Medium Effect (H2O versus MeCN) on Reactivity and · Draft Medium Effect (H2O versus MeCN) on...

Draft

Medium Effect (H2O versus MeCN) on Reactivity and

Reaction Pathways for SNAr Reaction of 1-Aryloxy-2,4-

dinitrobenzenes with Cyclic Secondary Amines

Journal: Canadian Journal of Chemistry

Manuscript ID cjc-2017-0454.R1

Manuscript Type: Article

Date Submitted by the Author: 01-Sep-2017

Complete List of Authors: Um, Ik-Hwan; Ewha Womans University,

Kim, Min-Young; Ewha Womans University, Dust, Julian; Grenfell Campus Memorial University of Newfoundland, Chemistry and Environmental Science

Is the invited manuscript for consideration in a Special

Issue?: N/A

Keyword:

https://mc06.manuscriptcentral.com/cjc-pubs

Canadian Journal of Chemistry

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1

Medium Effect (H2O versus MeCN) on Reactivity and Reaction Pathways for SNAr Reaction

of 1-Aryloxy-2,4-dinitrobenzenes with Cyclic Secondary Amines

Ik-Hwan Um,* Min-Young Kim, and Julian M. Dust

†*

Department of Chemistry, Ewha Womans University, Seoul 120 - 750, Korea

E-mail: [email protected]

†Departments of Chemistry and Environmental Science, Grenfell Campus-Memorial

University of Newfoundland, Corner Brook, Newfoundland and Labrador A2H 5G4,

Canada


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Abstract

A kinetic study on SNAr reactions of 1-aryloxy-2,4-dinitrobenzenes (1a-1h) with a series of

cyclic secondary amines in 80 mol% H2O / 20 mol% DMSO at 25.0 ± 0.1 oC is reported. The

plots of kobsd vs [amine] curve upward except for the reactions of substrates possessing a

strong electron-withdrawing group in the leaving aryloxide with strongly basic piperidine.

The curved plots indicate that the reactions proceed through both uncatalytic and catalytic

routes. Linear Brønsted-type plots have been obtained for the uncatalyzed and catalyzed

reactions of 1-(4-nitrophenoxy)-2,4-dinitrobenzene (1a) with βnuc = 0.84 and 0.78,

respectively. The Yukawa-Tsuno plot for the uncatalyzed reactions of 1a-1h with piperidine

results in an excellent linear correlation with ρ = 1.66 and r = 0.31. In contrast, rate constants

for catalyzed reactions are independent of the electronic nature of the substituent in the

leaving group. The current SNAr reactions have been proposed to proceed via a zwitterionic

intermediate (MC±) that partitions to products through uncatalytic and catalytic routes. The

catalyzed reaction from MC±

has been concluded to proceed through a concerted mechanism

with a six-membered cyclic transition state (TScycl) rather than via a stepwise pathway with a

discrete anionic intermediate (MC‒): the traditionally accepted mechanism. Medium effects

on reactivity and reaction mechanism are discussed. Particularly, hydrogen-bonding of the

amines to water precludes formation of kinetically significant dimers found in some aprotic

solvents; no explicit role for water in the catalytic transition state is required or proposed. The

specific stabilization of the leaving aryloxides substituted with strong electron-withdrawing

groups accounts for the lack of the catalytic pathway in these systems (1a-c) with piperidine

nucleophile.

Keywords: SNAr reaction, Brønsted-type plot, Yukawa-Tsuno plot, Zwitterionic intermediate,

Six-membered cyclic transition state.

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Introduction

In the toolkit of the synthetic organic chemist involved in the design and preparation of

new aromatic compounds, nucleophilic aromatic substitution on electron deficient substrates

is a versatile, even essential, implement. These reactions generally proceed via the SNAr

mechanism in which nucleophilic attack at the position substituted by the leaving group leads

to formation of a σ-bonded anionic adduct, termed a Meisenheimer complex (MC), as a

metastable intermediate.1-4

The MC is stabilized by one or more moderate to potent electron-

withdrawing groups (EWG).3 Ejection of the leaving group occurs in a second, usually fast,

step to yield the substitution product. Reaction at an unsubstituted site of the aromatic ring

can lead to transient MC5 or if the nucleophile is suitably substituted with its own leaving

group, Z, can undergo elimination of HZ in the Vicarious Nucleophilic Substitution (VNS)

reaction.6,7

(In the current kinetic study no evidence of the intervention of such isomeric MC

emerged).

