Reactivity in the nucleophilic aromatic substitution reactions of pyridinium ions

Article abstract of DOI:10.1039/c4ob00946k

The "element effect" in nucleophilic aromatic substitution reactions (S_NAr) is characterized by the leaving group order, L = F > NO₂ > Cl ≈ Br > I, in activated aryl substrates. A different leaving group order is observed in the subs

Full text of DOI:10.1039/c4ob00946k

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Reactivity in the nucleophilic aromatic substitution
reactions of pyridinium ions†
Cite this: Org. Biomol. Chem., 2014,
12, 6175
Jeannette T. Bowler,a Freeman M. Wong,a Scott Gronert,*b James R. Keeffe*a and
Weiming Wu*a
The “element effect” in nucleophilic aromatic substitution reactions (SNAr) is characterized by the leaving
group order, L = F > NO2 > Cl ≈ Br > I, in activated aryl substrates. A different leaving group order is
observed in the substitution reactions of ring-substituted N-methylpyridinium compounds with piperidine
in methanol: 2-CN ≥ 4-CN > 2-F ∼ 2-Cl ∼ 2-Br ∼ 2-I. The reactions are second-order in [piperidine], the
mechanism involving rate determining hydrogen-bond formation between piperidine and the substrate-
piperidine addition intermediate followed by deprotonation of this intermediate. Computational results
indicate that deprotonation of the H-bonded complex is probably barrier free, and is accompanied by
simultaneous loss of the leaving group (E2) for L = Cl, Br, and I, but with subsequent, rapid loss of the
leaving group (E1cB-like) for the poorer leaving groups, CN and F. The approximately 50-fold greater
reactivity of the 2- and 4-cyano substrates is attributed to the influence of the electron withdrawing
cyano group in the deprotonation step. The results provide another example of β-elimination reactions
poised near the E2-E1cB mechanistic borderline.
Received 7th May 2014,
Accepted 24th June 2014
DOI: 10.1039/c4ob00946k
www.rsc.org/obc
Introduction
aDepartment of Chemistry and Biochemistry, San Francisco State University,
San Francisco, CA 94132, USA. E-mail: keeffe@sfsu.edu, wuw@sfsu.edu,
The nucleophilic aromatic substitution (SNAr) reactions of acti-
vated substrates follow a two-step, addition–elimination mech-
anism and have been well studied.1–8 They also continue to
draw attention as a synthetic method.9 An order of halide
leaving group (L) abilities, F > Cl ≈ Br > I, is often found in
studies of rates of SNAr reactions of activated aryl halides. This
is commonly referred to as the “element effect”, and is con-
sidered evidence for a mechanism in which the first step,
addition of the nucleophile, is rate controlling.10–12 The
factors that can account for the element effect and for SNAr
reactivity in general are manifold, and have been thoroughly
discussed in the literature.10–14 These factors include polar,
polarizability, solvation, and negative hyperconjugative
effects as well as polarity reversal of the C–L bond from reac-
tant to transition state in the case of ArCl and ArBr compared
to ArF.
In related studies, we have observed that 2-substituted
pyridinium compounds are good substrates for SNAr reactions
due to their electron-deficient nature.15,16 In this report, we
examine experimentally the SNAr reactions of ring-substituted
N-methylpyridinium substrates with piperidine (Fig. 1).17 In
addition, intermediates and transition states associated with
the rate determining step were explored computationally.
