of 1b initially only yielded 4‐nitrophenol;
however, careful evaporation of the reaction mixture revealed
acrylonitrile as a second product, suggesting elimination
(assumedly by an E1cB mechanism) as the preferred reaction
path of the α‐cyano carbanion formed in situ (Scheme 3).
We have previously determined optimized reaction condi-
tions for the rearrangement of substrate 1c, using sodium
hydride as a base.[4d] These conditions were established to
be addition of 1.5 equivalents of sodium hydride to a
50 mM solution of 1c in anhydrous N,N‐dimethylformamide
(DMF) at 0°C under inert atmosphere followed by passive
warming to 20°C over 4 hours.[4d] We applied these prior
established optimized conditions to attempt the rearrange-
ment of 1a, 1b, 1d, and 1e when the newly optimized
LiHMDS in THF conditions failed to achieve rearrangement.
These NaH/DMF conditions failed to yield the rearranged
products. We have previously shown that increasing the reac-
tion temperature decreases reaction time for substrate 1c;[4d]
therefore, the rearrangement of substrates 1a, 1b, 1d, and
1e were attempted using reaction temperatures of 40°C and
60°C and at increasing lengths of time up to 20 hours.
Increasing reaction temperature and/or time failed to yield
product 2a, 2b, or 2e (Table 2, summarized as entries 2, 4,
and 10). The crude reaction mixtures of 1a and 1e were
composed of recovered substrate. The crude reaction
mixture of 1b again showed elimination products acryloni-
trile and 4‐nitrophenol. The rearranged product 2d was
isolated from reaction mixtures for 1d, showing the greatest
yield, 51%, when the reaction was conducted at 60°C for
20 hours (Table 2, entry 8). The remainder of the reaction
mixture constituted hydrolysis product 4‐nitrophenol and
recovered 1d.
These experiments therefore illustrated highest Truce‐
Smiles rearrangement reactivity for substrate 1c, which
proceeds through
a
5‐membered ring spirocyclic
Meisenheimer intermediate, and lower reactivity for
substrate 1d, which proceeds through a 6‐membered ring
intermediate. No apparent reactivity was observed for
substrates 1a and 1e, which proceed through 3‐membered
ring, and 7‐membered ring intermediates, respectively.
The ability to assess the reactivity of substrate 1b via
Truce‐Smiles rearrangement was confounded by the
competing reactivity of the substrate via the E1cB elimina-
tion mechanism and therefore cannot be determined by
these experiments.
A review of the literature reveals putative Truce‐Smiles
rearrangements that have proceeded through 3‐, 4‐, 5‐, and
6‐membered ring spirocyclic intermediates. Although there
have been no reported systematic studies of the effect of the
spacer structure, the incomplete data from this literature
survey reveal that substrates providing a 5‐membered ring
intermediate constitute the largest portion of the successful
TABLE 2 Truce‐Smiles rearrangement of alkanenitrile 4‐nitrophenyl ether substrates
Entry
1
n
Solvent
Base
Equivalents
Temperature, °C
Time, h
% yield 2
1
a
0
THF
LiHMDS
2.5
60
20
0
2
a
b
b
c
0
1
1
2
2
3
3
4
4
DMF
THF
DMF
THF
DMF
THF
DMF
THF
DMF
NaH
1.5
2.5
1.5
2.5
1.5
2.5
1.5
2.5
1.5
60
60
60
20
20
40
60
60
60
20
20
20
20
4
0
0
3
LiHMDS
NaH
4
0
5
LiHMDS
NaH
87
86
48
51
0
6
c
7
d
d
e
LiHMDS
NaH
20
20
20
20
8
9
LiHMDS
NaH
10
e
0
Abbreviations: DMF, dimethylformamide; THF, tetrahydrofuran.

4 of 11
FUSS ET AL.
SCHEME 3 Proposed elimination
mechanism for substrate 1b
rearrangement reactions. This is consistent with the reactivity
trend that we have revealed in the experiments reported here.