Even a cursory look at the literature shows the versatility of SNAr reactions, which have

been employed recently in at least one step of the reported syntheses of: fluorescent

teraaza[8]circulenes,8

2-amino- and 2-arylazoanulenes,9

aromatic ring substituted

porphyrins,10

substituted amidoazopyridines from perfluorinated pyridine,11

various

potentially therapeutic substituted pyrimidines12,13

and dipyridylazepines,14

and

benzimidazole N-oxides.15

The reactions of water-soluble polymers end-group substituted

with electron-deficient aromatics have been studied16,17

and in post-polymerization

functionalization, poly(acrylamide) bearing pendant 3,5-dichloro-2,4,6-triazinyl groups can

react via SNAr reaction to yield a wide range of modified poly(acrylamide)s.18

Some

significant potential environmental remediation protocols also rely on nucleophilic aromatic

displacement.19-21

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As a consequence fundamental studies, involving kinetic analysis22-27

as well as

calculational tools,24, 28-32

into the SNAr mechanism continue to evoke interest. Factors that

influence the nature of the SN Ar mechanism include, but are not restricted to: the nature of

the substrate, i.e. type and number of electron-withdrawing groups attached to the electron

deficient substrate; the nature of the leaving group; the nature of the nucleophile, e.g. anionic

versus neutral and; the effect of solvent.1-4

Our interests have included studies of SNAr

reactions of highly reactive, α-nucleophiles,33,34

effects of alkali metal ions,35

reactions of

primary and secondary cyclic amines24-26

with Sanger’s reagent (1-fluoro-2,4-

dinitrobenzene), a series of 1-halo-2,4-dinitrobenzenes and with 1-(substituted phenoxy)-2,4-

dinitrobenzenes as electron deficient substrates, usually in acetonitrile (MeCN) solvent often

with comparison to the results in water, as a standard reaction medium.

OAr

NO2

NO2

+ HNk1

k-1

ArO NH

k2NO2

NO2

HN

NO2

NO2

ArO

k3[NH]H

ArO NNO2

NO2

N

NO2

NO2

P

H

1a-1h MC PH

MC

ArO

fast

Scheme 1. Traditionally accepted reaction mechanism for SNAr reaction of 1-aryloxy-2,4-

dinitrobenzenes with amines.

Nucleophilic reaction of amines in the SNAr process is traditionally described,36

as shown

in Scheme 1, as a partition between two pathways after formation of the initial zwitterionic

MC, i.e., MC±; expulsion of the leaving group, a substituted phenoxide (ArO

‒) in current

work, gives the protonated product, PH+, that equilibrates rapidly to give the observed 2,4-

dinitroaniline product, P (Scheme 1) in the basic medium. This first pathway (MC± � PH

+ �

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P) is termed the uncatalyzed pathway and is characterized by the kinetic term, Kk2.

Alternatively, the zwitterionic MC±

may undergo deprotonation catalyzed by the amine base

in a k3 step to give the deprotonated MC‒, from which ejection of the ArO

‒ leaving group

yields the product aniline, P, in what overall may be termed the catalyzed pathway. Cases

have been made for rate-limiting proton transfer (RLPT) in the k3 step in polar aprotic

solvents.37,38

Further possibilities into direct concerted displacement of the leaving group by

an amine nucleophile without the intervention of any MC, as has been reported by the

Williams group for 4-aryloxy substituted 1,3,5-triazines39

and proton transfer within MC± that

occurs either directly from the aminium moiety to the aryloxyl oxygen or through the

intermediacy of one or more molecules of solvent to relay the proton, in concert with loss of

the ArOH leaving group.40

In terms of Scheme 1 this final possibility40

would constitute a

diagonal arrow (not shown) from MC± � P, representing a concerted path. In previous work

we have presented evidence in favour of a six-membered cyclic transition state (TScycl) for

this concerted path in the catalyzed route (Scheme 2) in MeCN.26

Given the similarities

between addition to C=O and to electron deficient aromatic carbon it is not surprising that we

have also found evidence for the intervention of comparable six-membered cyclic TS in

reaction of secondary cyclic amines with various ester systems in MeCN.41-43

In assessing the mechanism of aminolysis under SNAr conditions the role of solvent may

be paramount.44-47

In a recent study that examined 21 “conventional” solvents and 17 room-

temperature ionic liquid (RTIL) solvents, the relative degree of nucleophilic attack by a series

of cyclic secondary amines on sulfonyl sulfur as compared to SNAr displacement for 2,4-

dinitrobenzenesulfonyl chloride was found to depend significantly on the nature of the

solvent.48

Other studies into RTILs in SNAr displacement have focused on the synthetic utility

of these media49

or on the application of calculational methods to the reaction in such

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solvents.50

Part of the interest in RTIL media derives from the view that such solvents are

“greener”, i.e., more nearly environmentally benign,51

although Jessop has advanced the idea

that determination of relative greenness of a solvent requires a full life-cycle analysis

