Kinetics of base-catalysed hydrolysis and cyclisation of substituted acetamide and benzamide O-(phenoxycarbonyl)oximes

Article abstract of DOI:10.1135/cccc19991641

The reaction kinetics of acetamide O-(4-nitrophenoxycarbonyl)oxime have been studied in aqueous buffers at pH 2-11. At pH > 9, the pH dependence of k_obs is linear with slope 1, the cyclisation to 3-methyl-1,2,4-oxadiazol-5(4H)-one and 4-nitrophenol being the only reaction. At pH < 7.5, the only reaction is the hydrolysis giving 4-nitrophenol and acetamidoxime. The dependence of k_obs on pH has been used to determine the rate equation and to propose the reaction mechanism. The cyclisation kinetics of substituted benzamide O-(phenoxycarbonyl)oximes have been studied in the pH range from 9.25 to 11. The reaction mechanism has been proposed based on the ρ constants found. In the first reaction step, the proton is split off from the NH₂ group; the subsequent, rate-limiting step involves simultaneous N-C bond formation and C-O bond splitting.

Full text of DOI:10.1135/cccc19991641

Base-Catalysed Hydrolysis
1641
KINETICS OF BASE-CATALYSED HYDROLYSIS AND CYCLISATION
OF SUBSTITUTED ACETAMIDE AND BENZAMIDE
O-(PHENOXYCARBONYL)OXIMES
1,
2
3
Jaromír MINDL *, Jaromír KAVÁLEK , Helena STRAKOVÁ and Vojeslav ŠTĚRBA
Department of Organic Chemistry, Faculty of Chemical Technology, University of Pardubice,
1
2
532 10 Pardubice, Czech Republic; e-mail: jaromir.mindl@upce.cz, jaromir.kavalek@upce.cz,
vojeslav.sterba@upce.cz
3
Received July 2, 1999
Accepted Septem ber 13, 1999
Dedicated to Professor Otto Exner on the occasion of his 75th birthday.
Th e reaction kin etics of acetam ide O-(4-n itroph en oxycarbon yl)oxim e h ave been studied in
aqueous buffers at pH 2–11. At pH > 9, th e pH depen den ce of kobs is lin ear with slope 1, th e
cyclisation to 3-m eth yl-1,2,4-oxadiazol-5(4H)-on e an d 4-n itroph en ol bein g th e on ly reac-
tion . At pH
< 7.5, th e on ly reaction is th e h ydrolysis givin g 4-n itroph en ol an d
acetam idoxim e. Th e depen den ce of kobs on pH h as been used to determ in e th e rate equation
an d to propose th e reaction m ech an ism . Th e cyclisation kin etics of substituted ben zam ide
O-(ph en oxycarbon yl)oxim es h ave been studied in th e pH ran ge from 9.25 to 11. Th e reac-
tion m ech an ism h as been proposed based on th e ρ con stan ts foun d. In th e first reaction
step, th e proton is split off from th e NH2 group; th e subsequen t, rate-lim itin g step in volves
sim ultan eous N–C bon d form ation an d C–O bon d splittin g.
Key w ord s: Reaction kin etics; Reaction m ech an ism ; Oxim es; Am ides; Cyclisation s;
1,2,4-Oxadiazol-5(4H)-on es.
In th e last 20 years we h ave studied th e kin etics an d m ech an ism s of
cyclisation reaction s. As n ucleoph ilic groups were th e an ion s of ureido,
th ioureido, acylth ioureido, am ide, sulfon am ide, alkoxy an d aryloxy groups
an d as electroph iles were esters, carboxylate ion s, am ides, th ioam ides, car-
bam ates, n itriles an d keton es1.
Recen tly we decided to study th e cyclisation reaction of substituted
ben zam ide O-(ph en oxycarbon yl)- an d O-(alkoxycarbon yl)oxim es2. Th is
com poun ds cyclised in aqueous alkali m edium 3,4 an d som e of th e cyclic
products 1,2,4-oxadiazole derivatives are biology active5–7. Due to th eir low
solubility in water, we studied reaction s of th is com poun ds in m eth an olic
Collect. Czech. Chem. Commun. (Vol. 64) (1999)

1642
Mindl, Kaválek, Straková, Štěrba:
solution s of sodium m eth an olate. To our surprise, on ly m eth an olysis
occurs, rath er th an th e expected cyclisation reaction 2.
