Accelerating Effect of Triazolyl and Related Heteroaryl Substituents on SNAr Reactions: Evidence of Hydrogen-Bond Stabilized Transition States

Article abstract of DOI:10.1021/jacs.5b06189

The remarkable accelerating effect of 1,2,3-triazolyl substituents on S_NAr reactions has been investigated through systematic experiments and density functional theory calculations. The lone pair electrons of an ortho-triazolo substituent play

Full text of DOI:10.1021/jacs.5b06189

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Article
Accelerating Effect of Triazolyl and Related Heteroaryl Substitutents on
SNAr Reactions: Evidence of Hydrogen Bond Stabilized Transition States
Wenyuan Qian, Hao Wang, and Michael D. Bartberger
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b06189 • Publication Date (Web): 31 Aug 2015
Downloaded from http://pubs.acs.org on September 1, 2015
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Accelerating Effect of Triazolyl and Related Heteroaryl Substitutents on SNAr
Reactions: Evidence of Hydrogen Bond Stabilized Transition States
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Wenyuan Qian,*,1 Hao Wang,1 and Michael D. Bartberger*,2
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1Department of Medicinal Chemistry and 2Department of Molecular Structure, Therapeutic
Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, United
States
ABSTRACT: The remarkable accelerating effect of 1,2,3ꢀtriazolyl substituents on SNAr reactions has
been investigated through systematic experiments and density functional theory calculations. The lone
pair electrons of an orthoꢀtriazolo substituent play a key role in lowering the activation energy for
nucleophilic addition via formation of a preferential hydrogen bond with the amine nucleophile at the
transition state for addition. In an extension of this finding, a series of related heteroaryl groups with
similar electron pair donor properties have also been found to facilitate SNAr reactions. The
experimentally determined solvent effect provides further support for this rationale, which was utilized to
achieve an orthoꢀselective substitution on a difluoroarene substrate.
INTRODUCTION
Since the discovery of the copper catalyzed azide-alkyne cycloaddition reaction
(CuAAC, click chemistry), 1,2,3ꢀtriazole has become one of the most studied heterocycles in
chemical, biomedical and material research in the past decade.1ꢀ3 Apart from its efficient
formation and remarkable stability, the unique electronic properties of this heterocycle are also
of great interest (Figure 1). On one hand, incorporation of two extra electronegative nitrogen
atoms makes this heterocycle a more electronꢀdeficient aromatic system (πꢀacceptor) compared
to other fiveꢀmembered rings such as pyrrole. On the other hand, these two nitrogen atoms also
possess loneꢀpair electrons orthogonal to the πꢀsystem. This σ donor property has been applied
in some recent transition metal catalyzed reactions in which the triazole ring was utilized either
as an important part of the catalytic ligands or as a builtꢀin directing group on the reaction
substrates.4,5 Beyond metal complexation, however, the influence of this unique heterocycle on
the chemical reactivity of its neighboring groups remains largely unexplored.
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Figure 1. Dual electronic properties of 1,2,3ꢀtriazole.
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In a recent medicinal chemistry program, we observed an unexpected, significant
activating effect of the triazolyl substituent on the SNAr–type reaction. As illustrated in Scheme
1, treatment of a triazolyl substituted substrate I with a nucleophile led to a facile conversion to
III. In a control experiment, the corresponding azide II failed to afford SNAr product IV under
the same conditions. Based on this observation, we have developed a general “click and
activate” strategy for multiple component synthesis of heterocycle libraries. In this protocol, a
leaving groupꢀconjugated azide II, serving as an unactivated electrophile, was compatible with
the presence of both an alkyne and a nucleophile in a single pot, due to the specific reactivity
profile of azide and the alkyne. Addition of a copper catalyst to this mixture not only led to the
efficient union of the azide II and the alkyne, but also triggered the subsequent substitution
reaction with the nucleophile, achieving a rapid assembly of molecular diversity.6ꢀ8 The
successful application of this protocol in diversityꢀoriented synthesis stimulated our interest to
fully understand the origin of this intriguing activation effect of triazole.
Scheme 1. Activation effect of triazolyl group on SNAr reactions and its application in multiple
component reactions.