(LCA).52

In this regard, Pfizer chemists have suggested a “stoplight” system to quickly assess

the greenness of solvents used in pharmaceutical synthesis, where “green” solvents such as

water, acetone and common low molar mass alkanols, are preferred; “amber” solvents are

usable, including dimethyl sulfoxide, MeCN, THF and toluene; the “red” undesirable

solvents include pyridine, benzene, tetrachloromethane and diethyl ether.53

The current study of the pathways of SNAr reaction (Schemes 1 and 2) for reaction of a set

of secondary cyclic amines with 1-aryloxy-2,4-dinitrobenzenes is conducted in water, a green

solvent51,53

and the results are compared to those found in MeCN, an amber solvent.25,26

Substitution of the ArO‒(H) leaving group permits substituent effect analysis using Hammett-

type constants and application of the Yukawa-Tsuno equation, which we have previously

found useful in mechanistic assessment. The reaction system under study is also amenable to

Brønsted-type analysis.24-26

The results are also discussed with recourse to qualitative

comparative energy profiles.

Experimental

Materials. Substrates 1a-1h were prepared from the reaction of 1-fluoro-2,4-

dinitrobenzene with the respective Y-substituted-phenol under the presence of triethylamine

in anhydrous diethyl ether as reported previously.26

The crude products were purified by

column chromatography. Amines and other chemicals were of the highest quality available

and used without further purification. Doubly glass distilled water was further boiled and

cooled under nitrogen just before use.

Kinetics. Kinetic study was carried out by using a UV-Vis spectrophotometer equipped

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with a constant-temperature circulating bath to maintain the reaction temperature at 25.0 ±

0.1 oC. The reactions were followed by monitoring the appearance of N-(2,4-

dinitrophenyl)amines at a fixed wavelength corresponding to their maximum absorption.

Reactions were followed generally up to 9 ~ 10 half-lives. All reactions were carried out

under pseudo-first-order conditions (e.g., the amine concentration was kept at least 20 times

greater than the substrate concentration, 4 × 10‒5

M). Typically, the reaction was initiated by

adding 5 µL of a 0.01 M of substrate stock solution in MeCN by a 10 µL syringe to a 10 mm

UV cell containing 2.50 mL of solvent and the amine nucleophile.

Product Analysis. N-(2,4-Dinitrophenyl)piperidine was identified as one of the products for

the reactions with piperidine by comparison of the UV-vis spectra at the end of the reactions

with the authentic sample.

Results

All the reactions in this study obey pseudo-first-order kinetics. Pseudo-first-order rate

constants (kobsd) were calculated from the standard equation ln (A∞ – At) = –kobsdt + C. It is

estimated from, at least, replicate runs that the uncertainty in the kobsd values is less than ±

3 %. As shown in Figure 1 A, the plot of kobsd vs [amine] curves upward for the reaction of 1-

(4-nitrophenoxy)-2,4-dinitrobenzene (1a) with morpholine. Similarly curved plots are

illustrated in Figures S1A ~ S3A for the reactions of 1a with a series of secondary cyclic

amines, i.e., 1-(2-hydroxyethyl)piperazine, piperazine and 3-methylpiperidine and in Figures

S4A ~ S11A for those of substrates 1d-1h with piperidine as nucleophile in the

Supplementary Material (SM). Corresponding plots for the reactions of substrates possessing

a strong electron-withdrawing group (EWG) in the leaving group (e.g., 1a-1c) with piperidine

nucleophile were linear and, significantly, passed through the origin (Figures S1, S5 and S6

in the SM).

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0.000 0.025 0.050 0.075 0.1000.0000

0.0002

0.0004

A

kobsd / s

−1

[ amine ] / M

0.00 0.02 0.04 0.06 0.08 0.100.000

0.001

0.002

0.003

0.004

0.005

B

slope = (8.19 ± 0.26) x 10−3

intercept = (2.45 ± 0.01) x 10−3

R2 = 0.997

kobsd / [amine] M

−1s

−1

[amine] / M

Figure 1. Plots of kobsd vs [amine] (A) and kobsd/[amine] vs [amine] (B) for the reaction of 1-

(4-nitrophenoxy)-2,4-dinitrobenzene (1a) with morpholine in 80 mol% H2O / 20 mol%

DMSOat 25.0 ± 0.1oC.