Examples of Truce‐Smiles rearrangements occurring
through the formation of 3‐membered ring spirocyclic
Meisenheimer intermediates (Figure 1).are rare.[7] It could
be argued that the ring contractions observed as part of the
domino Ugi‐Smiles/Truce‐Smiles reactions reported by El
Kaïm et al are specially favored by stable conformations
accessible to the bicylic substrate, formed in situ, that are
not easily accessed by typical acylic substrates.[7a] The inter-
mediacy of an ionic benzyllithium species, in keeping with
the intramolecular SNAr mechanism of the Truce‐Smiles
rearrangement, is favored by Dudley's research group for
their reported 1,2‐aryl migration of 2‐benzyloxypyridines;
however, they also concede that a radical mechanism, in
keeping with the [1,2]‐Wittig reaction, cannot be entirely
ruled out.[7b]
Arguments for the involvement of 4‐membered ring
spirocyclic Meisenheimer intermediates are more compelling
than those for 3‐membered ring spirocyclic Meisenheimer
intermediates; however, examples of Truce‐Smiles rearrange-
ments occurring through the formation of 4‐membered ring
spirocyclic Meisenheimer intermediates are also relatively
uncommon[8] in comparison to examples occurring through
the formation of 5‐membered ring spirocyclic Meisenheimer
intermediates, which are most common in the literature.
These include the reactions reported by Dohmori and col-
leagues[9] and the research groups of Truce,[10] Drozd,[11]
Hirota,[12, 4a] Snape,[4c] and Wood,[4d] but also many iso-
lated,[13] seemingly adventitious, reactions reported. The so‐
called[14] “Clayden rearrangement” 1,4‐aryl migration reac-
tion[6,15] could be viewed as proceeding through an interme-
spirocyclic Meisenheimer intermediates such as would be
invoked for explaining the rearrangement of substrate 1d in
this report. However, examples of Truce‐Smiles rearrange-
ments occurring through the formation of 6‐membered ring
spirocyclic Meisenheimer intermediates are relatively
uncommon.[16, 4b] Generally, the structural linker connecting
the electrophilic aryl ring to the nucleophilic carbanion center
in the examples tend to be more unsaturated than in
substrates that favor smaller ring spirocyclic Meisenheimer
intermediates, perhaps suggesting that the fewer degrees of
rotational freedom of the atoms in the linker permits the
formation of these less common, larger intermediate rings.
To our knowledge, there are no reported examples of
Truce‐Smiles rearrangement reactions that have been
proposed to proceed through a spirocyclic Meisenheimer
intermediate with greater than 6 atoms in one ring.
The influence of various structural design features of sub-
strate molecules upon intramolecular rate enhancement has
not been extensively studied for SNAr reactions, in compari-
son to certain other reaction mechanisms. The addition step
of the SNAr reaction mechanism could be classified as an
exo‐trig process by extension of Baldwin's Rules for ring‐
forming reactions,[17] which would therefore predict no
disfavored ring sizes for the various substrates studied here.
Bimolecular nucleophilic substitution (SN2) is an example
of a mechanism for which the effect of ring size in ring‐clos-
ing reactions that has been examined in relatively greater
detail, likely due to its prevalent implication in many
enzyme‐catalyzed reaction mechanisms. The term “effective
molarity” has been used for several decades to make compar-
isons between intramolecular and intermolecular chemical
processes, and it is a useful parameter for evaluating the
effect of substrate structural variables upon an intramolecular
reaction.[18] Effective molarity is a quantitative parameter
defined as the ratio of the rate of a given intramolecular reac-
tion and its corresponding intermolecular analog following
an identical mechanism (kintra/kinter). Factors that influence
the extremely wide range (<1 to >1010) of observed effective
molarities for SN2 ring‐closing reactions have been shown to
include reaction type (particularly the nature of the nucleo-
phile), solvent, and ring size.[18] Comparison of the reaction
rate data for various different SN2 ring‐closing reactions,[18]
such as the formation of cycloalkanes and lactones, have
given the same trend for the ease of ring formation:
5 > 3 > 6 > 7 ≈ 4, which is similar to the trend observed
in our study of the Truce‐Smiles rearrangement, despite the
differences between the SN2 and the SNAr reaction
diate highly related to
Meisenheimer intermediate.
a
5‐membered spirocyclic
The relative stability of 6‐membered saturated carbocy-
clic rings supports the existence of 6‐membered ring
FIGURE 1 Putative 3‐membered ring spirocyclic Meisenheimer
intermediates from literature[7]

FUSS ET AL.
5 of 11
mechanisms. One major discrepancy is our lack of any
observed reactivity for the substrate, which proceeds through
a 3‐membered ring spirocyclic intermediate.
with ortho‐substituents of the aryl ring destabilizes 6‐ and
7‐membered spirocyclic intermediates relative to 5‐mem-
bered.[20] This last factor is one that could be predicted to
exert a strong influence especially on spirocyclic ring
systems[22] formed as the Meisenheimer intermediates in
intramolecular SNAr reactions due to the sterically congested
quaternary spirocenter.