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The SNAr reaction is one of the most important tools in the functionalization of aromatic
and heteroaromatic rings. The substituent effects of common electronꢀwithdrawing groups, such
as nitro, cyano, sulfonyl, keto, ester, or amide groups on the rate of SNAr reaction have been well
documented.9,10 However, to the best our knowledge, the effects of heterocyclic substituents
(including the triazolyl group) on this classical transformation have been largely overlooked.
In this paper, we explain the origin of this accelerating effect through detailed control
experiments and density functional theory calculations, using pyridazinone core 1 as the
substrate (Figure 2).11 It was further determined that triazole is not the only heterocycle to exhibit
this effect, as was predicted theoretically and experimentally validated for other heteroaromatic
substituents (R group in 1 below.). Lastly, it is demonstrated that this type of triazole group
activation is general and can be applied to SNAr reactions on broader aromatic substrates 2.
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Figure 2. Two types of substrates in this study.
RESULTS AND DISCUSSION
Initially, the observed rate accelerating effect of the ortho triazole on the SNAr reaction
depicted in Scheme 1 was simply attributed to the mild electronꢀwithdrawing property of the
triazole moiety. To confirm this hypothesis, 4ꢀchloroꢀpyridazinone analogs 1bꢀ1e with gradually
stronger electronꢀwithdrawing substitutents at the neighboring 5ꢀposition were prepared and
compared to triazole 1a in reactions with morpholine in DMF (Table 1). To our surprise, even
the strongest electronꢀwithdrawing paraꢀnitrophenyl group (1e) in this series, as gauged by both
substrate LUMO energy and relative electron affinity (vide infra) exhibited far less activating
effect (undetectable under our control experiment conditions) compared to the remarkable rate
accelerating effect of the triazole (1a).
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Table 1. Initial control experiments with electronꢀdeficient phenyl substituents.
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% conversiona,b
(6h)
LUMO Energyc
(Hartrees)
Relative
electron
(1h)
(24h)
Substrate
R
affinityd
(kcal/mol)
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0
100
0
ND
0
+0.04086
+0.04928
+0.05616
+0.03196
+0.01863
10.0
2.2
1a
1b
1c
1d
1e
N3
0
0
0
0e
0
0
0
14.5
24.8
0
0
0
a The reactions were conducted at 0.1 M substrate concentration.
b Conversion was calculated based on HPLC peak integration at 254 nm.
c From RHF/6ꢀ31G* singleꢀpoint energies of B3LYP/6ꢀ31G* optimized geometries.
d Relative electron affinities obtained from (U)B3LYP/6ꢀ31+G** singleꢀpoint energies of (U)B3LYP/6ꢀ31G*
optimized neutral and radical anion geometries.
e Parent phenylꢀsubstituted system 1c used as reference value (Relative electron affinity 1c = 0.0 kcal/mol)
This unexpected result prompted a computational investigation of the intrinsic
electrophilicity of substrates 1aꢀ1e.9,10 For reactions between a given nucleophile and a class of
homologous electrophilic substrates possessing a similar steric footprint, the kinetics of addition
should be governed to a significant extent by the LUMO of the substrate (Figure 3). A lower
substrate LUMO energy gives rise to a lower HOMOꢀLUMO gap, and hence a greater degree of
reactivity. The LUMO of systems 1a and 1c above, found to be primarily localized at the C=C
π* where the SNAr reaction was found to take place for all substrates, are depicted in Figure 3.
As expected, the increase in predicted relative adiabatic electron affinities reported in
Table 1 track identically with successively lower LUMO energy, with the overall electrophilicity
of 1a predicted to lie between phenylꢀ and cyanophenylꢀsubstituted substrates 1c and 1d,
respectively. Thus it is clear that triazole system 1a possesses substantially greater reactivity
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toward morpholine addition than would be predicted based solely on inherent substrate
electrophilicity.
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Figure 3. FMO interaction diagram and substrate LUMOs (RHF/6ꢀ31G*; 0.05 a.u. contour
level) of systems 1a and 1c.
