Substituent effect on acidity of substituted 2-(4-nitrobenzoylamino)alkanamidesin methanol-dimethyl sulfoxide mixtures

Article abstract of DOI:10.1135/cccc19980085

The dissociation constants of substituted 2-(4-nitrobenzoylamino)alkanamides, N-[2-(4-nitrobenzoylamino)aikanoyl]pyrrolidines, and N-alkyl-4-nitrobenzamides have been measured spectrophotometrically in 60 and 80% v/v DMSO. The pK_A values of these N-acids are discussed from the point of view of substituents at the acetamide a-carbon atom.

Full text of DOI:10.1135/cccc19980085

Substituent Effect on Acidity
85
SUBSTITUENT EFFECT ON ACIDITY OF SUBSTITUTED
2-(4-NITROBENZOYLAMINO)ALKANAMIDES IN
METHANOL–DIMETHYL SULFOXIDE MIXTURES
1
2
3
Petr MITAS , Milos SEDLAK and Jaromir KAVALEK
Department of Organic Chemistry, Faculty of Chemical Technology, University of Pardubice,
532 10 Pardubice, Czech Republic; e-mail: 1 mitas@hlb.upce.cz, 2 sedlak@hlb.upce.cz,
3 kavalek@hlb.upce.cz
Received August 13, 1997
Accepted October 20, 1997
Dedicated to Professor Vojeslav Sterba on the occasion of his 75th birthday.
The dissociation constants of substituted 2-(4-nitrobenzoylamino)alkanamides, N-[2-(4-nitrobenzoyl-
amino)alkanoyl]pyrrolidines, and N-alkyl-4-nitrobenzamides have been measured spectrophotometri-
cally in 60 and 80% v/v DMSO. The pKA values of these N-acids are discussed from the point of
view of substituents at the acetamide α-carbon atom.
Key words: Dissociation constants; Substituent effects; 2-(4-Nitrobenzoylamino)alkanamides; Solvent
effects; Steric effects.
The substituted 2-(4-nitrobenzoylamino)alkanamides contain two dissociation centres
in their molecules, viz. the benzamide and acetamide ones, and they were used as inter-
mediates in syntheses of imidazolinone derivatives in MeOH–DMSO media1. This cyc-
lization reaction, whose kinetics is described in ref.1, is base catalyzed and its
rate-limiting step is ionisation of the substrate (Scheme 1). It is only the anion formed
1
R
O N
2
CONCCONH
2
K
2
A
1
R
R
+
CH OH
3
+
O N
2
CONHCCONH
CH O
3
2
1
2
R
R
K’
A
O N
2
CONHCCONH
2
R
k
2
R
1
N
R
O N
2
O
N
SCHEME 1
H
Collect. Czech. Chem. Commun. (Vol. 63) (1998)

