Effect of the nature of the nucleophile and solvent on an SNAr reaction

Article abstract of DOI:10.1039/c7nj03212a

The reaction of 2,4-dinitrobenzenesulfonyl chloride toward propylamine was kinetically evaluated in 19 organic solvents and 10 ionic liquids as reaction media. This study was compared with a previous study to experimentally show that solvent effects and t

Full text of DOI:10.1039/c7nj03212a

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ISSN 1144-0546
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Jason B. Benedict et al.
The role of atropisomers on the photo-reactivity and fatigue of
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Nature of the nucleophile and solvent effect on a SNAr reaction.
Marcela Gazitúa,*a Ricardo A. Tapia,b Renato Contrerasc and Paola R. Campodónico a
Received 00th January 20xx,
Accepted 00th January 20xx
The reactions of 2,4-dinitrobenzenesulfonyl chloride toward propylamine was kinetically evaluated in 19 organic solvents
and 10 ionic liquids as reaction media. This study was compared with a previous work in order to experimentally show that
solvent effects and the nature of the reacting pair drastically affects the reaction rate and the reaction mechanism. While
the reaction of the reference electrhophile 2,4-dinitrobenzenesulfonyl chloride with piperidine is favored in polar solvents
with the ability to donate or accept hidrogen bonds; the reaction with propylamine is favored in solvents with the ability to
accept hidrogen bond.
DOI: 10.1039/x0xx00000x
www.rsc.org/
have been studied in conventional organic solvent (COS)10,12,20–24
and room temperature ionic liquids (RTILs),12,17,18,20,25–28 thereby
opening the discussion of the factors that determine its
Introduction
The study of mechanisms and reactivities in nucleophilic aromatic
substitution (SNAr) reactions have extensively been investigated1–18
and continue attracting the attention. In general, the SNAr
mechanism proceeds via stepwise mechanism5–11,13–15 that involves
a first step where the nucleophile attack at the substrate to gives an
intermediate, commonly called a Meisenheimer complex (MC) and
the leaving group (LG) departure in a second step through catalyzed
or non-catalyzed pathways.4,10-13,15 The general mechanism for the
reactions involving amine as nucleophiles is shown in Scheme 1.
selectivities, reaction rates and mechanisms. For instance, D´anna
et al.18 investigated the reaction of 2-substituted 5-nitrothiophenes
with secondary amines. In that work, it was shown that the
reactions were faster in all the RTILs used in comparison with
methanol or benzene. This kinetic response was attributed to the
stabilization of the MC trough polarity effects together with a
reduction of the reactivity of the amine traced to the ability of the
solvent to donate Hydrogen Bond (HB). In RTILs media, they suggest
that the improvement in the reactivity is caused by the anion/cation
pair of the RTILs. Habibi-Yangjeh et al.23 studied the reaction
between 1-chloro-2,4-dinitrobenzene and aniline in mixtures of 1-
ethyl-3-methylimidazolium ethylsulfate with methanol, chloroform,
and dimethylsulfoxide. They demonstrated through
multiparameter linear regression that the reaction rate constants
increase with normalized polarity parameters
(¡ª° ʛ
a
,
dipolarity/polarizability π* and Hydrogen Bond Basicity (HBB) and
decreases with Hydrogen Bond Acidity (HBA). Newington et al.24
investigated the reaction of p-fluorobenzene and p-anisidine in four
Scheme 1. General mechanism for a SNAr reaction.