An extension of these conclusions from the Smiles rear-
rangement studies to the reaction system that is the focus of
our study is complicated by the numerous differences
between the 2 systems studied. However, the observed trend
in reactivity is consistent between these fundamentally
related reactions. One particularly complicating factor to the
extension of Bernasconi and Crampton's hypotheses is the
presence of nitro substituents in the ortho‐positions flanking
the electrophilic site of reaction on the aryl ring in every sub-
strate (3a‐c) studied. Therefore, the argument that steric strain
between spacer atoms and ortho‐substituents is tainted by
electronic effects since distortion of the nitro groups' orienta-
tions will also result in destabilization of the intermediate due
to less efficient overlap of orbitals in the delocalized
cyclohexadienyl anion system.
Since the unique aspects of the Truce‐Smiles reaction
system that we have studied herein complicate the compari-
son of our results with similar results in the literature, we
have performed a computational study of the reaction path-
way of the α‐cyano carbanions derived from substrates 1a‐e
in their conversion to the corresponding spirocyclic
Meisenheimer intermediates, to elucidate the origins of the
observed trend in reactivity. The existence of the
Meisenheimer intermediate as a stable species has been
established from our previous 1H NMR spectroscopy experi-
ments showing the in situ formation of the intermediate in
DMSO‐d6 with NaH.[4d] To further understand the influence
of the spacer group length, we located the transition state
structures that produce the spirocyclic intermediates from
the α‐cyano carbanions by a SNAr mechanism as well as
the transition state structures that lead to the production of
the rearranged aryl migration product of the Truce‐Smiles
rearrangement. There has been one previous report of a com-
putational study into the potential energy surface of a Truce‐
Smiles rearrangement reaction pathway.[8d] Unfortunately,
the dissimilarity between the structures of the intermediates
involved in the previously studied reaction and the computa-
tional methods used with those used in this study preclude
comparison of the results.
It has been proposed that the strong dependency of SN2
ring‐closing reaction rates upon the size of the ring can be
attributed to factors influencing 2 major aspects of the reac-
tion: ring strain and the probability of the electrophile and
nucleophile reacting.[19] Factors that influence ring strain
include those that put constraints on molecular geometries
in a cyclic structure including steric strain, torsional strain,
and angle strain. Factors that influence the probability of
the nucleophile and electrophile reacting include those that
affect the proximity and orientation of the 2 functional
groups, including the increasing distance between the 2 with
increasing chain length, conformational flexibility in the
molecular spacer that links the 2, and the gem‐dialkyl effect.
These 2 sets of factors are independent of each other yet
result in the observed typical trend of the 5‐membered ring
being the easiest to form as a result of a compromise between
the trend in the proximity of nucleophile and electrophile typ-
ically decreasing with increasing ring size for
conformationally flexible systems comprised mostly of atoms
with tetrahedral geometries and the ring strain that would cor-
respondingly see a minimum value at the 6‐membered ring.
The increased stability of, and therefore ease of forming,
5‐membered ring spirocyclic intermediates over 6‐ and 7‐
membered is a trend that has been observed for the Smiles
rearrangement, which is believed to follow a SNAr mecha-
nism in analogy to the Truce‐Smiles rearrangement.[20] These
studies showed that, for the Smiles rearrangement system
shown in Scheme 4, spectrophotometrically determined rate
constants for the formation of the spirocyclic Meisenheimer
intermediates 4a‐c showed large decreases on increasing the
ring size from 5 to 6 or 7 members, while the deprotonation
step and the rate of the spirocyclic ring opening were largely
unaffected. The authors applied the previously seen argu-
ments of proximity and ring strain by hypothesizing that
increasing ring size was resulting in increasingly more nega-
tive activation entropies due to the increased rotational free-
dom of the larger rings and that this was combining with
the trend in ring strain, assuming that this spirocyclic ketal
ring series followed the observed trend for cycloalkanes[21]
with a minimum at the 6‐membered ring, to produce a trend
where the 5‐membered spirocyclic intermediate 4a showed
the greatest reaction rate for ring closure. It was also argued
that steric strain caused by interaction of the spacer atoms
SCHEME 4 Smiles rearrangement
reactions studied by Crampton and
Bernasconi[20]

6 of 11
FUSS ET AL.