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Since simple substrateꢀbased electronic factors were not sufficient to explain the unique
activation effect of triazole in this case, we shifted our attention to the other structural feature of
this heterocycle, the σ donor property. We reasoned that the central nitrogen atom (2ꢀN) of the
triazole moiety might enable an internal hydrogen bonding interaction with the incoming amine
nucleophile. This hypothesis is related to the concept of a “builtꢀinꢀsolvation” effect, first
proposed by Bunnett.12 This concept has been used to describe the favorable interactions
between nucleophiles and various ortho accelerating groups in the transition state of the SNAr
reaction through hydrogen bonding, electrostatic attraction, or metal counter ion coordination.
Nevertheless, the rare and scattered reports on this subject in the past six decades have only been
rationalized by conceptual images with little theoretical support.13,14 Moreover, only small
functional groups such as nitro, keto, carboxylate, ester and amide groups have been evaluated
experimentally. To the best of our knowledge, there has been no systematic investigation of
aromatic heterocycles as the orthoꢀ activating groups in simple SNAr reactions in the literature.
Thus, the structural and energetic features of the transition structures for morpholine addition to
a variety of substrates were investigated in detail herein.
Figure 4 depicts the lowest energy B3LYP/6ꢀ31G* transition structure (TS) for the
concerted, 1ꢀstep morpholine addition to 4’ꢀnitrophenyl substituted substrate 1e, within which a
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hydrogen bonding interaction is predicted to occur between the carbonyl oxygen of the
pyridazinone core and NH of the morpholine nucleophile.15 In contrast, in the presence of the
triazole substitutent (1a), a hydrogen bond involving the central 2ꢀN of the triazole is instead
more favorable, representing the lowest energy TS.16 The 7.2 kcal/mol preference for the 6ꢀ
membered TS involving intramolecular triazole complexation over the corresponding 5ꢀ
membered TS for 1e is in direct accord with the results of the control experiments in Table 1,
and provided a working rationale for the significant accelerating effect of triazole group on the
SNAr reaction. A portion of the preferential stabilization of the TS for 1a may also be attributed
to the larger (ca. 139°) ∠NꢀH···N angle at the TS for 1a, significantly closer to an ideal donorꢀ
acceptor angle (180°) than for 1e (∠NꢀH···O ca. 120°) along with a more favorable orientation
of the triazole N versus carbonyl O lone pair.
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Figure 4. Lowest energy transition structures for morpholine addition to substrates 1e and 1a
(B3LYP/6ꢀ31G*.) Distances denoted in Ångstroms, angles in degrees.
Intrigued by the structural and energetic aspects of the respective transition structures, we
subsequently extended our investigation to additional heteroaromatic and other appropriatelyꢀ
oriented, σꢀelectron donating groups in the same pyridazinone scaffold (Table 2).
The
B3LYP/6ꢀ31G* geometries of the morpholine nucleophile, substrates, and lowest energy
transition structures were further optimized utilizing the large and diffuse augꢀccꢀpVTZ basis,
and found to track well (albeit with higher absolute Eact values) compared to the B3LYP/6ꢀ31G*
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results. Comparison of the three regioisomeric pyridyl groups 1f-1h provided the most
compelling demonstration of this stabilizing effect. In compound 1f, the 2ꢀpyridyl group,
approximately isosteric and isoelectronic with respect to the triazolyl group in 1a, offered a
similar, experimentallyꢀdetermined rate acceleration in the SNAr reaction. This is in agreement
with the relatively low predicted Eact , involving a TS which is stabilized by a hydrogen bond
involving the 2ꢀN atom of the pyridine ring (Figure 5). Relocation of this hydrogen bond
acceptor, as in the cases of 3ꢀ and 4ꢀpyridyl analogs, removes the favorable 6ꢀmembered network
in the TS, necessitating stabilization by the pyridazinone carbonyl oxygen instead and raising the
predicted Eact by ca. 8 and 7 kcal/mol for 1g and 1h, respectively. As a result, both 1g and 1h are
nearly inert towards the nucleophile under the same conditions, despite 4ꢀpyridyl substrate 1h
possessing a greater inherent electrophilicty than 2ꢀpyridylꢀsubstituted analog 1f as gauged by
both LUMO energy and electron affinity (Table 2). The more πꢀelectron deficient pyrazine
derivative 1i is slightly more reactive. Fiveꢀmembered heterocycles, represented by thiazole (1j)
and oxazole (1k) also exhibit a remarkable rate accelerating effect. Interestingly, while two
different heteroatoms are available at the proper location for morpholine stabilization in oxazole
1k, the nitrogen atom is clearly preferred as the hydrogen bond acceptor in the lowest energy TS
(Figure 5)17,18 The inferior hydrogen bond acceptor capacity of the heterocyclic oxygen atom
was further showcased by the 2ꢀfuranyl substituent in 1l, offering no assistance in lowering the
energy of the TS. Accordingly, no rate acceleration was observed experimentally for 1l.