Th erefore, we decided to study th ese substan ces in aqueous m edia. Due
to th e low solubility of th e pure substrates, it was on ly possible to m easure
th e kin etics at pH > 9. However, derivatives of acetam idoxim e en abled us to
follow th e reaction across th e broadest pH ran ge possible.
EXPERIMENTAL
Meltin g poin ts were determ in ed on a Kofler h ot plate apparatus an d are un corrected. Th e
electron ic spectra were scan n ed with a Hewlett–Packard 8453 Diode Array Spectroph otom eter
at 25 °C. 1H NMR (360 MHz) spectra were recorded on a Bruker AMX spectrom eter in (CD3)2SO
(com poun ds 3a–3e) an d in CDCl3 (com poun ds 2a–2d ) with tetram eth ylsilan e as in tern al
referen ce; ch em ical sh ifts are given in ppm (δ-scale). Th e m easurem en ts of rate con stan ts
an d dissociation con stan ts were carried out spectroph otom etrically usin g th e sam e appara-
tus. Buffer pH values were determ in ed usin g an MV 870 apparatus (VEB Pröcitron ic) an d a
com bin ed glass an d silver ch loride electrode at 25 °C. Th e reaction products an d in term edi-
ates were iden tified by liquid ch rom atograph y-m ass spectrom etry usin g a W aters 616
ch rom atograph coupled with a VG-Platform Fison -ESP-3000D m ass spectrom eter, an d by gas
ch rom atograph y usin g a MEGA 5160 in strum en t.
Kin etic Measurem en ts
Th e reaction of com poun d 2d was followed kin etically in 0.01 m ol l–1 h ydroch loric acid an d
in ch loroacetate, acetate, ph osph ate, h ydrogen ph osph ate, N-m eth ylm orph olin e, an d carbon -
ate buffers. Th e kin etics of oth er substan ces were m easured on ly in carbon ate an d basic
ph osph ate buffers. Th e ion ic stren gth of buffers was adjusted at 1 m ol l–1 (com poun ds
2a–2d ) or 0.5 m ol l–1 (com poun ds 1a–1h ) by addition of 2 M potassium ch loride solution .
A 1 cm quartz cell with lid was ch arged with 2 m l of aqueous buffer solution an d placed
in th e th erm ostat block of th e spectroph otom eter cell com partm en t at 25 °C. After attain in g
th e tem perature required, 20–50 µl of a solution of th e substrate 1a–1h an d 2a–2d in
dioxan e (c = 5 · 10–3 m ol l–1) was added, th e con ten t of cell was m ixed an d th e absorban ce
ch an ge was recorded. Th e observed rate con stan t was calculated by th e program in stalled in
th e com puter of spectrom eter. Experim en ts with reaction h alf-lives below 5 s were carried
out usin g a Durrum D-150 stopped-flow spectroph otom eter.
Iden tification of Reaction Products
In th e case of com poun d 1e we used direct LC MS an alysis of th e reaction m ixture obtain ed
un der kin etic con dition s. Reaction in carbon ate buffer (pH 10.4) yielded equivalen t am oun ts
of th e cyclic product 3e an d 4-n itroph en ol. Not even trace am oun ts of ben zam idoxim e were
detected. A partly reacted sam ple in acetate buffer con tain ed ca 80% un reacted substrate 1e
an d equal proportion s of 4-n itroph en ol an d ben zam idoxim e. Th e presen ce of cyclic product
3e could n ot be foun d. In th e case of com poun d 2d we dissolved 100 m g sam ple in 10 m l
(i) carbon ate buffer (pH ca 10.4); (ii) ph osph ate buffer (pH ca 6.0); or (iii) 0.01 M h ydroch lo-
ric acid. At th e en d of reaction , each of th e th ree sam ples was evaporated, th e residue ex-
Collect. Czech. Chem. Commun. (Vol. 64) (1999)

Base-Catalysed Hydrolysis
1643
tracted with aceton e an d th e aceton e extracts an alysed by GC. In carbon ate buffer we could
un am biguously prove th e presen ce of 4-n itroph en ol an d th e cyclic product 5 in quan titative
am oun ts, th e h ydrolysis product of acetam idoxim e was n ot detected at all. In th e reaction s
carried out in ph osph ate buffer an d h ydroch loric acid 4-n itroph en ol an d acetam idoxim e
were form ed in quan titative am oun ts; th e cyclic product 5 was absen t.