Discussion

Dissection of kobsd into Kk2 and Kk3 kinetic terms. The curved plot shown in Figure 1A

implies that a second amine molecule is involved in the rate-determining TS. Clearly, the

current reaction is a composite one that proceeds through a stepwise mechanism with a

zwitterionic intermediate MC±, which decomposes to the products through both uncatalytic

and catalytic routes as shown in Scheme 1. In this case, kobsd can be expressed as eq (1) on the

basis of the kinetic results.37

Under the assumption k–1 >> k2 + k3[amine], eq (1) can be

simplified to eq (2). Accordingly, the plot of kobsd/[amine] vs [amine] should be linear with a

positive intercept in line with this assumption. In fact, Figure 1B shows a plot with excellent

linear correlation (R2 = 0.997) and a positive intercept. Thus, rate constants for the

uncatalyzed and catalyzed reactions (i.e., Kk2 and Kk3, respectively) were calculated from the

intercept and slope of the linear plot, respectively.

kobsd = (k1k2[amine] + k1k3[amine]2) / (k–1 + k2 + k3[amine]) (1)

kobsd/[amine] = Kk2 + Kk3[amine], where K = k1/k–1 (2)

On the other hand, the linear plots of kobsd vs [amine] for the reactions of 1a-1c with

piperidine indicate that the catalytic route is absent. Hence, kobsd may be expressed as eq (3),

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which can be simplified to eq (4) under the further assumption that k–1 >> k2. The second-

order rate term (Kk2) for the reactions of 1a-1c with piperidine were calculated from the slope

of the linear plots of kobsd vs [amine]. The rate constants calculated in this way are

summarized in Table 1 for the reactions of 1a with the five different amines studied and in

Table 2 for those of 1a-1h with piperidine.

kobsd = k1k2[amine]/(k–1 + k2) (3)

kobsd = k1k2[amine]/k–1 = Kk2[amine] (4)

Table 1. Summary of Kinetic Data for the Reactions of 1-(4-Nitrophenoxy)-2,4-

dinitrobenzene (1a) with Amines in 80 mol% H2O / 20 mol% DMSO at 25.0 ± 0.1 °C

amines pKaa Kk2 / M

–1s

–1 Kk3 / M

–2s

–1

1 piperidine 11.02 0.243 -

2 3-methylpiperidine 10.80 0.179 0.360

3 piperazine 9.85 0.0350 0.219

4 1-(2-hydroxyethyl)piperazine 9.38 0.0115 0.0201

5 morpholine 8.65 0.00245 0.00819 apKa data in 80 mol% H2O / 20 mol% DMSO were taken from ref. 54.

Effect of Amine Basicity on Reactivity and Reaction Mechanism. As shown in Table 1,

the second-order rate constant for the uncatalyzed reactions decreases as the amine basicity

decreases, e.g., Kk2 decreases from 0.243 to 0.0350 and 0.00245 M–1

s–1

as the pKa of the

conjugate acid of the amine decreases from 11.02 to 9.85 and 8.65, in turn. The rate term for

the catalyzed reactions exhibits a similar behavior although Kk3 is larger than Kk2. Note that

the Kk3 value is not accessible for the reaction involving strongly basic piperidine.

Focusing on the effect of amine basicity on reactivity Figures 2A and 2B are germane to

understanding. The Brønsted-type plots are linear with βnuc = 0.84 for Kk2 and βnuc = 0.78 for

Kk3, when the rate constants and pKa values are appropriately corrected for statistics p and q

(i.e., p = 2 while q = 1 except q = 2 and 4 for the uncatalyzed and catalyzed reactions with

piperazine, respectively). It is noteworthy that the uncatalyzed reactions result in a larger βnuc

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value than the catalyzed reactions. We have recently reported a similar result for the

corresponding reactions carried out in MeCN, although the difference in the βnuc values for

the uncatalyzed and catalyzed reactions is more significant for the reactions performed in the

aprotic solvent, e.g., βnuc = 1.10 for Kk2 and βnuc = 0.85 for Kk3.26

8 9 10 11 12-4

-3

-2

-1

0

A

βnuc = 0.84

R2 = 0.998

log Kk2 / q M

-1s-1

pKa + log(p/q)

8 9 10 11 12

-3

-2

-1

0

B

βnuc = 0.78

R2 = 0.984

log Kk3 / q M

-2s-1

pKa + log(p/q)

Figure 2.Brønsted-type plots of Kk2 (A) and Kk3 (B) for the reactions of 1-(4-nitrophenoxy)-

2,4-dinitrobenzene (1a) with amines in 80 mol% H2O / 20 mol% DMSO at 25.0 ± 0.1 °C.