sgronert@vcu.edu
bDepartment of Chemistry, Virginia Commonwealth University, 1001 W. Main Street,
Richmond, Virginia 23284, USA
†Electronic supplementary information (ESI) available: Full ref. 34; 1H and 13C
NMR data as well as mass spectrometry (MS) data for characterization of
N-methyl-2-piperidinopyridinium products; calculated electronic energies and zero
point vibrational energies for substrates are given in Table S1; calculated elec-
tronic energies, zero point vibrational energies and imaginary frequencies for
the transition states and products for the addition of piperidine to substrates are
in Table S2; calculated enthalpies of isomerization of 2-substituted to 4-substi-
tuted substrates and addition transition states are in Table S3; calculated enthal-
pies of solvation for substrates and transition states for the addition of
piperidine to 2- and 4-substituted N-methylpyridinium ions, Table S4; calculated
C–L and C–Nu distances in the transition states for addition of piperidine to
2- and 4-substituted N-methylpyridinium ions are in Table S5; calculated activation
enthalpies for addition of piperidine to 2- and 4-substituted N-methylpyridinium
ions are in Table S6; calculated npa charges for substrates and transition states
for the addition of piperidine to substrates, Table S7; calculated energies and
zero point vibrational energies for the hydrogen-bonded complexes formed by
addition of piperidine to 2-substituted N-methylpyridinium ions and electronic
energies for the subsequent proton transfer event, Table S8; enthalpies of associ-
ation forming the H-bonded complexes between piperidine and the addition
intermediate are in Table S9 along with activation enthalpies for proton transfer
within this complex; enthalpies of association forming the H-bonded complexes
from initial substrates and two piperidines are in Table S10, and Cartesian coor-
dinates for computed structures in this study are in Table S11. See DOI: 10.1039/
c4ob00946k
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lower, but are partly compensated by more negative activation
entropies.1
The reactivity of the cyanide substrates is noteworthy. There
is precedent for this result in our previous study of the basic
hydrolysis of ring-substituted N-methylpyridinium ions.15
Additionally Thompson and Huestis have recently observed
loss solely of cyanide in SNAr reactions even in the presence of
halides at reactive positions.19 We were surprised by these
results, and considered the possibility that the cyano sub-
strates react by a radical mechanism, e.g., the SRN1 pathway,
since the cyano group is well known to stabilize free
radicals.20,21 We examined the effect of two different radical
scavengers, 2,2,6,6-tetramethylpiperidine oxide (TEMPO) and
2,6-di-t-butylphenol, on the rate of reaction of piperidine with
all substrates, but found no inhibition at two or more scaven-
ger concentrations. Hence, if radical intermediates are formed
they are paired or otherwise inaccessible to the scavengers.
However, the greater reactivity of the cyano substrates in these
SNAr reactions is can perhaps be understood in a qualitative
way on the basis of the greater total electron withdrawing
effect of the cyano group relative to halogens as determined by
NMR studies on ring-substituted N-methylpyridinium ions.22
This effect must be present in the rate-controlling step, shown
below to be hydrogen-bond formation and proton transfer
from the addition complex to a second piperidine molecule,
activated by the electron-withdrawing cyano group.
Fig. 1 The overall result for reaction of piperidine with 2-substituted-
N-methylpyridinium+ substrates.
Experimental results and discussion
Third-order rate constants and activation parameters for the
reaction of nucleophilic piperidine with 2-cyano-, 4-cyano-,
2-fluoro-, 2-chloro-, 2-bromo- and 2-iodo-N-methylpyridinium
substrates in methanol are listed in Table 1. All the reactions
are first-order in substrate and second-order in piperidine, and
yield the corresponding piperidino-N-methylpyridinium ions
as the only products.
Negative entropies of activation are found throughout the
series, but are seen to be quite variable in magnitude, the
TΔS‡ term contributing from 0.9 to 6.6 kcal mol−1 to the free
energy of activation. The source(s) of the observed activation
entropies are complex, and probably include differential sol-
vation of reactants and transition states. For comparison we
call attention to the fact that ΔS‡ values for a host of SN2 pro-
cesses are known to be highly variable.18 The rate constant Mechanism
differences for the halide substrates are very small, and are
The reaction mechanism could, in principle, be termolecular,
associated with irregular changes in the enthalpies and entro-
pies of activation. The cyano compounds are exceptional in
that their reactivities are greater than those of the halides.