Up to date, few studies have considered systems that involve the COS, nine RTILs and solvent-free conditions. They found that the
possible existence of competing reactions between traditional nature of the solvent exerts a dramatic effect on the reaction due
nucleophilic substitution (SN) and SNAr. For example Bunnet et al.17 to their polarities and abilities to donate or accept HB.
studied
a number of mono and dinitrophenyl esters of p- Much of our recent efforts have been focused in this area. For
toluenesulfonic and mesitylenesulfonic acid. The authors suggested instance, in one of our previous works, we reported the reaction of
that the attack at the carbon or sulphur centres depends on the 2,4-dinitrophenylsulfonyl chloride (DNBSCl) with secondary alicyclic
reagent used and the yield of SNAr or SN products is strongly amines.13 In this reaction, the possibility of competitive SN/SNAr
influenced by the solvent. Now, solvent effect in SNAr reactions pathways was discarded, thereby suggesting that this reaction
occurs only via SNAr pathways and that the solvent polarity affects
the route of SNAr reactions. The dual character of water and
formamide as HB donor and acceptor resulted in a nucleophilic
activation at the nitrogen atom of piperidine and consequently its
reactivity was increased. On the other hand, when RTILs were used
as reaction media, EMIMDCN qualified as the best solvent, being
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the reaction 5 times faster than in aqueous medium, a result SNAr product; in agreement with our previous results.13 The
probably due to the high polarizability of the dicyanamide anion.13
formation of a unique SNAr product discards the possibility of
In this work, we are revisiting this reaction to answer a few nucleophilic attack at the unsubstituted position on the ring.29
questions: first, is the solvent effect affected under a change in the Under amine excess, pseudo first order rate constants (kobs
)
amine structure; e.g. from secondary (piperidine in previous work) were found for COS and RTILs. The values of kobs for all the
to primary amine (propylamine in this work)? Secondly, which reactions are in accordance with Eqn. 1 where k0 and kN are
reactions could be predicted to be accelerated or decelerated when the rate coefficients for solvolysis and aminolysis of the
using a RTILs rather than a COS? And third, to evaluate whether the substrate, respectively. We shall first analyse the solvent
anion or the cation are responsible for the changes in reactivities effects on the model reaction in COS, to have a reference
when RTILs are used as solvents. Scheme 2 shows the acronyms of system to discuss solvent effects in the series of RTILs
the RTILs, structures of substrate and amines that were used in this afterwards.
Linear plots of kobs vs NT (total amine
study.
concentration), for a series of COS is observed (see Figure 1).
N,N-DMF
MeCN
27
DMSO
FMA
tert-butanol
2-propanol
Butanol
18
Methanol
Ethanol
Water
Ethyl acetate
9
0
0
15
30
102 NT / M
45
Figure 1. Linear plot of kobs against NT of the reactions of DNBSCl with
propylamine at 25.0 °C in a series of COS.
The values of kN were obtained as the slope of linear plots of
Eqn. 1. These plots pass through the origin and the reactions
occurs via a non-catalyzed route (k2 in Scheme 1 and Figures
S9-S19 and Tables S1-S11 in ESI).
Amines:
kobs = k0 + kN[N]T
(1)
H2N
Table 1. Values of kN for the reactions of DNBSCl with propylamine
and piperidinea in a series of COS.
HN
Piperidine
Propylamine
Solvent
104 kN
Propylamine
104kN
Piperidinea
N,N-DMF
MeCN
173 ± 6.0
69.0 ± 3.3
36.0 ± 2.8
29.0 ± 1.6
25.0 ± 0.68
20.0 ± 0.66
14.0 ± 0.56
8.44 ± 0.32
8.40 ± 0.31
1.76 ± 0.040
30.9 ± 1.0
-
Scheme 2. Acronyms of the RTILs, structures of substrate and
-
amines that were used in this study.
DMSO
278 ± 9
577 ± 11
16.4 ± 0.90
6.40 ± 0.29
9.20 ± 0.43
4.80 ± 0.12
7.20 ± 0.30
156 ± 2.2
-
FMA
tert-Butanol
2-Propanol
Butanol
Methanol
Ethanol
Results and discussion
In this work, we report a kinetic study on the reactions of DNBSCl
with propylamine in a series of COS and RTILs as reaction media.