Gresser and Jencks concluded that amine basicity does not affect the k2 value in aminolysis

of 2,4-dinitrophenyl aryl carbonates, where there is little or no electron donation from the

aminium moiety of a zwitterionic tetrahedral intermediate (T±) that could eject the leaving

group.55

Castro et al. have drawn a similar conclusion for aminolysis of various diaryl

thionocarbonates where the reaction proceeds via a stepwise mechanism with T±

as a central

intermediate.56

It is generally expected that amine basicity will not influence the k3 value, if

the current reaction proceeds in accord with Scheme 1. This is because more basic amines

would deprotonate sequentially more rapidly the aminium moiety of MC±, whereas the

aminium ion would hold the proton more strongly as a similar function of increasing amine

basicity. Therefore, if the current reactions proceed as shown in Scheme 1, both k2 and k3

would not be affected by amine basicity. Accordingly, one might expect the βnuc value for the

uncatalyzed and catalyzed reactions to be similar. However, the Brønsted-type plot yields a

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larger βnuc value for the uncatalyzed reactions than for the catalyzed reactions (Figure 2),

although the difference in the βnuc values is not as significant as that reported for the

corresponding reactions in MeCN.26

This is an unexpected result if the current reactions

proceed as shown in Scheme 1.

Therefore, we propose that the catalyzed reaction in this study does not proceed through a

stepwise mechanism via an anionic intermediate (MC‒) as shown in Scheme 1, rather, it

proceeds via a concerted pathway with a six-membered cyclic transition state as modelled by

TScycl in Scheme 2. Note that the second amine molecule in TScycl relays a proton from the

aminium moiety of MC± to the oxygen atom of the leaving group with simultaneous but not

necessarily synchronous C‒OAr bond scission. In this case, amine basicity could influence

the rate of the catalytic reaction because the proton donation from the second amine molecule

to the O atom of the leaving group would be retarded as the amine basicity increases. This

idea is consistent with the kinetic result that the catalytic route (i.e., the k3 process) is absent

for the reaction of 1a with the most basic amine in this study (i.e., piperidine).

ArO NNO2

NO2

N

NO2

NO2

ArOH

H HN

δ

δ

k3

OAr

NO2

NO2

+ HNk1

k-1

ArO NH

k2

NO2

NO2

HN

NO2

NO2

ArO

H

1a-1h MC PH

P

HN

TScycl

HN

Scheme 2. Our proposed reaction mechanism for the SNAr reaction of 1-aryloxy-2,4-

dinitrobenzenes (1a-1h) with amines (i.e., a concerted pathway from MC± via TScycl to yield

P).

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Effect of Leaving-Group Substituent on Reactivity and Reaction Mechanism. To

support the proposal that the catalyzed reaction proceeds through a concerted mechanism

with a six-membered cyclic TS (TScycl) but not via a stepwise mechanism with MC‒ as an

intermediate (Scheme 1), reactions of 1-aryloxy-2,4-dinitrobenzenes (1a-1h) with piperidine

have been carried out in 80 mol% H2O / 20 mol% DMSO at 25.0 ± 0.1 °C. The kinetic data

are summarized in Table 2 together with those reported previously for the corresponding

reactions carried out in MeCN for comparison.

Table 2. Summary of Kinetic Data for the Reactions of 1-Aryloxy-2,4-dinitrobenzenes (1a-

1h) with Piperidine in 80 mol% H2O / 20 mol% DMSO at 25.0 ± 0.1 °Ca

substituent Kk2 / M–1

s–1

Kk3 / M–2

s–1

1a 4-NO2 0.243(0.300) - (2.64)

1b 4-CN 0.159(0.105) - (2.47)

1c 4-CHO 0.113(0.0627) - (1.76)

1d 4-COMe 0.0766(0.0356) 0.335(1.50)

1e 3-Cl 0.0477(0.0191) 0.389(1.18)

1f 4-Cl 0.0251(0.0143) 0.315(1.05)

1g H 0.00666(0.00459) 0.218(0.577)

1h 4-Me 0.00434(0.00257) 0.211(0.499) aThe kinetic data in the parenthesis for the reactions run in MeCN were taken from ref. 26.

As shown in Table 2, the rate constant for the uncatalyzed reactions of 1a-1h in the

aqueous medium decreases as the substituent in the leaving group becomes a weaker EWG,

e.g., the Kk2 value decreases from 0.243 to 0.0477 and 0.00434 M–1

s–1

as the substituent

changes from 4-NO2 to 3-Cl and 4-Me, in turn. In contrast, the rate constant term for the

catalyzed reactions (Kk3) in the aqueous medium is almost independent of the electronic

nature of the substituent. Furthermore, the Kk3 value is not available for the reactions of

substrates possessing a strong EWG in the leaving group (e.g., 1a-1c).