Unlike the reactions of piperidine with 2,4-dinitrophenyl
halides there is no evidence of an “element effect”.
but it is much more likely that more than one bimolecular
step is involved. Given the second-order dependence of the
rate on piperidine concentration we conclude that step 1,
nucleophilic addition forming intermediate I-1 is not rate con-
trolling for these SNAr reactions, but that a subsequent step,
deprotonation of I-1 with or without departure of nucleofuge
L−, both paths requiring a second piperidine molecule, deter-
mines the overall rate (see Fig. 2). The results presented so far
also explain the absence of the element effect, an effect identi-
fied with the addition step.10–14 An additional pertinent result
is that there is no observation of an intermediate species at
zero-time as monitored by 1H NMR or by UV spectrometry.
Thus we treat the addition intermediate, I-1, as a reactive inter-
mediate subject to the steady-state approximation, and formu-
late the rate law as eqn (1). Taking k−1 ≫ k2[pip] then leads to
eqn (2)
Reactivity
From Table 1 we see that reactivity is fairly high although less
so than for the reactions of piperidine with 2,4-dinitrophenyl
halides for which experimental activation enthalpies are much
Table 1 Kinetic parameters for nucleophilic aromatic substitution reac-
tions of 2-substituted N-methylpyridinium substrates with piperidine in
methanola
Overall third-
2
kexp ¼ k1k2½pipꢀ =ðkꢁ1 þ k2½pipꢀÞ
ð1Þ
ð2Þ
order rate
constant
Relative
rate at
25 °C
ΔG‡
ΔH‡
ΔS‡ (cal
Substrates (25° C, M−2 s−1
)
(kcal mol−1
)
(kcal mol−1
)
mol−1 K−1
)
2
kexp ¼ k1k2½pipꢀ =k
ꢁ1
2-Cyano
2-Fluoro
2-Chloro
2-Bromo
2-Iodo
1.26 × 10−3
2.02 × 10−5
2.10 × 10−5
2.67 × 10−5
2.62 × 10−5
8.30 × 10−4
∼50
∼1
20.6
22.5
22.4
22.3
22.3
20.9
18.4
19.8
16.3
20.9
15.7
20.0
−7.5
−9.1
Loss of the leaving group could occur from I-1 in a one-step
E2 process, or in two steps: deprotonation of the piperidinium
NH+ moiety giving intermediate I-2, followed by loss of the
leaving group in step 3. Step 2, deprotonation to form inter-
mediate I-2, could be rate controlling. Alternatively, the rate
controlling step could be expulsion of the leaving group from
I-2 (step 3).
∼1
−20.6
−4.8
∼1
∼1
−22.2
−2.9
4-Cyano
∼30
a Piperidine concentration is 0.5 M whereas initial substrate concentration is
10 mM. Kinetic parameters were calculated from temperature dependent
studies using the Eyring equation.
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Fig. 2 Proposed mechanism for reaction of piperidine with pyridinium substrates. A hydrogen-bonded complex between I-1 and the second piper-
idine is implied, but not shown.
Bernasconi has presented a thorough and persuasive ana-
Computational results and discussion
The elimination step(s)
lysis of the kinetic behavior of reactive tetrahedral intermedi-
ates.4 He concludes that in protic solvents the general-base
catalyzed breakdown of such intermediates proceeds by rate- Computation provides useful information regarding the
controlling deprotonation of the addition intermediate, I-1 in details of the elimination step(s). The calculated structures for
the reaction studied here. It might seem counter-intuitive that I-2 differ in significant ways as the leaving group is changed.