Ch em icals
Th e substituted X-ben zam ide O-(Y-ph en oxycarbon yl)oxim es (1a–1h ; Sch em e 1) were syn th e-
sised from th e appropriate substituted ben zam idoxim es an d aryl ch loroform ates as described
elsewh ere2.
Substituted Acetam ide O-(Y-Ph en oxycarbon yl)oxim es (2a–2d ; Sch em e 2);
Gen eral Procedure
Acetamidoxime. A solution of h ydroxylam in e8 (18 g, 0.54 m ol) in dry butan -1-ol (100 m l)
was stirred an d treated with aceton itrile (25 m l, 0.48 m ol), added at on ce, an d th e reaction
m ixture was stirred at 50–55 °C for 55 h . After distillin g off 60 m l butan ol, th e rem ain in g
solution was filtered with ch arcoal. Th e product th at separated on coolin g (18 g, 50%) (m .p.
135–137 °C in accordan ce with ref.9) was pure en ough to be used for th e subsequen t step.
Oximes 2a–2d . A 100 m l flask was ch arged with acetam idoxim e (0.74 g, 0.01 m ol), dry di-
ch lorom eth an e (20–50 m l) an d trieth ylam in e (1.45 m l, 0.01 m ol). Th e m ixture was cooled
to 0–5 °C an d treated dropwise with a solution of th e respective aryl ch loroform ate in
10–20 m l dich lorom eth an e. After distillin g off th e solven t, th e residue was suspen ded in
75 m l dry aceton e. Th e in soluble trieth ylam in e h ydroch loride was filtered off an d th e ace-
ton e filtrate evaporated. Th e oily residue crystallised on stan din g, an d was recrystallised
from ch loroform or a ben zen e–h exan e m ixture.
Acetamide O-(phenoxycarbonyl)oxime (2a). Yield: 67%, m .p. 109–111 °C. For C6H10N2O3
(194.2) calculated: 55.67% C, 5.19% H, 14.43% N; foun d: 55.61% C, 5.21% H, 14.54% N. 1H
NMR (CDCl3): 7.17–7.21 m , 2 H (H-2, H-6); 7.35–7.40 m , 2 H (H-3, H-5); 7.23–7.25 d, 1 H
(H-4); 4.93 brs, 2 H (NH2); 1.95 s, 3 H (CH3).
Acetamide O-(4-chlorophenoxycarbonyl)oxime (2b). Yield: 27%, m .p. 84–86 °C. For C9H9ClN2O3
(228.2) calculated: 47.28% C, 3.97% H, 15.51% Cl, 12.25% N; foun d: 47.52% C, 4.03% H,
51.28% Cl, 12.32% N. 1H NMR (CDCl3): 7.13–7.15 d, 2 H (H-2, H-6); 7.32–7.35 d, 2 H (H-3,
H-5); 4.96 brs, 2 H (NH2); 1.97 s, 3 H (CH3).
Acetamide O-(3-nitrophenoxycarbonyl)oxime (2c). Yield: 61%, m .p. 107–110 °C. For
C9H9N3O5 (239.2) calculated: 45.19% C, 3.79% H, 17.57% N; foun d: 45.43% C, 3.75% H,
17.76% N. 1H NMR (CDCl3): 8.09–8.18 m , 2 H (H-2, H-4); 7.55–7.61 m , 2 H (H-5, H-6); 4.96 brs,