The kinetic products were confirmed spectrophotometrically and
they correspond to the product of SNAr reaction for all the reaction
media studied. The product analysis was performed using HPLC, by
comparing the retention times and UV-visible spectra with those of
the authentic samples at the same experimental conditions (See
Figures S1-S8 in Electronic Supplementary Information, ESI). HPLC
analyses at different times shown that the SN product is formed in
minor proportion and it reacts with the excess of amine to give the
H2O
Ethyl acetate
Acronyms of COS: N,N-DMF is N,N-dimethylformamide, MeCN is acetonitrile,
DMSO is dimethyl sulfoxide and FMA is formamide. The value accompanying the kN
constant corresponds to the error of the slope to obtain these values. akN data were
obtained from ref 13.
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Despite the small values of the rate constants, if we compare the kN is enhanced in aprotic solvents for the reaction with propylamine.
values of the reaction of DNBSCl with propylamine vs piperidine13 In summary, the reaction rate coefficients are solvent dependent
quoted in Table 1 in a series of COS we note that the rate constants mainly in the ability of the solvent to accept or donate HB; their
with piperidine is higher than propylamine in DMSO, FMA and intrinsic polarity and the structure of the nucleophile.
water as solvents. These data allow assessing the nature of the Now, to see if these medium effects are universal in any solvent, we
nucleophile over the reaction. Note that the reactions of DNBSCl undertook a similar kinetic study in solvents of quite different
with piperidine are approximately 8, 20 and 88 times faster than nature, namely RTILs. We included a series of 10 RTILs for this
the reaction of DNBSCl with propylamine, in DMSO, FMA and water purpose. Table 2 shows kN values for the reactions of DNBSCl with
respectively. This response can be attributed to the more polar propylamine and piperidine13 in RTILs and Figure 2 displays linear
character of these solvents as compared to the remaining series of relationships between kobs and NT for propylamine to evaluate their
COS studied: they can interact more efficiently with the proton of solvent effects on the same reaction and similar conditions.
piperidine. This result is probably to two factors: i) despite
displaying similar values of pKa (i.e. similar basicity), their structures
are different. Propylamine is linear and piperidine presents a chair
conformation, which is the most stable one and producing the
30
20
10
0
BMIMBF4
lowest steric hindrance, thereby suggesting that polar solvents
would remove the proton from the amine more easily. ii) the
double effect of hyperconjugation of -CH2 groups adjacent to the
nitrogen atom of piperidine increases its electron density thereby
enhancing its nucleophilicity which is favoured in polar solvents in
comparison to propylamine.10,30 Furthermore, we can observe that
DMSO, FMA and water display different HB abilities. For instance,
DMSO presents only HB accepting properties, while H2O and FMA
can accept and donate HB. The high rate value in H2O (using
piperidine as nucleophile) suggests the presence of a HB between a
hydrogen atom of H2O acting as a bridge between the nucleophile
and the leaving group.13 This bridge facilitates the relay of electron
density from the amine towards the electrophilic centre; thereby
enhancing the nucleophilicity of the amine.13 This interaction is
marginal when propylamine is used as nucleophile if we consider
the low value of its rate constant (see Table1). This would give us an
indication of the reaction with piperidine is favoured in more polar
solvents with the ability of donate and accept HB, whereas the
reaction with propylamine is more favoured in solvents that can
accept HB and less favoured in those solvents that can donate HB.
On the other hand, when alcohols are used as solvents, the
reactions with propylamine are at most 3 times faster than
piperidine. However, since the kN values are so small, we could say
that the rate constants of both amines are practically the same. This
is probably due to the low polarity of all alcohols and the better
packing between the molecules of alcohol and propylamine in the
bulk of solvent in comparison to piperidine.
BMIMNTF2
BM2IMNTF2
HMIMNTF2
BMIMDCN
NEMMPNTF2
BMIMFAP
BMIMPF6
EMIMNTF2
EMIMDCN
0
15
30
102 NT / M
45
Figure 2: Linear plots of kobs against NT for the reactions of DNBSCl with
propylamine at 25.0 °C in a series of RTILs.