For our computational study, stationary points (minima
equatorial position (conformer A) was found to have
ΔG‡ = 30.8 kJ·mol−1, which was the lowest for any of the
substrates studied here. The calculated activation energies
for the conversion of the α‐cyano carbanions derived from
substrates 1a‐e to their corresponding spirocyclic
cyclohexadienyl anion intermediate via the SNAr pathway
correspond to relative rates giving a trend in reactivity of
1c >> 1d ≈ 1a > 1e >> 1b (ie, 5 >> 6 ≈ 3 > 7 >> 4) at
25°C. Although we observed no reactivity for substrate 1a,
the trend is still generally in qualitative agreement with the
reactivity observed experimentally, bearing in mind that mea-
suring the rearrangement reactivity of 1b was potentially
obscured by the competing elimination reaction shown in
Scheme 3.
The calculated potential energy surface shown in Figure 2
provides an illustration of the experimentally observed stabil-
ity of the Meisenheimer intermediate derived from substrate
1c,[4d] in that this structure is a thermodynamic minimum.
The calculated potential energy surface also provides support
for the observed high conversion of the Meisenheimer inter-
mediate by the forward direction to break the C–O bond pref-
erentially (isolated yield of 87%), this reaction having a lower
ΔG‡ barrier than the reverse, unproductive, C–C bond break-
ing reaction.
and saddle points) on the determined at the ωB97X‐D/6‐
31 + G(d,p) level of theory,[23] with solvation in DMF simu-
lated using the SMD solvent model.[24] The connection of
each transition state structure to its corresponding minima
(reactant and product) was determined by an intrinsic reac-
tion coordinate calculation, and each stationary point was
verified by harmonic frequency analysis. Energies were
corrected for zero‐point and thermodynamic effects at
298 K.[25] The influence of ion pairing was not investigated.
The Truce‐Smiles rearrangement of substrates 1a‐e is a
stereogenic reaction; however, the products are enantiomeric
and so calculation of the 2 reaction scenarios would be redun-
dant. For each substrate the pathways to the formation of 2
conformational isomeric spirocyclic intermediates, referred
to here as conformer A and conformer B, were calculated
individually. Each of these pairs of 2 conformers can be
viewed as differing by the orientation of the cyano group
(ranging between an axial or equatorial orientation at the
extreme) on the conformationally flexible cycloalkane ring
of the spirocyclic intermediate. The results obtained from
these calculations are summarized in Table 3, with a repre-
sentative potential energy surface for the reaction of 1c to
yield 2c shown in Figure 2. The transition state for the forma-
tion of the C–C bond during the Truce‐Smiles rearrangement
of substrate 1c when the cyano group is oriented in an
The trend in free energies of reaction, ΔG, follows that of
the free energies of activation, ΔG‡ (Table 3). Due to the
TABLE 3 Calculated thermodynamic and kinetic parameters for α‐cyano carbanions derived from substrates 1a‐e to their corresponding
spirocyclic cyclohexadienyl anion Meisenheimer intermediate via the SNAr pathway
Relative Rate
at T= 25°C
9 × 10−5
Reactant
1a
n
Conformer
ΔG, kJ·mol−1
ΔG‡, kJ·mol−1
ΔH‡, kJ·mol−1
ΔS‡, J·mol−1·T−1
−16
0
A
+10
54
+49
B
+11
+34
+34
−51
−44
−36
−32
−37
−31
54
83
83
31
34
59
54
61
58
+48
+80
+80
+28
+29
+47
+44
+48
+47
−20
−10
−10
−10
−18
−39
−35
−46
−37
8 × 10−5
9 × 10−10
8 × 10−10
1
1b
1c
1d
1e
1
2
3
4
Aa
Bb
Ac
Bd
Aa
Bb
Aa
Bb
0.2
1 × 10−5
7 × 10−5
5 × 10−6
2 × 10−5
aCyano group occupies pseudo‐equatorial position.
bCyano group occupies pseudo‐axial position.
cCyano group occupies equatorial position.
dCyano group occupies axial position.

FUSS ET AL.
7 of 11
FIGURE 2 Calculated potential energy
surface for the reaction of the α‐cyano
carbanion derived from 1c via the Truce‐
Smiles rearrangement with 2 possible
Meisenheimer intermediate conformers: (A)
cyano group equatorial and (B) cyano group
axial
relative simplicity in which the Meisenheimer adduct is
formed from the carbanion (ie, the formation of a single
C–C bond), the transition state structures resemble the struc-
ture of the α‐cyano carbanion intermediates quite closely.