2 H (NH2); 2.00 s, 3 H (CH3).
Acetamide O-(4-nitrophenoxycarbonyl)oxime (2d ). Yield: 77%, m .p. 118–120 °C. For
C9H9N3O5 (239.2) calculated: 45.19% C, 3.79% H, 17.57% N; foun d: 45.39% C, 3.67% H,
17.32% N. 1H NMR (CDCl3): 7.39–7.42 d, 2 H (H-2, H-6); 8.26–8.29 d, 2 H (H-3, H-5); 4.89 brs,
2 H (NH2); 2.01 s, 3 H (CH3).
Substituted 3-Ph en yl-(4H)-1,2,4-oxadiazol-5-on es (3a–3e; Sch em e 2) – Gen eral Procedure
Oxim e 1 (0.02 m ol) was dissolved in aqueous solution of sodium h ydroxide (50 m l, 2 m ol l–1
)
at 30–40 °C. After 10 m in stirrin g, th e reaction m ixture was cooled an d acidified with h y-
Collect. Czech. Chem. Commun. (Vol. 64) (1999)

1644
Mindl, Kaválek, Straková, Štěrba:
droch loric acid to pH 3–4. Th e separated oxadiazolon e 3 was isolated by filtration , wash ed
with ice water, an d recrystallised from eth an ol. Th e com poun d 3e can be purified by subli-
m ation un der reduced pressure.
3-(4-Methoxyphenyl)-1,2,4-oxadiazol-5(4H)-one (3a ). Yield: 65%, m .p. 210–212 °C. For
C9H8N2O3 (192.2) calculated: 56.25% C, 4.20% H, 14.58% N; foun d: 56.09% C, 4.22% H,
14.56% N. 1H NMR (CD3)2SO: 7.80–7.81 m , 2 H (H-2, H-6); 7.16–7.19 d, 2 H (H-3, H-5); 3.41 brs,
1 H (NH); 3.88 s, 3 H (CH3).
3-(4-Methylphenyl)-1,2,4-oxadiazol-5(4H)-one (3b ). Yield: 61%, m .p. 222–224 °C. For
C9H8N2O2 (176.2) calculated: 61.36% C, 4.58% H, 15.90% N; foun d: 61.26% C, 4.66% H,
15.66% N. 1H NMR (CD3)2SO: 7.74–7.76 m , 2 H (H-2, H-6); 7.42–7.44 d, 2 H (H-3, H-5); 3.58 brs,
1 H (NH); 2.43 m , 3 H (CH3).
3-(4-Chlorophenyl)-1,2,4-oxadiazol-5(4H)-one (3c). Yield: 57%, m .p. 281–283 °C. For
C8H5ClN2O2 (196.6) calculated: 48.88% C, 2.56% H, 18.03% Cl, 14.25% N; foun d: 48.92% C,
2.59% H, 18.36% Cl, 14.21% N. 1H NMR (CD3)2SO: 7.71–7.74 m , 2 H (H-2, H-6); 7.86–7.88 d,
2 H (H-3, H-5); 3.40 brs, 1 H (NH).
3-(4-Nitrophenyl)-1,2,4-oxadiazol-5(4H)-one (3d ). Yield: 54%, m .p. 313–315 °C. For
C8H5N3O4 (207.2) calculated: 46.39% C, 2.43% H, 20.29% N; foun d: 46.40% C, 2.38% H,
20.38% N. 1H NMR (CD3)2SO: 7.10–7.13 m , 2 H (H-2, H-6); 8.45–8.48 d, 2 H (H-3, H-5); 3.41 brs,
1 H (NH).
3-Phenyl-1,2,4-oxadiazol-5(4H)-one (3e). Yield: 65%, m .p. 203–204 °C. For C8H6N2O2
(162.2) calculated: 59.26% C, 3.73% H, 17.28% N; foun d: 59.24% C, 3.73% H, 17.34% N.
1H NMR (CD3)2SO: 7.60–7.68 m , 2 H (H-2, H-6); 7.85–7.87 m , 3 H (H-3, H-4, H-5); 3.41 brs,
1 H (NH).
Acetamide O-(methoxycarbonyl)oxime (4; Sch em e 3) was prepared in th e sam e way from
acetam idoxim e an d m eth yl ch loroform ate in 30% yield, m .p. 86–88 °C. For C4H8N2O3
(132.1) calculated: 36.36% C, 6.10% H, 21.20% N; foun d: 36.11% C, 6.16% H, 21.43% N.