In general, keto and ester groups are more electron withdrawing than most aryl and
heteroaryl groups. At the same time, the ortho- carbonyl group were found to act as a powerful
hydrogen bond acceptor to the amine hydrogen to stabilize the cyclic TS, thus significantly
lowering the barrier to reaction (Figure 5) in addition to their electronꢀwithdrawing nature in the
classical sense14b,c As expected, both ketone 1m and ester 1n are highly reactive towards
morpholine and the SNAr reactions, reaching completion within 10 minutes. The extreme facility
by which system 1m undergoes reaction compared to cyanoaryl species 1d (Tables 2 and 1
respectively), despite possessing similar inherent substrate electrophilicities, further underscores
the importance of the hydrogen bonding ability of the ortho substituent at the TS for nucleophile
addition.
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Table 2. Product conversions (%) and predicted activation barriers (at the B3LYP/6ꢀ31G* and
B3LYP/augꢀccꢀpVTZ levels) demonstrating activating effect of triazole and other related
heterocycles.
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%
%
%
LUMO energyc
(Hartrees) /
Eact
conversiona,b conversion conversion
(kcal/mol)
f,g
Substrate
R
(1h)
(6h)
(24h)
Relative electron
affinityd,e
(kcal/mol)
14.9 /
14.7 h
(20.1) h
15.3
(20.7)
23.3
(28.2)
22.6
(27.5)
14.8
(20.3)
12.2
(17.6)
14.5
(19.3)
22.7
(27.7)
10.5
+0.04086/
10.0
60
100
ND
1a
+0.04768/
4.3
+0.04862/
4.9
+0.04304/
8.2
+0.03782/
10.4
+0.03379/
12.3
+0.03425/
6.7
+0.04497/
0.7
+0.03048/
13.6
30
0
72
0
100
0
1f
1g
1h
1i
0
0
4
65
57
100
0
100
92
ND
0
ND
100
ND
0
1j
1k
1l
100
100
ND
ND
ND
ND
1m
1n
(15.4)
10.6
(16.4)
+0.03540/
9.6
•
•
•
•
a Reactions were conducted at 0.1 M substrate concentration
b Conversion was calculated based on HPLC peak integration at 254 nm.
c From RHF/6ꢀ31G* singleꢀpoint energies of B3LYP/6ꢀ31G* optimized geometries.
d Relative electron affinities obtained from (U)B3LYP/6ꢀ31+G** singleꢀpoint energies of (U)B3LYP/6ꢀ
31G* optimized neutral and radical anion geometries.
•
•
•
e Parent phenylꢀsubstituted system 1c used as reference value (Relative electron affinity = 0.0 kcal/mol)
f B3LYP/6ꢀ31G* + ZPE versus separated reactants.
g Bold parenthesized values indicate B3LYP/augꢀccꢀpVTZ + ZPE versus separated reactants.
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h Data for parent unsubtituted (desꢀphenyl) triazole analog 1p due to poor SCF convergence behavior for
larger analogs.
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Figure 5. Structural parameters (B3LYP/augꢀccꢀpVTZ) and Eact values (B3LYP/6ꢀ31G* and
B3LYP/augꢀccꢀpVTZ; latter in bold italic; kcal/mol) for morpholine addition to heteroarylꢀ and
acylꢀsubstituted substrates 1p, 1k, 1m (alternate view) and 1f-1h. Distances denoted in
Ångstroms, angles in degrees.