86
Mitas, Sedlak, Kavalek:
by the ionisation at the acetamide centre, which can provide the cyclization reaction
product (the respective substituted derivative of imidazolinone).
The aim of the present communication was to find out the way in which substituents (R1, R2)
at the acetamide α-carbon atom affect the acidity of the benzamide and acetamide centres
in the molecules of substituted 2-(4-nitrobenzoylamino)alkanamides, and which of the
nitrogen atoms of the substrates is preferably deprotonated and what is the proportion
of individual anions in their mixtures in MeOH–DMSO media.
EXPERIMENTAL
1
The temperature data have not been corrected. The H NMR spectra were measured on an AMX 360
Bruker spectrometer at 360.14 MHz at 25 °C in deuteriochloroform and hexadeuteriodimethyl sulfoxide.
The chemical shifts have been referenced to the signals of the nondeuteriated solvents (δ(1H) 7.25
CHCl3 and δ(1H) 2.55 DMSO). The electronic spectra were measured on a Hewlett–Packard 8453
Diode Array apparatus at 25 °C.
Chemicals
Methanol p.a. (Aldrich) was redistilled under argon and kept in a bottle with molecular sieve A4.
Dimethyl sulfoxide p.a. (Aldrich) was kept in a bottle with molecular sieve A4. The water content
(according to Fischer) was 0.09–0.12% w/w. Sodium methoxide was prepared as a 5 M solution by
dissolving sodium metal in methanol which had been rid of carbon dioxide by distillation under
argon. The solutions of definite concentration were prepared by diluting with methanol, and their
MeONa concentration was determined by means of titration with a standard solution of hydrochloric
acid. The MeOH–DMSO solutions with MeONa concentrations above 5 mol l–1 were prepared by
dissolving solid MeONa (Aldrich) in MeOH–DMSO mixtures, and their MeONa concentration was
determined as above.
N-Acids: N-(4-nitrobenzoylamino)pyrrolidine (1a), N-[2-(4-nitrobenzoylamino)propanoyl]pyrro-
lidine (1b), N-[2-(4-nitrobenzoylamino)-3-methylbutanoyl]pyrrolidine (1c) and N-[2-(4-nitrobenzoyl-
amino)-2-methylpropanoyl]pyrrolidine (1d) were prepared from the corresponding amino acids,
which were esterified (methanol and gaseous hydrogen chloride), then acylated with 4-nitrobenzoyl
chloride in chloroform, and finally aminolyzed2 with pyrrolidine. The adopted 2-(4-nitrobenzoyl-
amino)ethanamide (2a), 2-(4-nitrobenzoylamino)propanamide (2b), 2-(4-nitrobenzoylamino)-3-
methylbutanamide (2c), 2-(4-nitrobenzoylamino)-2-methylpropanamide (2d), 2-(4-nitrobenzoyl-
amino)-2,3-dimethylbutanamide (2e), 1-(4-nitrobenzoylamino)-1-cyclohexanecarboxamide (2f), 2-(4-
nitrobenzoylamino)-2-phenylpropanamide (2g), 2-(4-nitrobenzoylamino)-2,4-(nitrophenyl)propan-
amide (2h), and 2-amino-2-(4-nitrophenyl)propanamide (4a) were prepared from the corresponding
ketones by the modified Strecker synthesis3. The obtained 2-aminoalkanenitriles were hydrolyzed in
the medium of hydrogen peroxide or sulfuric acid to give the respective 2-aminoalkanamides, which
were acylated3 with 4-nitrobenzoyl chloride in anhydrous chloroform except for compound 4a. The
carboxamides 4-nitrobenzamide (3a), N-methyl-4-nitrobenzamide (3b), and N-(2-methylpropyl)-4-
nitrobenzamide (3c) were prepared from 4-nitrobenzoyl chloride and the corresponding amine in an-
hydrous chloroform using triethylamine as a base. The identity of compounds 1b–1d, 2b and 2c was
verified by the 1H NMR spectra which are presented in Table I. The results of elemental analyses,
melting points and yields are given in Table II.
Collect. Czech. Chem. Commun. (Vol. 63) (1998)

Substituent Effect on Acidity
87
Collect. Czech. Chem. Commun. (Vol. 63) (1998)