Therefore, we believe that trends observed in both energies
regarding spacer length, n, are due to the same phenomena
and will be discussed as such. The apparently anomalous
increase in ΔG and ΔG‡ upon increasing the spacer length
from n = 0 to n = 1 is due to the exceptional stability of
1b. Unlike 1a and 1c‐1e, 1b can decompose by transfer of
the negative charge to the O and formation of a CC double
bond, as indicated by Scheme 3. The increased stability of
the carbanion by negative hyperconjugation[26] attained
through resonance with the pseudo‐eliminated structure
(supported by increased C–O and decreased C–C bond
lengths, decreased C–O bond order,[27] and LMO analysis[28]
[see Supporting Information]) lowers its energy with respect
to the transition structure and intermediate compared to the
reactants of other spacer lengths.
The ΔG values for 1c are lower than those for 1a and 1b,
and this is explained by the decrease in ring strain of the
intermediate as the size of the ring is increased. However,
upon going from a 5‐membered ring (1c) to a 6‐membered
ring (1d), a system with arguably less or the same amount
of strain, ΔG increases. The overall trend (1a‐1e) in ΔG
and ΔG‡ is reproduced when considering only enthalpies or
internal energies with no thermal correction, which means
entropy does not play a significant role. The increase in ΔG
from 1c to 1d is explained by considering the relative
stability of the spirocyclic intermediates. Compared to the
5‐membered ring intermediate of 1c, there may be less strain
in the 6‐membered ring of the 1d intermediate, but there is
also more electrostatic repulsion between the oxygen (O)
and the cyano‐substituted carbon (CCN), adjacent to the
spirocarbon (Cspiro), and the para‐nitrophenyl group where
the negative charge resides. Interaction energies between
fragments of molecules were obtained for gas phase
ωB97X‐D/6‐31 + G(d,p) structures using the localized
molecular orbital energy decomposition analysis (LMO‐
EDA)[29] by Su and Li. The increase in electrostatic repulsion
is due to the larger CCN–Cspiro–O bond angle in the 1d inter-
mediate of 108.4°, compared to 101.4° in the 1c intermediate,
which puts these groups in closer proximity to each other.
Therefore, the optimal spacer length of n = 2, which corre-
sponds to a 5‐membered ring, is a result of a balance between
ring strain and electrostatic repulsion between the 2 rings.
3 | CONCLUSION
This study has filled its intended goal of continuing our
systematic survey of the substrate scope of the Truce‐Smiles
rearrangement. The length of the molecular tether connecting
the carbanion nucleophile to the electrophilic aromatic ring
determines the size of one ring in the spirocyclic
Meisenheimer intermediates of the Truce‐Smiles rearrange-
ment. Literature reports of successful rearrangement reac-
tions imply a trend that substrates bearing a tether that
results in a 5‐membered ring spirocylic intermediate are
favored substrates. Our experimental results support this
trend showing highest yields for product 2c, which we have
previously shown to proceed through the proposed SNAr
spirocyclic Meisenheimer intermediate incorporating a 5‐
membered ring,[4d] and for product 2d, which is proposed
to proceed through a 6‐membered ring intermediate, by
analogy. The reactivity of substrate 1b via the Truce‐Smiles
rearrangement could not be measured due to a competing
elimination reaction. Computational studies derived a series
of calculated relative reaction rates for the formation of
spirocyclic Meisenheimer intermediates from substrates 1a‐
e that also support the trend implied by the literature,
predicting an optimal reaction rate for substrate 1c and
decreasing as the variable ring in the proposed spirocyclic
Meisenheimer intermediate becomes either larger or smaller

8 of 11
FUSS ET AL.
than a 5‐membered ring. Examination of the structures of the
calculated transition states derived from substrates 1a‐e sug-
gest that the factors of ring strain, as measured by enthalpy
of activation, and electrostatic repulsion between the 2 rings
of the Meisenheimer adduct, combine to produce the
observed trend in reactivity. Steric interactions between the
ortho‐substituents of the aromatic ring and atoms in the
tether, which has been proposed for related Smiles rearrange-
ment ring‐size reactivity trends, do not seem to exert a strong
influence upon the reactivity of substrates 1a‐e in the Truce‐
Smiles rearrangement studied here.
layer from the extraction was dried, filtered, and
concentrated.