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Next, the influence of different substituents on the triazole moiety was systematically
studied, with results reported in Table 3 below. While Nꢀlinked triazoles 1o and 1a, possessing
alkyl and phenyl groups at the 4’ꢀposition, showed little difference in reaction rates, the 4,5ꢀ
unsubstituted triazole analogue 1p was found to be slightly more reactive. An electronꢀ
withdrawing ester group at the 4ꢀposition of the triazole further activated the substrate 1q as the
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electrophile. Surprisingly, the “reversed”, Cꢀlinked triazolyl group in 1r was found to be
significantly less reactive, despite the availability of the 3ꢀN atom on the triazole ring for
hydrogen bond formation with the incoming morpholine nucleophile. In addition to the inherent
increase in electrophilicity between 1a and 1r as gauged by LUMO energy and electron affinity
(vide infra), this significant isomeric effect can be further explained by the electrostatic potentialꢀ
derived atomic charges of the regioisomeric nitrogen atoms in the triazole ring of the substrate
(Figure 6). In general, the central 2ꢀN is found via electrostatic potential calculations to be more
electron rich in both Nꢀ and Cꢀlinked scenarios by ca. 0.08 – 0.1 electrons, and thus should act as
a better hydrogen bond acceptor than the corresponding 3ꢀN atom. The starkly differing
electrophilicities and hydrogen bond acceptor capacity is reflected in a ca. 4 kcal/mol difference
in Eact between the two regioisomers 1a and 1r.
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Table 3. Product conversions (%) and predicted activation barriers (B3LYP/6ꢀ31G*) for various
substituted and regioisomeric triazolyl substrates.
%
%
%
LUMO energyc
(Hartrees) /
Relative electron
affinityd (kcal/mol)
+0.04086 /
10.0
Eact
conversiona,b conversion conversion
(kcal/mol)e
Substrate
R
(1h)
(6h)
(24h)
60
56
100
100
ND
ND
14.9
15.1
1a
1o
+0.04466f
6.5
+0.04172
8.0
90
100
ND
14.7
1p
+0.03436g
13.0
100
4
ND
10
ND
25
14.1
19.2
1q
1r
+0.04996
4.2
•
•
•
a The reactions were conducted at 0.1 M substrate concentration
b The conversion was calculated based on HPLC peak integration at 254 nm.
c From RHF/6ꢀ31G* singleꢀpoint energies of B3LYP/6ꢀ31G* optimized geometries.
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d Relative electron affinities obtained from (U)B3LYP/6ꢀ31+G** singleꢀpoint energies of (U)B3LYP/6ꢀ
31G* optimized neutral and radical anion geometries.
e B3LYP/6ꢀ31G* + ZPE versus separated reactants.
•
•
f Theoretical data for methylꢀsubstituted triazole.
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g Theoretical data for methyl esterꢀsubstituted triazole.
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Figure 6. Molecular electrostatic potentials (a.u. ; 0.001 a.u. contour level; B3LYP/6ꢀ31G*) and
resultant atomic charges (electrons) of the 2ꢀN and 3ꢀN of the triazole ring.
Having fully rationalized the activation effect of the orthoꢀheteroaryl groups on the
pyridazinone platform, we expanded our investigation scope to the more general benzene
substrates (Table 4).19 In the control experiments, both 2ꢀfluoroꢀ and 4ꢀfluorobenzonitriles (2a
and 2c) were found to react slowly with morpholine in DMF. In this case, the cyano group was
chosen because it cannot form a cyclic transition state with the amine nucleophile due to its
linear geometry. The observation that 2ꢀfluorobenzonitrile reacted slower than the 4ꢀfluoro
analogue is possibly due to the intrinsic electronic difference and/or steric hindrance of the
orthoꢀ substitution pattern. Introducing a triazolyl group paraꢀ to fluorine in 2a enhanced the
reaction rate (2a and 2b). This indicated that the remote triazolyl group exhibits a moderate
electronꢀwithdrawing effect on the benzene substrate. As expected, a triazolyl substitution
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orthoꢀ to fluorine in 2d provided an even more significant acceleration as the combined result of
both electronic and the hydrogen bonding assisted TS effects.
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The importance of the hydrogen bonding assisted TS was further demonstrated in the
solvent effect on this set of substrates. It is well known that solvents with high dielectric
constant and high solvent hydrogen bond basicity such as DMF (εr = 36.71 and pKHB = 2.10)
generally favor SNAr reactions by stabilizing charge separation in the transition states or
intermediates.14,20 In comparison, the same reactions in Table 4 in the less polar and less
hydrogen bond basic solvent 1,4ꢀdioxane (εr = 2.21 and pKHB = 1.03) are much slower. As
expected from our rationale, the gap of the relative reaction rates between the two isomeric
substrates 2b and 2d becomes much more pronounced. While 2b is completely unreactive in this
solvent, 2d still undergoes a steady SNAr reaction due to the assistance from the neighboring
triazolyl group via hydrogen bonding interaction.