88
Mitas, Sedlak, Kavalek:
TABLE II
Melting points, yields of syntheses, and elemental analyses of N-acids 1a–1d, 2a–2h, 3a–3c, and 4a
Calculated/Found
M.p., °C
(ref.)
Yield
%
Formula
(M.w.)
Compound
Solvent
% C
% N
% H
1a
1b
1c
1d
2a
2b
2c
2d
2e
2f
171–175
52
68
70
35
67
66
67
72
81
70
79
90
85
80
78
53
C13H15N3O4
(277.3)
CHCl3–C6H12
(3 : 1)
–
–
–
–
–
–
(171–175)a
180–182
–
C14H17N3O4
(291.3)
CHCl3–C6H12
(2 : 1)
57.72
57.72
5.88
5.92
14.42
14.36
152–154
–
C16H21N3O4
(319.4)
CHCl3–C6H6
(1 : 1)
60.17
59.66
6.62
6.49
13.16
12.90
154–156
–
C15H19N3O4
(305.3)
CHCl3–C6H12
(3 : 1)
59.00
58.79
6.27
6.25
13.76
13.30
244–246
C9H9N3O4
(223.2)
CHCl3–C6H12
(1 : 1)
–
–
–
–
–
–
(244–246)b
237–238
–
C10H11N3O4
(237.2)
CHCl3–CH3OH
(1 : 1)
50.63
50.86
4.67
4.80
17.71
17.56
202–204
–
C12H15N3O4
(265.3)
CHCl3–C6H12
(3 : 1)
54.33
54.72
5.70
5.66
15.84
14.14
229–232
C11H13N3O4
(251.2)
CHCl3–C6H12
(2 : 1)
–
–
–
–
–
–
(229–232)c
181–183
C13H17N3O4
(279.3)
CHCl3–C6H12
(1 : 1)
–
–
–
–
–
–
(181–183)c
201–202
C14H17N3O4
(291.3)
CHCl3–C6H12
(1 : 1)
–
–
–
–
–
–
(201–202)c
2g
2h
3a
3b
3c
4a
125–128
C16H15N3O4
(313.3)
CHCl3–CH3OH
(1 : 1)
–
–
–
–
–
–
(125–128)c
198–201
C16H14N4O6
(251.2)
CHCl3–CH3OH
(1 : 1)
–
–
–
–
–
–
(198–201)c
197–199
C7H6N2O3
(166.1)
H2O
H2O
H2O
–
–
–
–
–
–
(199–200)d
220–221
(220)b
C8H8N2O3
(180.2)
–
–
–
–
–
–
117–118
C11H14N2O3
(222.2)
–
–
–
–
–
–
(117–118)b
111–112
C9H11N3O3
(209.2)
CHCl3–C6H12
(1 : 1)
–
–
–
–
–
–
(111–112)c
f
a Ref.17. b Ref.18. c Ref.3. d Ref.19. e Ref.20. Ref.21.
Collect. Czech. Chem. Commun. (Vol. 63) (1998)

Substituent Effect on Acidity
Dissociation Constants
89
Spectrophotometry in 60 and 80% v/v DMSO was used to determine the dissociation constants of
N-acids 1a–1d, 2a–2h, 3a–3c, and 4a: a 1 cm closeable quartz cell placed in thermostated cell com-
partment of spectrophotometer was charged with 2 ml of respective sodium methoxide solution, and
20 µl methanolic solution of substrate (c 1 . 10–2 mol l–1) was injected thereto; the solution was
mixed and its spectrum was measured within 5 s.
RESULTS AND DISCUSSION
When measuring the electron spectra of N-acids 1a–1d, 2a–2h, 3a–3c, and 4a in a
series of sodium methoxide solutions in MeOH–DMSO, we obtained records with well-
developed isosbestic points. N-Acids 1b (60% v/v DMSO), 2b (80% v/v DMSO), and
2c and 2d (60 and 80% v/v DMSO) showed a second isosbestic point in the most
concentrated sodium methoxide solutions. For these substances the analytical wave-
length was chosen just in this newly formed isosbestic point in order to ensure the
constant value of absorbance of the conjugated base of indicator. The values of disso-
ciation constants pKA (where pKA = –pKexp) were read from the dependence of log I on
−
−
−
log cMeO , or from the dependence of log Q (log I – log cMeO ) on cMeO if the base
concentration was above 0.1 mol l–1. In these cases the activity coefficients of the
individual species are not equal to one, hence the dissociation constants were read from
−
the straight-line dependence of log Q on cMeO . The intercept at the axis of ordinates
represented the value of dissociation constant extrapolated to infinitely diluted solution
of sodium methoxide4 (Table III).
The changes in composition of MeOH–DMSO binary mixtures considerably affected
the values of dissociation constants of N-acids. Increasing content of polar aprotic
DMSO (which solvates anions less efficiently) in the mixture shifted the reaction of
N-acid with methoxide ion in the direction of lower solvation requirements, i.e. in the
direction of N-anion5, which resulted in an acidity increase of all the N-acids measured
when going from 60 to 80% v/v DMSO (Table III). On the other hand, sodium meth-
oxide is considerably solvated in methanol, hence the sodium cation itself is less ac-
cessible to formation of ion pairs with N-anions. Increasing DMSO content decreases
solvation of methoxide, which makes the formation of ion pairs more likely. The sta-
bilization of N-anions by ion pairs results in increased acidity of the N-acids measured.
The formation of the new isosbestic point in the case of the N-acid containing a single
centre of dissociation (compound 1b in 60% v/v DMSO) could be interpreted by forma-
tion of ion pairs, but we rejected this interpretation on the basis of the following experi-
ment: into each methoxide solution used such an amount of 18-crown-6-ether was
added that all the sodium ions present were transformed into the complex. From the
records it is obvious, that the new isosbestic point is formed even at these conditions.
The existence of the new point must only be due to formation of some other entity in
Collect. Czech. Chem. Commun. (Vol. 63) (1998)