Table 2. Values of kN for the reactions of DNBSCl with propylamine
and piperidinea in a series of RTILs.
RTILs
104kN / s-1M-1
Propylamine
104kN / s-1M-1
Piperidinea
BMIMBF4
BMIMNTF2
BMIMDCN
BMIMFAP
BMIMPF6
59.1 ± 4.0
448 ± 42
266 ± 21.3
235 ± 5.30
186 ± 5.60
206 ± 10.0
263 ± 15.0
291 ± 20.0
-
58.2 ± 4.0
48.2 ± 2.0
17.9 ± 1.0
40.9 ± 2.0
It´s seems that not only the solvents effects are implicated in the
reactivity patterns in these systems; the nature of the amine is one
of the additional factors on which the observed reactivity depends.
This response is apparent after a sight to Figure 1. Note that, the
best solvent for the reaction of DNBSCl with propylamine is N,N-
DMF. The rate constant is 2.5 times faster in N,N-DMF in
comparison to MeCN, 20 times faster than in ethanol and 98 times
faster than in water. Note also that, the oxygen atom of N,N-DMF
could accept a HB from propylamine and the -CH3 groups in N,N-
DMF generates an additional inductive effect on the nitrogen atom
of the solvent, suggesting an enhancement of the reactivity of the
system.10,30 Besides, N,N-DMF, MeCN, ethyl acetate and DMSO only
have the ability to accept HB while water, FMA and all alcohols can
accept and donate HB which probably causes a decrease in the rate
constants. This leads us to think that the rate constants for DNBSCl
BM2IMNTF2
HMIMNTF2
NEMMPNTF2
EMIMNTF2
EMIMDCN
104.3 ± 5.0
29.3 ± 1.2
35.9 ± 1.6
27.3 ± 1.3
360 ± 19.0
717 ± 32.0
38.2 ± 1.3
The value accompanying to the kN value correspond to the error of the slope to obtain
this value. akN data were obtained from ref 13.
If we compare the kN values for the reaction of DNBSCl with
propylamine vs piperidine (see Table 2), it may be seen that the
reactivity with piperidine is higher than propylamine in all RTILs
evaluated. The reaction of DNBSCl with piperidine in EMIMDCN is
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19 times faster than the same reaction in propylamine. The slowest solvents. A definitive answer about differential solvent effects
rate constant is in BMIMFAP for both amines; being 10 times faster would be the study in mixtures COS/RTILs that could contribute to
for piperidine than propylamine. These responses are probably add evidence on probable preferential solvation effects. This work
traced to the fact that all RTILs used can donate and accept HB. This is in course in our group.
result is similar to that observed in the series of COS. This suggests
that the reactivity follows the same pattern observed for both types
Conclusions
of solvents. The reaction in study with piperidine is favoured in
solvents that can donate and accept HB while in propylamine is
The reaction of DNBSCl and propylamine have been examined for a
favoured in solvents that can accept HB.
series of conventional and non-conventional solvents and
If we now analyse the kinetic responses among RTILs for
compared to a previous work with piperidine. The analysis based on
propylamine, the reaction rate is 6 times faster in BM2IMNTF2 as
the kinetic study shown that DNBSCl is more reactive toward
compared to BMIMFAP; the worst RTILs within the series.
piperidine like nucleophile in comparison with propylamine in polar
BM2IMNTF2 seems to be the best solvent and the fact that the
solvents with the ability of donate and accept HB, while that the
acidic proton of imidazolium is blocked, could also become a key
reaction in propylamine is favoured only with solvent that can
contribution to the enhancement of the reactivity. The presence of
accept HB. The reactivity is marginally changed when alcohols are
a -CH3 in position 2 on the imidazolium group prevents HB with
used as solvents; probably due to its low polarity and the better
propylamine thereby increasing the reactivity, a result which agrees
packing between the molecules of alcohol and propylamine in
with that observed for the COS series. The remaining RTILs series
comparison to piperidine. For the reaction between DNBSCl with
have this acidic proton available to form HB with propylamine
propylamine in COS, the best solvent is N,N-DMF and in the case of
which decreases the reactivity (Details in Figures S20-S29 and
RTILs, the best solvent is BM2IMNTF2. The optimal solvent is the one
Tables S12-S21 in ESI).