3-Methyl-1,2,4-oxadiazol-5(4H)-one (5; Sch em e 3). Oxim e 4 (2.1 g, 28 m m ol) was dissolved
in water (25 m l) an d sodium h ydroxide solution (2–3 drops, 1 m ol l–1) added. After 12 h ,
th e solution was acidified with h ydroch loric acid to pH 2–3. Th e water was distilled off, an d th e
oily residue was left to crystallise (several days). Repeated recrystallisation from a ben zen e–
cycloh exan e m ixture (2 : 3) gave 1.6 g (75%) wh ite crystals, m .p. 63–64 °C in accordan ce
with ref.10. For C3H4N2O2 (100.1) calculated: 36.01% C, 4.03% H, 28.00% N; foun d: 35.98% C,
40.10% H, 27.62% N.
RESULTS
Th e preparation of startin g com poun ds 1, 2, an d 4 was ach ieved by stan -
dard procedure2. Cyclisation of th ese com poun ds in alkalin e aqueous solu-
tion s afforded th e correspon din g 1,2,4-oxazol-5(4H)-on es 3 an d 5 in good
yields (Sch em es 1–3). Detailed kin etic studies of th ese reaction s h ave been
perform ed.
Th e kin etics of th e reaction of com poun d 2d accom pan ied by splittin g
off of 4-n itroph en oxide ion was followed in 0.01 M h ydroch loric acid an d
in aqueous buffer solution s in th e pH ran ge from 2 to 11.86. Th e kin etics of
th e reaction of com poun ds 2a–2c was m easured in carbon ate an d two
Collect. Czech. Chem. Commun. (Vol. 64) (1999)

Base-Catalysed Hydrolysis
1645
Y
O
O
NH2
NH
N
C
O
OH
O
C
C
+
X
N O C O
X
Y
1a - 1h
3a - 3e
1
a
b
c
d
X
Y
1
e
f
X
H
H
H
H
Y
4-CH3O
4-CH3
4-Cl
4-NO2
4-NO2
3-Cl
4-Cl
H
3
c
d
e
a
b
4-NO2
4-NO2
4-NO2
4-Cl
4-OCH3 4-CH3
4-NO2 H
X
g
h
4-NO2
SCHEME 1
NH2
H3C C
NH2
H3C C
N OH
O
C O
Cl
Y
O
Y
+
N O C O
2
2
c
d
a
b
4-Cl
H
3-NO2 4-NO2
Y
SCHEME 2
O
NH2
C
N O C OCH3
NH2
NH
N
C
CH3OCOCl
OH
O
H3C
H3C
C
H3C
C
N OH
O
4
5
SCHEME 3
ph osph ate buffers (pH 10.35–11.59) an d of 1a–1h in carbon ate buffer
(pH 10.35). Th e reaction s followed pseudo-first-order kin etics in all
solution s. In th e case of com poun ds 2a–2d th e kobs values in creased lin early
with th e buffer con cen tration an d were extrapolated to th e zero buffer com -
pon en t. In th e case of com poun ds 1a–1h th e kobs values were in depen den t
of th e buffer con cen tration or sh owed on ly m ild in crease. Th e rate
constants kOH related to the activity of hydroxyl ion are given in Tables I and II.
TABLE I
Rate con stan ts kOH (l m ol–1 s–1) of cyclisation reaction 2→5. Th e respective Ham m ett con -
stan t is ρ = 0.96 ± 0.03
Com poun d
2a
2b
2c
2d
kOH
2.5 ± 0.08
4.0 ± 0.4
11.5 ± 0.6
17.5 ± 0.5
Collect. Czech. Chem. Commun. (Vol. 64) (1999)

1646
Mindl, Kaválek, Straková, Štěrba:
Th e depen den ce of buffer in depen den t log k values on pH of 2d is pre-
sen ted in Fig. 1. At pH > 9, wh ere th e depen den ce is lin ear with slope 1, th e
on ly reaction products are 4-n itroph en oxide an d 5. At pH < 7.5, h ydrolysis
is th e on ly reaction (Sch em e 4).