4.1.2 | 2‐(4‐Nitrophenoxy)acetonitrile (1a)
General procedure A: The product was prepared from
chloroacetonitrile (0.63 mL). Flash column chromatography
(30% ethyl acetate, 70% hexanes) yielded the product as a
light yellow crystalline solid (1.26 g, 71%). CAS: 33901‐
46‐1; mp 70‐73°C (lit.[30] 73‐75°C); TLC Rf = 0.34 (30%
ethyl acetate, 70% hexanes); IR (KBr, thin film) vmax
= 3090, 2941, 2831, 2258, 1601, 1507, 1331, 1216,
850 cm−1 1H NMR (400 MHz, CDCl3) δ = 8.29 (d,
;
J = 6.9 Hz, 2H), 7.09 (d, J = 6.9 Hz, 2H), 4.88 (s, 2H)
ppm (consistent with lit.[30]); 13C NMR (100 MHz, CDCl3)
δ = 161.0 (arom. C1), 143.5 (arom. C4), 126.3 (arom. C3,
C5), 115.1 (arom. C2, C6), 114.1 (C≡N), 53.7 (OCH2)
ppm; LRMS (ESI) m/z (relative intensity) = 201.0 (100%);
HRMS (ESI) m/z: [M + Na]+ calcd for C8H6N2O3:
201.0271, found: 201.0266.
4 | EXPERIMENTAL
General methods
All glassware used for Truce‐Smile rearrangement reactions
was flame‐dried under a vacuum and reactions were run
under an inert atmosphere of nitrogen. All reagents and
solvents were commercial grade. All organic layers collected
from extractions were dried using anhydrous MgSO4. Thin
layer chromatography (TLC) was performed using alumi-
num‐backed silica gel plates (250 μm), and flash column
chromatography used 230‐400 mesh silica. Compounds were
visualized using UV light (λ = 254 nm) and either
phosphomolybdic acid or vanillin solutions. Melting points
were determined using a capillary melting point apparatus
and are reported uncorrected. FTIR spectra were recorded
of samples as a thin film on a KBr plate (transmission).
NMR spectra were acquired on a 400 MHz instrument.
Chemical shifts are reported relative to tetramethylsilane as
4.1.3 | 3‐(4‐Nitrophenoxy)propanenitrile (1b)
The product was prepared using a procedure modified from
literature.[31] To a round‐bottom flask fitted with a reflux
condenser was added 4‐nitrophenol (1.38 g, 10 mmol), acry-
lonitrile (66 mL, 1.0 mol, 100 equiv.), anhydrous potassium
carbonate (0.069 g, 0.5 mmol, 0.05 equiv.), and tert‐butanol
(0.10 mL, 1.0 mmol, 0.1 equiv.). The reaction mixture was
heated with stirring to the boiling point of acrylonitrile using
a heating block, and reflux was maintained for 8 hours.
Anhydrous potassium carbonate was added (0.069 g,
0.5 mmol, 0.05 equiv.). Reflux was maintained for 28 hours.
Phosphoric acid (85 wt% in H2O, 0.09 mL, 0.8 mmol, 0.08
equiv.) was added and the mixture stirred for 0.5 hours. The
mixture was concentrated, diluted with toluene (100 mL),
washed with 1 M HCl(aq) (30 mL), and washed with 1 M
NaOH(aq) (2 × 30 mL). The organic layer from the extraction
was dried, filtered, and concentrated. Flash column chroma-
tography (40% ethyl acetate, 60% hexanes) yielded the prod-
uct as a light yellow crystalline solid (0.29 g, 17%). CAS:
69333‐42‐2; mp 61‐63°C (lit.[32] 78‐79°C, lit.[33] 53.1°C);
TLC Rf = 0.50 (40% ethyl acetate, 60% hexanes); IR (KBr,
thin film) vmax = 3089, 2941, 2838, 2258, 1599, 1509,
1
an internal standard set to δ 0.00 ppm for H and relative to
the CDCl3 solvent residual as an internal standard set to δ
77.16 ppm for 13C. Multiplicities are reported as apparent
(app), broad (br), singlet (s), doublet (d), triplet (t), quartet
(q) and combinations thereof, or multiplet (m). HRMS data
are obtained by electrospray (ESI) using an ion trap.