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Table 4. Triazoleꢀaccelerated SNAr reactions on benzene core.
Reaction
(solvent)
A (DMF)
% conversion
% conversion
% conversion
(1h)a,b
0
(6h)
3
(24h)
9
B (DMF)
10
30
60
C (DMF)
D (DMF)
A (dioxane)
B (dioxane)
C (dioxane)
D (dioxane)
2
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100
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ND
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65c
•
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•
aReactions were conducted at 0.1 M substrate concentration.
bConversion was calculated based on HPLC peak integration at 254 nm.
c91% conversion at 48 h.
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The differentiation of the two activation modes by triazole (or other related heterocycles)
in different solvents can be utilized to achieve high regioselectivity on aromatic substrates with
more than one leaving groups such as 5 in Scheme 2. Electronically, both the ortho- and the
para- (fluoro) positions of 5 are activated by the moderately electronꢀwithdrawing triazolyl
moiety (as the only activating group).21 Therefore, SNAr reaction with morpholine in highly
polar and highly hydrogen bond basic solvent DMSO (εr = 46.45 and pKHB = 2.58) led to a
nearly 1:1 ortho- and para- isomers 6a and 6b. On the other hand, because only the ortho-
position is capable of forming a hydrogen bond assisted sixꢀmembered TS with the incoming
nucleophile, a high orthoꢀselectivity (~15:1 o/p ratio) can be obtained in dioxane, which has poor
hydrogen bond forming capability and low polarity. In control experiments, no substitution
product could be observed on 1,3ꢀdifluorobenzene under the same conditions in either solvents.
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Scheme 2. Triazoleꢀdirected regioselective SNAr reaction on difluoroarene 5.
CONCLUSION
In summary, we have demonstrated that an orthoꢀ1,2,3ꢀtriazole substituent can provide a
significant accelerating effect on the SNAr reaction due to its dual electron acceptor/donor
properties. Compared to its moderate electronꢀwithdrawing effect, the capability of forming a
preferential hydrogen bond with the amine nucleophile can sometimes play a more important
role in stabilizing the transition state and lowering the activation energy. Extension of this
rationale led to the first systematic investigation and discovery of various related heteroaryl
substitutions that facilitate SNAr reaction under the similar mechanism. The different degree of
activation between the Nꢀlinked triazole and the “reversed”, Cꢀlinked triazole highlights the
importance of the lone pair electron richness (2ꢀN > 3ꢀN) in determining the strength of
hydrogen bond in the transition state in addition to the inherent electrophilicity. The same
hypothesis is further supported by control experiments in different solvents and enables an orthoꢀ
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selective substitution on a difluoroarene substrate. Combined with the remarkable compatibility
of azides and alkynes with various nucleophiles and electrophiles, this triazole activation effect
provides unique opportunity in the design of conceptually novel multiple component reactions.6ꢀ8
Further experimental and computational studies are underway to understand other related
heteroaryl assisted reactions.
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ASSOCIATED CONTENT
Supporting Information
Detailed description of experimental procedures and characterization data, H and 13C NMR
1
spectra for compounds 1-6, and full description of theoretical methodology, including geometric
and energetic data for reactants and transition structures for systems 1aꢀ1r. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
*Email: wqian@amgen.com
mbartber@amgen.com
Notes
The authors declare no competing financial interest.
ACKNOWLEDGEMENTS
We thank Christopher Wilde (Amgen) for support in NMR analysis and Iain Campuzano
(Amgen) for supplying HRMS data. Hao Wang thanks Amgen Therapeutic Discovery for
financial aid during a summer internship at Amgen. Useful discussions with Dr. Brian Lanman
(Amgen) are acknowledged with gratitude.
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REFERENCES
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1. (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem. Int. Ed.
2002, 41, 2596; (b) Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67,
3057.