proton transfer between electronegative atoms, two nitrogens For the 2-cyano, 4-cyano, and 2-fluoro versions of I-2 the
in this case, can be rate controlling. However, as Bernasconi heterocyclic rings are puckered, the C–L bonds are slightly
points out, all that is necessary is that the subsequent step be longer than normal length for sp3 carbon, especially the C–F
much faster than the reverse of the deprotonation step. He bond, and, importantly, the N–C2 distances within the hetero-
also provides evidence that in general the secondary amine cycle are longer (1.460, 1.506, and 1.492 Å, respectively) than
moiety in addition intermediate I-2 is less basic than the those in the original aromatic substrates (1.352, 1.340, and
amine itself, hence that the reverse of step 2 will be endoergic. 1.329 Å, respectively). The latter lengths reflect the degree of
Finally, loss of L− is accompanied by re-aromatization of the aromaticity in the ring, and tell us that in these three cases I-2
heterocyclic ring, further accelerating the product-forming is an ordinary molecule, not aromatic, albeit with some
elimination in step 3. Thus we favor the pathway shown in “hyperaromatic” character, particularly for L = F.26 In contrast
Fig. 2 with step 2, hydrogen-bond formation between I-2 and I-2 for the 2-chloro and 2-bromo versions show flat heterocyclic
piperidine and/or deprotonation of the addition intermediate, rings, very long C–L bonds (2.949 and 3.045 Å, respectively)
rate controlling, whether accompanied by leaving group departure and short N–C2 bonds within the heterocycle: 1.365 and
(E2) or not (E1cB-like) and in the latter case with step 3, loss 1.367 Å, respectively; compare with 1.342 and 1.343 Å for the
of the leaving group, fast compared with step 2. Fig. 2 is a substrates. In fact for L− = chloride and bromide I-2 can be
summary of this proposal. The activating effect of the cyano considered an ion-pair complex between product and L−,
group can now be understood as strengthening the acidity of formed by departure of L− from I-2, and not a stable covalent
the NH proton in the addition complex, I-1, thereby favoring neutral. This assessment is supported by the large negative
formation of the hydrogen-bonded complex preceding the npa charges on the chlorine and bromine in I-2: −0.95 in both
proton-transfer event, step 2. These details and the mechanism cases. Structures constrained to have shorter C–Cl and C–Br
of the elimination step(s) will be further considered below. bonds were of higher energy than those with the long C–L
In summary we propose that as the second, basic piperidine bonds.
reactant approaches I-1 it undergoes hydrogen-bond formation
On the basis of these differences we propose that the
with the δ-positive NH proton of the nucleophilic piperidine, elimination stage for the poorer leaving groups, CN and F,
that nitrogen becoming thereby more nucleophilic, thus uses an E1cB-like mechanism (probably the E1cB irreversible
bonding more strongly to electrophilic carbon-2. Proton trans- variant) while for the chloro, bromo and iodo leaving
fer to the basic piperidine leads directly and irreversibly to a groups the elimination mechanism is E2, enforced by
hydrogen-bonded complex between piperidinium cation and the instability of I-2 in those cases. We do not have experi-
neutral intermediate I-2, thence to rapid loss of the leaving mental evidence regarding the exclusion of a reversible E1cB
group and ultimate product formation. Thus, the mechanism mechanism. A classic isotopic exchange experiment is not
is an example of catalysis by preassociation,23–25 and the feasible for two reasons, either of which obviates the experi-
greater reactivity of the cyano substrates is then associated ment. In the first place the N–H proton of piperidine
with this set of events.
exchanges essentially “immediately” with solvent methanol.27
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Fig. 3 (a) Proton-transfer transition state for deprotonation of the 2-bromo hydrogen-bonded complex; (b) the transition state for the 2-fluoro
complex; (c) the neutral deprotonated adduct (I-2) for the 2-bromo reaction; (d) the neutral I-2 for the 2-fluoro reaction.