which is capable of assist propylamine to enhance its nucleophilicity
To evaluate the performance of the RTILs as reaction media based
and the ability of accept HB. Therefore, solvent effects and the
on cation/ anion effects, we compared different families of RTILs by
nature of the reacting pair should be considered to analyse the
fixing the cation (BMIM) and varying the anion (i.e. to evaluate the
reaction mechanism and its reactivities because both, the reaction
anion effect) and fixing the anion (NTF2) and varying the cation (i.e.
pair and the reaction medium are determining factors in these
to evaluate the cation effect) (see Fig S30 y S31 in ESI). When we fix
processes.
the anion, no big differences in reaction rates were observed. EMIM
presents the same kobs values as HMIM. Apparently, varying the
length of the alkyl chain of the imidazolium moiety from two to six
Experimental section
carbons, does not produce any change in the value of the rate
Materials
constant in accordance with previous work.13 BM2IM appears to be
Propylamine was purified before of to be used. All the organic
the most favourable reaction medium within the anions evaluated.
solvent used were commercial available from Sigma-Aldrich and
Apparently, the steric hindrance effects going from two to six
Merck with purity ≥ 99%. They were stored under anhydrous
carbon atoms in the alkyl chain in the cation is less important than
conditions and used as they were received. The certificate of
the absence of the acidic proton of the imidazolium group.
analysis given by Merck S.A. of all RTILs show purity values between
Now, when we fix the cation the results show the following
99 and 100%, presence of halides ≤ 0.1 % and its content of water ≤
anion-dependent order of decreasing quality as reaction
1 %. To ensure that they had no water, we put the RTILs into a
media: BF4 > NTF2 > DCN > PF6 > FAP. The rate constant in BF4 is
vacuum drying oven LabTech Model LVO-2013 for 4 hours at a
twice that in FAP. As we can see, the size of the anion shows
pressure of -0.06 MPa before of to be used.
an inverse relationship with the reaction rate. At higher anion
size, lower rate constant, probably caused by
a steric
Synthetic protocol of 2,4-Dinitro-N-n-propylaniline.
hindrance that hinders the interaction between the
nucleophile and the electrophile, (see Figure S31 in ESI)
To a stirred solution of 1-fluoro-2,4-dinitrobenzene (200 mg, 1.07
mmol) in dry DMSO (2.0 mL), containing potassium carbonate (280
mg, 2.03 mmol), was slowly added n-propylamine (72 mg, 1.22
mmol). Stirring was continued for 2 h at room temperature and the
reaction mixture was poured onto ice-water (20 g). The solid was
filtered, washed with water, dried and recrystallized from
dichloromethane–hexane (1:1) to give 2,4-dinitro-N-n-propylaniline
(170 mg, 70%), mp 98–100 °C (Lit.P. Gangopadhyay,2000: 100-102
°C); IR (KBr) νmax cm−l 3380, 3100, 1630, 1590, 1520, 1420, 1350,
1300. 1H (400 MHz, CDCl3): δ = 1.10 (t, J = 7.4 Hz, 3H), 1.83
(sextuplet, J = 7.1 Hz, 2H), 3.40 (q, J = 7.1 Hz, 2H), 6.93 (d, J = 9.5 Hz,
1H), 8.28 (dd, J = 9.5, 2.6 Hz, 1H), 8.59 (br s, 1H), 9.16 (d, J = 2.6 Hz,
1H). 13C NMR (100 MHz, CDCl3): δ 11.9, 22.5, 45.7, 114.3, 124.8,
130.7, 130.8, 136.3, 148.8.