2. For recent reviews on click chemistry, see: (a) Themed issue: Click chemistry: Function
follows form, Finn, M. G.; Fokin, V. V., Eds.; Chem. Soc. Rev. 2010, 39, 1221ꢀ1408; (b)
Agalave, S. G.; Maujan, S. R.; Pore, V. S. Chem. Asian J. 2011, 6, 2696. (c) Lauria, A.;
Delisi, R.; Mingoia, F.; Terenzi, A.; Martorana, A.; Barone, G.; Almerico, A. M. Eur. J. Org.
Chem. 2014, 16, 3289.
3. Click Chemistry for Biotechnology and Materials Science; Lahann, J., Ed.; John Wiley &
Sons: Hoboken, NJ, 2009.
4. (a) Verma, A.K.; Keshwarwani, T.; Singh, J.; Tandon, V.; Larock, R. C. Angew. Chem. Int.
Ed. 2009, 48, 1138; (b) Yan, W.; Ye, X.; Akhmedov, N. G.; Petersen, J. L.; Shi, X. Org. Lett.
2012, 14, 2358; (c) Dyan, J.; Sengupta, S.; Petersen, J. L.; Akhmedov, N.; Shi, X. J. Am.
Chem. Soc. 2009, 131, 12100; (d) Detz, R. J.; Arevalo H., S.; De Gelder, R.; Van Leeuwen,
P. W. N. M.; Hiemstra, H.; Reek, J. N. H.; Van Maarseveen, J. H. Org. Lett. 2006, 8, 3227;
(e) Wassenaar, J.; Detz, R. J.; de Boer, S. Y.; Lutz, M.; van Maarseveen, J. H.; Hiemstra, H.;
Reek, J. N. H. J. Org. Chem. 2015, 80, 3634.
5. (a) Ackermann, L.; Vicente, R. Org. Lett. 2009, 11, 4922; (b) Ackermann, L.; Vicente, R.;
Potukuchi, H. K.; Pirovano, V. Org. Lett. 2010, 12, 5032; (c) Ye, X.; He, Z.; Ahmed, T.;
Weise, K.; Akhmedov, N. G.; Petersen, J. L.; Shi, X. Chem. Sci., 2013, 4, 3712.
6. (a) Qian, W.; Winternheimer, D.; Allen, J. Org. Lett. 2011, 13, 1682; (b) Qian, W.;
Winternheimer, D.; Amegadzie, A.; Allen, J. Tetrahedron Lett. 2012, 53, 271.
7. For a related “click and activate nucleophile” protocol, see: (a) Qian, W.; Amegadzie, A.;
Winternheimer, D.; Allen, J. Org. Lett. 2013, 15, 2986; (b) Qian, W.; Wang, H.; Allen, J.
Angew. Chem. Int. Ed. 2013, 52, 10992.
8. For a recent review of multicomponent syntheses based upon copperꢀcatalyzed alkyneꢀazide
cycloaddition, see: Hassan, S.; Mueller, T. J. J. Adv. Syn. & Cat. 2015, 357, 617.
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9. For discussion of the classical SNAr reaction, see: (a) Carey, F. A.; Sunddberg, R. J.
Advanced Organic Chemistry Part A: Structure and Mechanism 4th; Kluwer
Academic/Plenum Publishers: New York, Boston, Dordrecht, London, Moscow, 2004; (b)
March, J. Advanced Organic Chemistry, 2nd ed.; McGrawꢀHillNew York, 1984.
10. For a recent review of SNAr reactions, see: Crampton, M. R. Nucleophilic Aromatic
Substitution. In Organic Reaction Mechanisms, 2005; Knipe, C., Eds.; John Wiley & Sons:
West Sussex, UK, 2008.
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11. The first triazole accelerated SNAr reaction was discovered on this substrate (Ref. 6a).
12. (a) Bunnett, J. F.; Morath, R. J. J. Am. Chem. Soc. 1955, 77, 5051. (b) Bunnett, J. F.;
Morath, R. J.; Okamoto. T. J. Am. Chem. Soc. 1955, 77, 5055.