Secondly, the pertinent intermediate, I-2, is too short-lived to
These results add an example to the study of the mechanis-
be observed.
tic borderline in β-elimination reactions, a topic of continuing
Transition states and their precursor hydrogen-bonded interest and activity.28,29 It is easy to imagine that a leaving
complexes were also found for the deprotonation of I-1 by group, intermediate in nucleofugacity between fluoride and
piperidine (see ESI†). The energies of the transition states and chloride, would provide a mechanistically ambiguous case
the H-bonded complexes are so similar as to suggest that the with, perhaps, a metastable neutral intermediate (I-2) and an
exothermic proton transfer event does not have a significant almost barrier-free departure of the leaving group.
enthalpic barrier. Thus, we propose that the elimination stage
of the overall reaction includes the critical free energy barrier
(i.e., is in fact rate controlling), starting with hydrogen bond
formation and continuing with a facile proton transfer and
Summary
leaving group departure, the latter either concurrent with
proton transfer (L = Cl, Br, I) or subsequent to it (L = F, CN).
The loss of the leaving group from I-2 is expected to be rapid
for F and CN, relative to reprotonation,4 supporting our sug-
gestion that the elimination mechanism is probably the
E1cBIRR variant in those two cases. Fig. 3 shows calculated
structures for two of the proton-transfer transition states and
the corresponding neutral deprotonation products, I-2. We see
that in I-2, L = Br, that the C–Br distance is very large com-
pared with that in the ts. This result suggests that proton
transfer and loss of leaving group, though very likely concerted
for the better leaving groups, are not closely coupled.
The nucleophilic aromatic substitution reactions of 2-substi-
tuted N-methylpyridinium ions with piperidine in methanol
do not proceed through rate controlling addition of the
nucleophile, but by rate controlling deprotonation of the
addition intermediate by a preassociation mechanism. Thus,
the “element effect”10,11 commonly observed for activated SNAr
reactions in which nucleophilic addition is rate controlling, is
not observed. The reactivity order is 2-cyano ≥ 4-cyano >
2-fluoro ∼ 2-chloro ∼ 2-bromo ∼ 2-iodo. The elimination of the
leaving group, L−, is proposed to occur by a piperidine-cata-
lyzed E1cBIRR-like mechanism for L = F and CN, but by a con-
certed E2 mechanism for the better leaving groups, L = Cl, Br
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and I. The data suggest that the cyano group’s ability to
enhance the stability of the preassociation complex is a key
driver in the higher substitution rates for these substrates.
J. Chem. Soc., 1963, 4389; D. A. Brown and J. R. Raju,
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4 C. F. Bernasconi, Acc. Chem. Res., 1978, 11, 147–152.
5 F. Terrier, Nuclear Aromatic Displacement: The Influence of
the Nitro Group, VCH, New York, 1991.
6 F. Terrier, Nucleophilic Aromatic Substitution, Wiley,
Singapore, 2013.
Experimental section
2-Cyano-N-methylpyridinium iodide as well as the 4-cyano-,
2-fluoro-, 2-chloro-, and 2-iodo iodides as well as 2-bromo-
pyridinium bromide were prepared according to literature
procedures.22,30–32 The rate constants of the reactions were
determined under pseudo-first order conditions (large excess
7 M. Makosza, Chem. Soc. Rev., 2010, 39, 2855–2868.
8 E. Buncel, J. M. Dust and F. Terrier, Chem. Rev., 1995, 95,
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9 K. Walsh, H. F. Sneddon and C. J. Moody, ChemSusChem,
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of piperidine) by following the disappearance of substrate and 10 J. F. Bunnett, E. W. Garbisch Jr. and K. M. Pruitt, J. Am.
appearance of products using NMR spectroscopy. The concen- Chem. Soc., 1957, 79, 385–391.
trations of the substrates and products were measured by the 11 J. F. Bunnett, J. Am. Chem. Soc., 1957, 79, 5969–5974.
integration of signals of the aromatic protons.
12 J. F. Bunnett and W. D. Merritt, J. Am. Chem. Soc., 1957, 79,
5967.