4.1 | Preparation of alkanenitrile 4‐
nitrophenoxy ether substrates 1a, b, d, e
4.1.1 | General procedure A
To a round‐bottom flask fitted with a reflux condenser was
added 4‐nitrophenol (1.53 g, 11 mmol, 1.1 equiv), anhydrous
potassium carbonate (1.38 g, 10 mmol, 1.0 equiv.), ω‐
haloalkanenitrile (10 mmol), and acetone (30 mL). The reac-
tion mixture was heated with stirring to the boiling point of
acetone using a heating block, and reflux was maintained
for 20 hours. The solution was concentrated, diluted with
ethyl acetate (50 mL), washed with 1 M HCl(aq) (30 mL),
and washed with 1 M NaOH(aq) (2 × 30 mL). The organic
1343, 1264, 852 cm−1 1H NMR (400 MHz, CDCl3)
;
δ = 8.24 (d, J = 7.0 Hz, 2H), 7.00 (d, J = 7.0 Hz, 2H),
4.30 (t, J = 6.3 Hz, 2H), 2.91 (t, J = 6.3 Hz, 2H) ppm (con-
sistent with lit.[32]); 13C NMR (100 MHz, CDCl3) δ = 162.6
(arom. C1), 142.4 (arom. C4), 126.1 (arom. C3, C5), 116.7
(C≡N), 114.7 (arom. C2, C6), 63.3 (OCH2), 18.6 (CH2CN)
ppm (consistent with lit.[32]); LRMS (ESI) m/z (relative inten-
sity) = 215.0 (100%); HRMS (ESI) m/z: [M + Na]+ calcd for
C9H8N2O3: 215.0427, found: 215.0426.

FUSS ET AL.
9 of 11
and brought to a temperature for an amount of time as
described in Table 2. The solution was neutralized at room
temperature with 1 M HCl(aq), diluted with ethyl acetate
(30 mL), washed with 1 M HCl(aq) (15 mL), and washed with
water (2 × 20 mL). The organic layer from the extraction was
dried, filtered, and concentrated.
4.1.4 | 5‐(4‐Nitrophenoxy)pentanenitrile (1d)
General procedure A: The product was prepared from 5‐
bromovaleronitrile (1.2 mL). Flash column chromatography
(30% ethyl acetate, 70% hexanes) yielded the product as a
light yellow crystalline solid (2.09 g, 95%). CAS: 104296‐
36‐8; mp 31‐33°C (lit.[34] 35‐36°C); TLC Rf = 0.34 (30%
ethyl acetate, 70% hexanes); IR (KBr, thin film) vmax
= 3114, 2974, 2834, 2258, 1509, 1409, 1321, 853 cm−1
;
4.3 | General procedure C
1H NMR (400 MHz, CDCl3) δ = 8.21 (d, J = 7.1 Hz, 2H),
6.95 (d, J = 7.1 Hz, 2H), 4.11 (t, J = 5.8 Hz, 2H), 2.47 (t,
J = 6.9 Hz, 2H), 2.05‐1.98 (m, 2H), 1.94‐1.87 (m, 2H)
ppm; 13C NMR (100 MHz, CDCl3) δ = 163.7 (arom. C1),
141.4 (arom. C4), 125.8 (arom. C3, C5), 119.4 (C ≡ N),
114.4 (arom. C2, C6), 67.6 (OCH2), 27.9 (OCH2CH2), 22.2
(CH2CN), 16.9 (CH2CH2CN) ppm; LRMS (ESI) m/z (rela-
tive intensity) = 244.1 (100%); HRMS (ESI) m/z: [M + Na]
To a round‐bottom flask was added the rearrangement sub-
strate (1) (1.0 mmol), and the flask was evacuated and
backfilled with nitrogen three times. Anhydrous DMF
(20 mL) was added, and the solution was cooled with stirring
using an ice water cooling bath. Sodium hydride (60% disper-
sion in oil) (0.060 g, 1.5 mmol, 1.5 equiv.) was added, and
low temperature was maintained for 10 minutes. The reaction
mixture was removed from the cooling bath and brought to a
temperature for an amount of time as described in Table 2.
The solution was neutralized at room temperature with 1 M
HCl(aq), diluted with ethyl acetate (30 mL), washed with
1 M HCl(aq) (15 mL), and washed with water (2 × 20 mL).
The organic layer from the extraction was dried, filtered,
and concentrated.
+
calcd for C11H12N2O3: 243.0740, found: 243.0731.