90
Mitas, Sedlak, Kavalek:
the most concentrated solutions of methoxide, the structure of which could not be elu-
cidated.
Our discussion will start from pyrrolidine derivatives 1a–1d, where the dissociation
centre is unambiguous and, at the same time, these substances bear the closest resem-
blance to the intermediates of the cyclization reaction studied.
Carboxamide group has practically identical electron-acceptor properties as carboxy-
pyrrolidide group, which follows from the values σI (refs6,7) (σI(CONH2) = 0.28 and
σI(CON(CH3)2) = 0.28, the value found for a group most similar to CON(CH2)4). On
the other hand, there is a considerable difference in the size of the two groups and,
moreover, carboxamide group contains relatively acidic hydrogen atoms. The effect of
replacement of carboxamide group by carboxypyrrolidide group can be documented on
the values of dissociation constants of N-acids 1a and 2a (Table III). N-Substituted
pyrrolidine 1a is a weaker acid by 0.3 and 0.8 orders of magnitude in 60 and 80% v/v
DMSO, respectively, as compared with 2-(4-nitrobenzoylamino)alkanamide 2a. The
TABLE III
pKA values of N-acids 1a–1d, 2a–2h, 3a–3c, and 4a and values of their absorption maxima (λmax, nm)
in 60 and 80% v/v DMSO
pKA
λmax
N-Acid
60% v/v DMSO
80% v/v DMSO
60% v/v DMSO
60% v/v DMSO
1a
1b
1c
1d
2a
2b
2c
2d
2e
2f
–0.52
0.06
2.04
2.38
–0.83
–0.70
–0.21
0.27
0.42
–
–1.23
–1.22
1.12
268
269
268
268
268
274
268
268
271
–
271
270
266
267
269
275
268
269
270
275
269
272
265
268
268
–
2.05
–2.00
–1.73
–1.29
–1.12
–1.00
–0.90
–1.94
–3.05
–0.53
–0.47
0.02
2g
2h
3a
3b
3c
4a
–0.60
–1.92
0.40
0.75
1.35
1.25
267
276
264
267
268
282
–
Collect. Czech. Chem. Commun. (Vol. 63) (1998)