13. For examples of accelerated SNAr reactions involving anionic nucleophiles, see: (a) Isanbor,
C.; Emokpae, T. A.; Crampton, M. R. J. Chem. Soc.; Perkin Trans. 2002, 2, 2019. (b)
Gozzo, P. R.; Buckle, R. N.; Chou, M.; Dinn, S. R.; Flaugh, M. E.; Kiefer, A. D., Jr.; Ruter,
K. T.; Sampognaro, A. J.; Tregay, S. W.; Xu, Y.ꢀC. J. Org. Chem. 2003, 68, 770; (c) Yap, J.
L.; Hom, K.; Fletcher, S. Tetrahedron Lett. 2011, 52, 4172; (d) Brandt, S. V.; Rombouts, F.
J. R.; MartinezꢀLamenca, C.; Leenaerts, J.; Rauws, T. R. M.; Trabanco, A. A. Eur. J. Org.
Chem. 2012, 7048.
14. For examples of accelerated SNAr reactions involving neutral amine nucleophiles, see: (a)
Arnone, C.; Consiglio, G.; Frenna, V.; Spinelli, D. J. Org. Chem. 1997, 62, 3093; (b) Wang,
X.; Salaski, E. J.; Berger, D. M.; Powell, D. Org. Lett. 2009, 11, 5662; (c) Wendt, M. D.;
Kunzer, A. R. Tetrahedron Lett. 2010, 51, 641; (d) Cheron, N.; El Kaim, L.; Grimaud, L.;
FleuratꢀLessard, P. Chem. Eur. J. 2011, 17, 14929.
15. In the case of our pyridazinone / morpholine systems, the reactions were found to be
concerted on the B3LYP surface. In the literature, various kinetic and computational studies
have demonstrated that the preference for a concerted versus stepwise mechanism in SNAr
reactions can be dependent on the substitution pattern and/or nature of the
substrate/nucleophile pair: (a) Liljenberg, M.; Brinck, T.; Herschend, B.; Rein, T.; Tomasi,
S.; Svensson M. J. Org. Chem. 2012, 77, 3262; (b) Fernandez, I.; Frenking,G.; Uggerud, E.
J. Org. Chem. 2010, 75, 2971; (c) Glukhovtsev, M. N.; Bach, R. D.; Laiter, S. J. Org. Chem.
1997, 62, 4036; (d) Renfrew, A. H. M.; Taylor, J. A.; James M. J. Whitmore, J. M. J.;
Williams, A. J. Chem. Soc. Perkin Trans. 1993, 2, 1703.
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16. The TS for 1a instead involving pyridazinone C=O complexation (analogous to that of 1e) is
found to lie +2.7 kcal/mol higher in energy at the B3LYP/6ꢀ31G* level of theory, and may
too benefit from a small degree of stabilization between the adjacent, axiallyꢀdisposed
methylene CHs of the morpholine and the triazole 2ꢀN (r(CꢀH···N) = 2.4 – 2.7 Å.). Please
see Supporting Information.
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17. The nitrogen atom of an oxazole moiety is the more electronegative heteroatom, as supported
by B3LYP/6ꢀ31G* electrostatic potentialꢀderived charges (MerzꢀKollman scheme,
constrained to dipole moment.) For the oxazole molecule: χ(N) = ꢀ0.500 vs. χ(O) = ꢀ0.185 ;
for substrate 1k: χ(N) = ꢀ0.481 vs. χ(O) = ꢀ0.156.
18. The corresponding transition structures (see Supporting Information) involving complexation
by the carbonyl and oxazole oxygen atoms lie +2.9 and +4.4 kcal/mol, respectively, above
that corresponding to oxazole nitrogen stabilization at the B3LYP/6ꢀ31G* level of theory.
19. While SNAr reactions of substrates 2a-d may potentially occur via either a concerted or
stepwise mechanism, it is generally accepted that in either case, initial addition of the
nucleophile to substrates is typically rate limiting (Ref. 9a).
20. (a) Taft, R. W.; Gurka, D.; Joris, L.; Schleyer, P. R.; Rakshys, J. W. J. Am. Chem. Soc.1969,
91, 4801; (b) Kamlet, M. J.; Taft, R. W. J. Am. Chem. Soc.1976, 98, 377.
21. For a recent example of direct Nꢀarylation using unactivated fluorobenzenes under harsh
conditions, see: Diness, F.; Fairlie, D. P. Angew. Chem. Int. Ed. 2012, 51, 8012.
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