4.1.5 | 6‐(4‐Nitrophenoxy)hexanenitrile (1e)
General procedure A: The product was prepared from 6‐
bromohexanenitrile (1.3 mL). Flash column chromatography
(30% ethyl acetate, 70% hexanes) yielded the product as a
light yellow crystalline solid (2.04 g, 87%). CAS: 100135‐
38‐4; mp 33‐35°C (lit.[34] 38‐39°C); TLC Rf = 0.40 (30%
ethyl acetate, 70% hexanes); IR (KBr, thin film) vmax
= 3115, 3086, 2946, 2871, 2245, 1515, 1339, 1264,
4.3.1 | 4‐Hydroxy‐2‐(4‐nitrophenyl)
butanenitrile (2c)
1045 cm−1 1H NMR (400 MHz, CDCl3) δ = 8.20 (d,
;
General procedure B: Flash column chromatography (40%
ethyl acetate, 60% hexanes) yielded the product as a yellow
oil (0.179 g, 87%). CAS: 1791439‐23‐0
J = 9.3 Hz, 2H), 6.94 (d, J = 9.3 Hz, 2H), 4.08 (t,
J = 6.2 Hz, 2H), 2.41 (t, J = 6.9 Hz, 2H), 1.92‐1.85 (m,
2H), 1.81‐1.63 (m, 4H) ppm; 13C NMR (100 MHz, CDCl3)
δ = 163.9 (arom. C1), 141.3 (arom. C4), 125.8 (arom. C3,
C5), 119.5 (C≡N), 114.4 (arom. C2, C6), 68.2 (OCH2),
28.1 (OCH2CH2), 25.1 (CH2CH2CN), 25.0 (OCH2CH2CH2),
17.0 (CH2CN) ppm; LRMS (ESI) m/z (relative inten-
sity) = 257.1 (100%); HRMS (ESI) m/z: [M + Na]+ calcd
for C12H14N2O3: 257.0897, found: 257.0889.
4.3.2 | 5‐Hydroxy‐2‐(4‐nitrophenyl)
pentanenitrile (2d)
General procedure B: Flash column chromatography (50%
ethyl acetate, 50% hexanes) yielded the product as a
colourless oil (0.105 g, 48%). mp <25°C; TLC Rf = 0.21
(50% ethyl acetate, 50% hexanes); IR (KBr, thin film) vmax
= 3090, 2941, 2258, 1599, 1509, 1332, 1110, 850 cm−1
;
4.1.6 | Preparation of rearrangement prod-
ucts 2c, d
1H NMR (400 MHz, CDCl3) δ = 8.27 (d, J = 8.7 Hz, 2H),
7.56 (d, J = 8.7 Hz, 2H), 4.05 (t, J = 7.5 Hz, 1H), 3.75‐
3.74 (m, 2H), 2.11‐2.05 (m, 2H), 1.81‐1.74 (m, 2H), 1.37
(br s, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ = 147.9
(arom. C4), 143.0 (arom. C1), 128.5 (arom. C2, C6), 124.5
(arom. C3, C5), 119.6 (C ≡ N), 61.8 (CH2OH), 37.2
(CHCN), 32.6 (CH2CH2OH), 29.7 (CH2CH2CH2OH) ppm;
LRMS (ESI) m/z (relative intensity) = 243.1 (100%); HRMS
(ESI) m/z: [M + Na]+ calcd for C11H12N2O3: 243.0740,
found: 243.0744.
4.2 | General procedure B
To a round‐bottom flask was added the rearrangement sub-
strate (1) (1.0 mmol), and the flask was evacuated and
backfilled with nitrogen 3 times. Anhydrous THF (20 mL)
was added, and the solution was cooled with stirring using
an ice water cooling bath. Lithium bis(trimethylsilyl)amide
solution (1M in THF) (1.0 mL g, 1.0 mmol, 1.0 equiv.) was
added, and low temperature was maintained for 10 minutes.
The reaction mixture was removed from the cooling bath
General procedure C: Flash column chromatography
(50% ethyl acetate, 50% hexanes) yielded the product as a
colourless oil (0.112 g, 51%).

10 of 11
FUSS ET AL.
[11] a) V. N. Drozd, Int. J. Sulfur Chem. 1973, 8, 443; b) V. N. Drozd,
Dokl. Akad. Nauk SSSR 1966, 169, 107.
ACKNOWLEDGEMENTS
Financial support for this work was provided by the Natural
Sciences and Engineering Research Council (NSERC) of
Canada (402608‐2011‐RGPIN, 435374‐2013‐RGPIN), the
University of Winnipeg, and the Government of Manitoba
Career Focus Program. We thank Westgrid and Compute
Canada for supercomputing resources. We also would like
to thank Mr Xiao Feng (Dalhousie University Maritime Mass
Spectrometry Laboratories) for obtaining the mass spectra of
all synthesized compounds.
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Hollett JW, Wood TE. Effect of the tether length upon
Truce‐Smiles rearrangement reactions. J Phys Org
Chem. 2017;e3742. https://doi.org/10.1002/poc.3742
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