Substituent Effect on Acidity
91
acidity of N-acid 1a is lowered by steric hindrance to solvation8,9 of benzamide centre
due to the distant bulky CON(CH2)4 group. Introduction of methyl (1b) or isopropyl
(1c) substituent on the acetamide α-carbon atom in N-substituted pyrrolidines brings
about a drop in acidity by 0.45 or 2.5 (in 60% v/v DMSO) and by 0.0 or 2.4 (in 80%
v/v DMSO) orders of magnitude, respectively, as compared with N-acid 1a. Introduc-
tion of two methyl groups to the same centre (1d) causes another acidity drop, namely
by 2.9 and 3.3 orders of magnitude in 60 and 80% v/v DMSO, respectively, as com-
pared with N-acid 1a. The magnitude of alkyl substituents at α-carbon atom of acet-
amide in N-acids 1b–1d, together with the bulky carboxypyrrolidide group, distinctly
affect the extent of steric hindrance to solvation of N-anions and, hence, their acidities.
The series was not extended by further N-acids with still bulkier alkyl or aryl substi-
tuents on the acetamide α-carbon atom because of their too low acidity in the medium
used.
1
1
R
R
O N
2
CONHC CON
O N
2
CONHC CONH
2
2
2
R
R
1
2
h
g
a
b
c
d
e
1, 2
f
1
H
H
H
H
CH CH
-(CH ) - CH CH
2 5 3
R
3
3
3
2
CH
i-C H CH
i-C H
3
C H 4-NO -C H
R
3
3
7
3
7
6
5
2
6
4
NH
C
2
O N
2
CONHR
O N
2
CONH
3
2
CH
3
4
a
b
c
H
CH
3
i-C H
4
9
The values of dissociation constants of pyrrolidine derivatives 1b–1d were con-
fronted with pKA of 2-(4-nitrobenzoylamino)alkanamides 2a–2d bearing the same sub-
stituents on the acetamide α-carbon atom. From the dissociation constant values (Table III)
it is obvious that the steric hindrance to solvation of benzamide centre is practically
insignificant, the acidity drop of N-acids 2a–2d being predominantly due to the electron
saturation of this centre by adjacent electron-donor alkyl groups.
A suitable model for quantification of the extent of inductive effect of alkyl substi-
tuent was found in N-alkyl substituted 4-nitrobenzamides 3a–3c whose acidity de-
creases proportionately to the substituent inductive effect; this corresponds with the
Collect. Czech. Chem. Commun. (Vol. 63) (1998)

92
Mitas, Sedlak, Kavalek:
conclusion10 made from measurements of a more extensive series of N-acids (N-alkyl
and aryl substituted benzenesulfonamides). Therefore, the series of N-alkyl substituted
4-nitrobenzamides was not extended by other N-acids.
Let us now deal with the question of the hydrogen atom which is split off from the
molecules of the N-acids 2a–2h studied. With regard to the experiments carried out by
Bordwell11,12 and other authors13,14 (pKA of acetamide and benzamide in DMSO is 25.5
and 23.35, respectively), we presumed from the beginning that the hydrogen atom in
question came from benzamide group. This can now be supported by the following
arguments: the absorption maxima of N-acids 2a–2h are within a narrow interval (267–276 nm,
see Table III), which can be interpreted as a change in the same chromophore (4-nitro-
benzamide itself has λmax = 275 nm in ethanol15,16), and none of N-acids 2a–2c under-
goes the cyclization reaction (the corresponding derivative of imidazolinone was not
prepared) because the ionisation takes place at the benzamide centre. N-Acids 2d–2h
give the respective cyclization products, which means that the ionisation at acetamide
centre is possible, but the values of dissociation constants can hardly tell us anything
about the ability of the substrate to cyclize. From the values of dissociation constants of
amides 2d–2h it is also impossible to estimate the amounts of benzamide anion and
particularly of the reactive acetamide anion or their proportions in the reaction mixture.
A possibility leading to an approximate comparison of acidities of the two centres was
offered by measurements of dissociation constants of 2-aminoalkanamide 4a, which
can only undergo dissociation at its acetamide centre. A comparison of acidities of both
centres was only possible with the pair of model substances 4a (pKA of acetamide
centre) and 2h (pKA of benzamide centre): compound 4a showed “a measurable
acidity” as an N-acid in the medium studied (making a quite acceptable presumtion that
the replacement of amine hydrogen by 4-nitrophenyl group in indicator 4a did not mar-
kedly affect the acidity of acetamide centre in compound 2h). The values of dissoci-
ation constants of 2-aminoalkanamide 4a (60% v/v DMSO) and its N-(4-nitrobenzoyl)
derivative 2h (Table III) show that the acetamide centre is at least 3 orders weaker acid
than the benzamide centre. From this finding it follows that in the cyclization reaction
of substituted 2-(4-nitrobenzoylamino)alkanamide in MeOH–DMSO solution of so-
dium methoxide the concentration ratio of reactive acetamide anion to benzamide anion
present in the rapid pre-equilibrium is about 1 : 1 000. The low concentration of acet-
amide anion is compensated by its considerable reactivity in the subsequent cyclization
reaction.
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93
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