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To investigate the effect of the substituents on reactivity, Hammett and Yukawa-Tsuno

plots have been constructed for the uncatalyzed reactions of 1a-1h with piperidine. The

Hammett plots correlated with σ‒ and σ

o constants exhibit varying degree of random scatter

for the data though the correlation with σo constants is marginally better (R

2 = 0.974) than

that found with σ‒ constants (R

2 = 0.965) as shown in Figures S12 A and B in the SM. In

contrast, the Yukawa-Tsuno plot shown in Figure 3 exhibits an excellent linear correlation (R2

= 0.990) with ρ = 1.66 and r = 0.31. It is noted that the r value obtained from the Yukawa-

Tsuno plot represents the resonance demand of the reaction center or the extent of resonance

contribution.57,58

Thus, an r value of 0.31 implies that a negative charge, which can be

delocalized to the substituent through resonance interactions, is developing, but only a small

degree, on the O atom of the leaving group in the RDS. This is consistent with the fact that

the Hammett plots correlated with σ‒ (highly dependent on through resonance) and σ

o (not

dependent on resonance) constants exhibit random scatter (Figure S12 in the SM) because

correlation of Kk2 with σ‒ or σ

o constants should result in good linearity when r = 1 (a full

negative charge) or r = 0 (no negative charge on the O atom of the leaving aryloxide).

0.0 0.5 1.0-3

-2

-1

0

1b

1c

1d

1e

1f

1g1h

1a

ρ = 1.66

r = 0.31

R2 = 0.990

log Kk2 / M

−1s

−1

σo + r (σ

− − σ

o)

Figure 3. Yukawa-Tsuno plot for the uncatalyzed reactions of 1-aryloxy-2,4-dinitrobenzenes

(1a-1h) with piperidine in 80 mol% H2O / 20 mol% DMSO at 25.0 ± 0.1 °C. The identity of

the points is given in Table 2.

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One might expect that the acidity of the aminium moiety of T± would be little influenced

by the electronic nature of the substituent on the leaving aryloxide as a consequence of the

long distance between the substituent and the NH+ moiety of MC

± (distal). Accordingly, if the

catalyzed reaction proceeds through a stepwise mechanism with an anionic intermediate MC‒

as shown in Scheme 1, the electronic nature of the substituent would have little or no effect

on the rate of deprotonation of the NH+ moiety of MC

± by a second amine molecule. In

contrast, if the catalytic reaction proceeds through a concerted mechanism with a six-

membered cyclic TS, as we have proposed for this SNAr reaction in MeCN,26

as shown in

Scheme 2, the electronic nature of the substituent would strongly influence the rate of proton

transfer from the second amine molecule to the O atom of the leaving group (proximal). This

is because the O atom of the leaving group becomes a poorer proton acceptor as the

substituent in the leaving group becomes a stronger EWG (or as the leaving group becomes a

weaker base). In fact, the catalytic route (the k3 process) is absent for the reactions of

substrates possessing particularly strong EWG in the leaving group (e.g., 1a-1c). This is

inconsistent with a catalyzed reaction that proceeds through MC‒ as shown in Scheme 1 but

is in good agreement with the proposal that the catalyzed reaction proceeds through a six-

membered cyclic TS as shown in Scheme 2. TScycl is the minimum and necessary case in

MeCN. In water, H2O may also be involved as an intermediary to relay protons and to

stabilize the initial amines through hydrogen-bonding, but water-free TScycl is still the

simplest case. Further, hydrogen-bonding of the amines to water precludes formation of

kinetically significant dimers found in some aprotic solvents.23,27, 39,40,59

Medium Effect on Reactivity and Reaction Mechanism. It is clear that the reaction

mechanism for the current reactions is governed by basicity of the leaving group and

incoming amine, since the catalytic route is absent for the reactions of substrates possessing a

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strong EWG in the leaving group, i.e., a weakly basic leaving group, with highly basic

piperidine. This is in contrast to our previous result where the corresponding reactions carried

out in MeCN proceed through both uncatalytic and catalytic routes throughout the range of

basicity of the leaving aryloxide and nucleophilic amine studied.26

Generally, ArO‒ is a poor leaving group in MeCN due to the strong electronic repulsion

between the anionic aryloxide and the negative dipole end of MeCN. Thus, the leaving ArO‒

for the catalyzed reaction in MeCN prefers to depart from MC± as a protonated form (i.e.,

ArOH) to reduce the electronic repulsion as shown in Scheme 2, rather than as an anionic

ArO‒ as shown in Scheme 1. Furthermore, the leaving aryloxide in the TScycl is a strong

proton acceptor in MeCN, although it bears a strong EWG. This is because ArO‒ is 13 ~ 19

pKa units more basic in the aprotic solvent than in H2O.60

This explains why the reactions of

1a-1h with piperidine in MeCN proceed through both the uncatalytic and catalytic routes

regardless of the leaving-group basicity.