13 G. Bartoli and P. E. Todesco, Acc. Chem. Res., 1977, 10, 125.
14 N. A. Senger, B. Bo, Q. Cheng, J. R. Keeffe, S. Gronert and
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Computational methods
Structures were built and optimized at lower levels using the 15 S. Huang, F. M. Wong, G. T. Gassner and W. Wu, Tetra-
MacSpartan Plus software package,33 then optimized at HF/
hedron Lett., 2011, 52, 3960–3962.
6-31+G* then MP2/6-31+G* using the Gaussian 03 quantum 16 R. C. Tan, J. Q. T. Vien and W. Wu, Bioorg. Med. Chem.
mechanical programs.34 Frequency and zero-point energy
Lett., 2012, 22, 1224–1225.
values were calculated at the HF/6-31+G* level, and the ZPVE 17 The 4-halopyridinium substrates were not investigated due
values scaled as recommended by Scott and Radom.35 All
structures reported here represent electronic energy minima,
to the instability of 4-halopyridines: A. Roe and
G. F. Hawkins, J. Am. Chem. Soc., 1947, 69, 2443–2444.
and all structures identified as transition states (tss) have one 18 Activation entropies in nucleophilic substitutions (SN2)
imaginary frequency, that corresponding to the reaction coor-
dinate for the reaction event. The optimized MP2 geometries
for substrates and transition states were used to obtain ener-
have been shown to be sensitive to a variety of reaction con-
ditions. See: F. G. Bordwell and W. T. Brannen Jr., J. Am.
Chem. Soc., 1964, 86, 4645–4650.
gies with the Polarizable Continuum Model (PCM), solvent = 19 A. D. Thompson and M. P. Huestis, J. Org. Chem., 2013, 78,
methanol (see ESI†).
762–769.
20 The bond dissociation energy of the C–H bond in aceto-
nitrile is smaller than that in methane by ten kcal mol−1
.
See: J. Berkowitz, G. B. Ellison and D. Gutman, J. Phys.
Chem., 1994, 98, 2744–2764.
Acknowledgements
This investigation was supported by the National Institutes of 21 M. T. Pirnot, D. A. Rankic, D. B. C. Martin and
Health, Grant SC1 GM095419 and by a grant from the Center D. W. C. MacMillan, Science, 2013, 339, 1593–1596.
for Computing for Life Sciences at SFSU (WW). J.T.B. was sup- 22 S. Huang, J. C. S. Wong, A. K. C. Leung, Y. M. Chan,
ported by a Beckman Scholarship. We thank Dr Robert Yen for
obtaining the mass spectra. The Mass Spectrometry Facility
L. Wong, M. R. Fernendez, A. K. Miller and W. Wu, Tetra-
hedron Lett., 2009, 50, 5018–5020.
was funded by National Science Foundation (CHE-1228656). 23 W. P. Jencks and K. Salvesen, J. Am. Chem. Soc., 1971, 93,
The NMR facility was funded by the National Science Foun- 1419–1427.
dation (DUE-9451624 and DBI 0521342). SG acknowledges 24 R. L. Schowen and L. D. Kershner, J. Am. Chem. Soc., 1971,
funding from the National Science Foundation (CHE-1300817).
93, 2014–2024.
25 W. P. Jencks, Acc. Chem. Res., 1976, 9, 425–432.
26 J. S. Kudavalli, S. N. Rao, D. E. Bean, N. D. Sharma,
D. R. Boyd, P. W. Fowler, S. Gronert, S. C. L. Kamerlin,
J. R. Keeffe and R. A. More O’Ferrall, J. Am. Chem. Soc.,
2012, 134, 14056–14069.
27 A reaction solution, less the substrate, shows no trace of
the N–H proton at times less than ten minutes. This is the
expected result: see: E. Grunwald and D. Eustace, Proton
Transfer Reactions, ed. V. Gold and E. F. Caldin, Chapman
and Hall, London, 1975, ch. 4.
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