If we compare the performance of the best COS with the best RTIL
for the reaction between DNBSCl and propylamine (Tables 1 and 2),
N,N-DMF is 1,7 times faster than BM2IMNTF2. This result may be
probably traced to the higher HB accepting capability of N,N-DMF
as compared to BM2IMNTF2. Note that, the difference between
them is their sizes that can cause a greater steric hindrance and
consequently a decreasing in the reactivity.
In summary, the reactivity of the model substrate in RTILs is slightly
more favourable with piperidine as nucleophile. Note that
EMIMDCN is the best solvent for the reaction of DNBDCl with
piperidine, but it is not for the same reaction with propylamine.
These results indicate that HB effects from the solvent to the
nucleophile are qualitatively the same, and that the nature of the
nucleophile is also similar in both sets of molecular and ionic
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ARTICLE
protocol
propylbenzenesulfonamide.31
of
2,4-Dinitro-N-n-
1991.
3
M. R. Crampton, T. A. Emokpae, C. Isanbor, A. S. Batsanov,
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A solution of 2,4-dinitrobenzenesulfonyl chloride (266.6, 1.0 mmol)
in dry dichloromethane (20 mL) was slowly added to a mixture of n-
propylamine (72 mg, 1.22 mmol) and pyridine (118.8 mg, 1.5 mmol)
in dry dichloromethane (20 mL) at 0 ºC. The reaction mixture was
stirred at room temperature for 6.0 h. The solution was washed
with 1 M HCl (5.0 mL) and water (5.0 mL), dried (Na2SO4) and
concentrated. The residue was purified by column chromatography
on silica gel using petroleum ether /cloroform (1:1) to give 2,4-
dinitro-N-n-propylbenzenesulfonamide (165 mg, 57%), mp 81-82 ºC
1H NMR (400 MHz, CDCl3): δ 0.92 (t, J=7.4 Hz, 3H), 1.55 (sextuplet, J
= 7.4 Hz, 2H), 3.09 (q, J = 7.4 Hz, 2H), 5.36 (br.s, 1H), 8.37 (d, J = 8.7
Hz, 1H), 8.56 (dd, J = 8.7, 1.7 Hz, 1H), 8.66 (d, J = 1.7 Hz, 1H); 13C
NMR (100 MHz, CDCl3): δ 10.9, 23.0, 45.6, 120.7, 127.0, 132.5,
139.3, 148.2, 149.7.
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Kinetic Measurements
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chloride were measured by a diode array spectrophotometer at
25.0 °C y monitoring the formation of the product between 350-400 12
nm depending of the solvent used. The initial substrate
concentration was 5x10-5 M. Under excess amine, pseudo-first- 13
order rate coefficients (kobs) were found throughout. The kobs values
were obtained through the kinetic software (for first-order 14
reactions) of the spectrophotometer.
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Chromatographic system and conditions
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The HPLC system used for the analysis of the samples was a UV-
DAD Elite Lachrom with quaternary pump L-2100 with a UV-DAD
detector L-2455, 8μL injection loop, oven column L-2300 and
autosampler L-2200 with cooling unit. The column attached was a
Chromolith Fast Gradient RP 18 50-3mm (Merck). The UV detector
was set at 260 nm which was found to be the most suitable
wavelength for the detection of all the substrates, product and
internal standard. The flow-rate of the mobile phase was adjusted
to 0.5 mL/min to keep the column pressure between 47 – 50 bar.
The system was thermostated at 25°C, to maintain the same
reactions conditions. Chromatograms were recorded in a computer
system using EZChrom Elite software from Agilent.
17
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This work was supported by Postdoctoral fellowships 3120060,
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130006
- CILIS, granted by Fondo de Innovación para La
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Chile and Instituto de Ciencias e Innovación en Medicina (ICIM-CAS
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