However, ArO‒ is not so basic in aqueous medium especially when it possesses a strong

EWG (e.g., 4-NO2, 4-CN and 4-CHO). Besides, ArO‒ can be stabilized in H2O through H-

bonding interactions. Notably, H-bonding of NO2 by H2O has been shown to lead to

enhanced acidity for nitrophenols; the nitrophenoxide anions are stabilized in water relative

to the non-hydrogen bond donor solvent MeCN through what has been termed “substituent

solvation assisted resonance”.61

Accordingly, protonation of the leaving group through TScycl

is not required in H2O for the reactions of substrates bearing a strong EWG in the leaving

group. This idea is consistent with the kinetic result that the catalytic route is absent for

reactions of 1a-1c with piperidine carried out in the aqueous medium.

To account for our finding that basicity of the leaving group and incoming amine governs

the presence/absence of the k3 process, a qualitative energy profile is illustrated in Figure 4

Page 15 of 25



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16

for the processes from MC± to PH

+ and MC

‒ (or TScycl) (cf. Schemes 1 and 2). It is apparent

that the reaction would proceed through MC± to MC

‒ (or TScycl) if the energy barrier for the

k2 process is higher than that for the k3 path. On the contrary, the reactions would proceed

through MC± to PH

+ if the energy barrier to form PH

+ from MC

± is lower than that to form

MC‒ (or TScycl).

MC

MCPH

k3 k2

R. C.

E

(TScycl)

Figure 4. A qualitative comparative energy profile for the process from MC± to PH

+ and MC

‒

(or TScycl).

It is apparent that the energy barrier for the k2 process (i.e., departure of the leaving group

from MC± to give PH

+) would be strongly dependent on the basicity of the leaving aryloxide

whether the reaction proceeds either through MC‒ (Scheme 1) or via TScycl (Scheme 2).

However, the energy barrier for the k3 process (i.e., to form MC‒ from MC

±) should be little

influenced by the leaving-group basicity if the reaction proceeds via MC‒ (Scheme 1). The

energy barrier for the k3 process would be also independent of amine basicity, since a more

basic amine would deprotonate more rapidly the aminium moiety of MC± but, conversely, the

aminium ion would tend to hold the proton more strongly as the amine becomes more basic.

Thus, the reaction mechanism (i.e., presence or absence of the k3 process) would be mainly

governed by leaving-group basicity but not by basicity of the incoming amine, if the reaction

proceeds through the traditionally accepted pathway as shown in Scheme 1.

On the contrary, if the reaction proceeds via TScycl as shown in Scheme 2, the energy

Page 16 of 25



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17

barrier for the k3 process should be affected by the basicity of the leaving group and the

amine nucleophile. This is because a weakly basic leaving aryloxide would not accept a

proton readily from the second amine molecule in MC± while a strongly basic amine would

not donate a proton easily to the leaving aryloxide. This idea can account for the current

kinetic result that the k3 process is absent for the reaction of substrates possessing a weakly

basic leaving group (e.g., 1a – 1c) with strongly basic piperidine.

Another important piece of evidence that supports the proposed mechanism (i.e., TScycl) is

provided by analysis of medium effects on reactivity. As shown in Table 2, the rate term for

the uncatalyzed reaction (Kk2) is larger in H2O than in MeCN, although the nucleophilic

piperidine is over 7 pKa units less basic in the aqueous medium.62

This is consistent with the

idea that ArO‒ is not a poor leaving group in H2O as compared to MeCN. In contrast, the rate

constant term for the catalyzed reaction (Kk3) is smaller in the aqueous medium than in the

aprotic solvent. Moreover, the catalytic effect, i.e., the k3/k2 ratio, is smaller for the reactions

in H2O than in MeCN. This also supports the proposal that the leaving ArO‒ prefers to depart

from MC± as a protonated form (i.e., ArOH) in MeCN and that protonation of ArO

‒ by a

second amine molecule is not strongly required for the reaction in H2O.

Conclusion

The current SNAr reactions of 1a-1h with a series of cyclic secondary amines have led us

to conclude the following: (1) The reactions proceed with a zwitterionic intermediate MC±,

which decomposes to the products through uncatalytic and catalytic routes except for the

reactions of strongly basic piperidine with substrates that possess a strong EWG in the

leaving group (e.g., 1a-1c). The catalytic process is absent for reaction of 1a-1c with

piperidine. (2) The Brønsted-type plots for the reactions of 1a result in a smaller βnuc value

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18

for the catalyzed reactions than for the uncatalyzed reactions. (3) The Yukawa-Tsuno plot for

the uncatalyzed reactions of 1a-1h with piperidine exhibits an excellent linear correlation (R2

= 0.990) with ρY = 1.66 and r = 0.31, whereas the rate constants for the catalyzed reactions

are almost independent of the electronic nature of the substituent in the leaving group. (4)

The catalyzed reaction from MC± proceeds in a concerted fashion via a six-membered cyclic

TS (i.e., TScycl) rather than via a stepwise mechanism with an anionic intermediate MC‒. (5)

The Kk2 values for the reactions of 1a-1h with piperidine are larger in the aqueous medium

than in the aprotic solvent although piperidine is over 7 pKa units less basic in H2O. In

contrast, the Kk3 values are smaller in H2O than in MeCN. Furthermore, the catalytic effect

shown by a second amine molecule (i.e., the k3/k2 ratio) is also smaller for the reactions in

H2O. (6) The rate of protonation of the leaving ArO‒ by a second amine molecule through

TScycl (i.e., the catalytic process) decreases as the amine basicity increases or as the leaving-

group basicity decreases. (7) The leaving ArO‒ is not a poor nucleofuge in the aqueous

medium especially when it possesses a strong EWG. Thus, protonation of ArO‒ by a second

amine molecule through TScycl is not strongly required for the reactions in the aqueous

medium.

Acknowledgement. This research was supported by Basic Science Research Program

through the National Research Foundation of Korea (NRF) funded by the Ministry of

Education (2015-R1D1A1A-01059624). Support of the Vice-President’s Research Fund

(Grenfell Campus-MUN) is also acknowledged.

Supplementary material. The plots of kobsd vs. [amine] for the reactions of 1a with four

different secondary cyclic amines are illustrated in Figures S1-S4, and those for the reactions

of 1b-1h with piperidine are in Figures S5-S11. Hammett plots correlated with σ‒ and σ

o

constants are shown in Figure S12. Supplementary material is available with the article

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through the journal Web site.

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Captions for Figures and Tables

Figure 1. Plots of kobsd vs [amine] (A) and kobsd/[amine] vs [amine] (B) for the reaction of 1-

(4-nitrophenoxy)-2,4-dinitrobenzene (1a) with morpholine in 80 mol% H2O / 20 mol%

DMSOat 25.0 ± 0.1oC.

Figure 2.Brønsted-type plots of Kk2 (A) and Kk3 (B) for the reactions of 1-(4-nitrophenoxy)-

2,4-dinitrobenzene (1a) with amines in 80 mol% H2O / 20 mol% DMSO at 25.0 ± 0.1 °C.

Figure 3. Yukawa-Tsuno plot for the uncatalyzed reactions of 1-aryloxy-2,4-dinitrobenzenes

(1a-1h) with piperidine in 80 mol% H2O / 20 mol% DMSO at 25.0 ± 0.1 °C. The identity of

the points is given in Table 2.

Figure 4. A qualitative comparative energy profile for the process from MC± to PH

+ and MC

‒

(or TScycl).

Table 1. Summary of Kinetic Data for the Reactions of 1-(4-Nitrophenoxy)-2,4-

dinitrobenzene (1a) with Amines in 80 mol% H2O / 20 mol% DMSO at 25.0 ± 0.1 °C

Table 2. Summary of Kinetic Data for the Reactions of 1-Aryloxy-2,4-dinitrobenzenes (1a-

1h) with Piperidine in 80 mol% H2O / 20 mol% DMSO at 25.0 ± 0.1 °Ca

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Graphical Abstract

Medium Effect (H2O versus MeCN) on Reactivity and Reaction Pathways for SNAr Reaction

of 1-Aryloxy-2,4-dinitrobenzenes with Cyclic Secondary Amines

Ik-Hwan Um,* Min-Young Kim, and Julian M. Dust

†*

Department of Chemistry, Ewha Womans University, Seoul 120 - 750, Korea


†Departments of Chemistry and Environmental Science, Grenfell Campus-Memorial

University of Newfoundland, Corner Brook, Newfoundland and Labrador A2H 5G4,

Canada


ArO NNO2

NO2

N

NO2

NO2

ArOH

H HN

δ

δ

k3

OAr

NO2

NO2

+ HNk1

k-1

ArO NH

k2

NO2

NO2

HN

NO2

NO2

ArO

H

1a-1h MC PH

P

HN

TScycl

HN

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