H
O
N
Me
O
NO2
+
O
N
NH2
5
O
Me
C
pH > 9
N O C O
NO2
pH 2 ~ 6
2d
NH2
HO
NO2
Me
+
N OH
SCHEME 4
Th e rate of form ation of 4-n itroph en oxide ion was also m easured with
com poun d 1d in four carbon ate an d two basic ph osph ate buffers (pH
9.25–10.90). Th e reaction kin etics was pseudo-first order; again th e de-
pen den ce of buffer in depen den t log k values on pH was lin ear with slope 1
(Fig. 1). At lower pH values is th e reaction slower an d th e m easurem en t is
com plicated by association of th e substrate: th e spectral lin es did n ot cross
th e isosbestic poin ts, an d th e absorban ce–tim e depen den ce was n o lon ger
expon en tial. Th e results of th ese m easurem en ts were n ot used in th e calcu-
lation s of kobs. At still lower pH values, th e solution began to becom e turbid
due to separation of th e substrate.
DISCUSSION
From th e depen den ce of log k on pH of com poun d 2d (Fig. 1) an d th e reac-
tion products iden tified it follows th at in th e region of th e depen den ce of k
vs pH with slope 1 th e reaction product is cyclisate 5. In th e region of th e
TABLE II
Rate con stan ts kOH (l m ol–1 s–1) of cyclisation reaction 1→3. Th e Ham m ett con stan ts for
com poun ds 1a–1e an d 1e–1h are ρ = 0.52 ± 0.02 an d 1.04 ± 0.03, respectively
Com -
poun d
1a
1b
1c
1d
1e
1f
1g
1h
kOH
114 ± 3 121 ± 2 184 ± 3 370 ± 5 143 ± 4
56 ± 2 39.0 ± 0.5 23.1 ± 0.4
Collect. Czech. Chem. Commun. (Vol. 64) (1999)

Base-Catalysed Hydrolysis
1647
depen den ce of log k vs pH with slope 0 or –1, th e substrate is on ly h ydro-
lysed. Both th ese region s can be discussed separately.
Th e rate of th e cyclisation reaction in wh ich substrate 2d reacts with OH–
ion is expressed by Eq. (1).
v = kOH[2d ]aOH = kOH[2d ]Kw/aH
(1)
Th e sam e is also true for th e cyclisation reaction s of th e oth er substan ces 1
an d 2. Th e values of th e respective kOH con stan ts are given in Tables I an d II.
At pH below 7.5, th e relation sh ip between th e observed rate con stan t an d
proton activity is of th e form given by Eq. (2).
kobs = (a + baH)/(c + daH)
(2)
At pH < 6, th e reaction obviously in volves th e proton ated substrate SH+
an d water, an d th e reaction rate in creases with in creasin g proton activity as
th e con cen tration of th e proton ated substrate in creases sim ultan eously,
too.
At pH < 3.5, alm ost all th e substrate is presen t in its proton ated form , an d
th e reaction rate becom es pH-in depen den t. Th e ch an ge in slope of th e de-
pen den ce log k vs pH from 1 to 0 gives rise to a value of pKA = 4.6 for th e
proton ated substrate. Th is part of th e depen den ce in Fig. 1 is defin ed by th e
Eq. (3).
kextr = k0SH aH/(aH + KA)
(3)
–1
log k
FIG. 1
–2
Logarith m ic depen den ce of rate con stan ts k
(s–1) on pH of th e reaction s of am idoxim e car-
bon ates 1e (❍) an d 2d (❍) m easured at 25 °C
in aqueous solution s of 0.01 M h ydroch loric
acid an d buffers with con stan t ion ic stren gth
(I = 1.0 m ol l–1 for com poun d 2d an d I = 0.5
m ol l–1 for com poun d 1e). Th e solid lin e is th e
th eoretical depen den ce calculated from Eq. (6)
an d th e con stan ts given in Discussion
–3
–4
2.5
5.0
7.5
10.0
pH
Collect. Czech. Chem. Commun. (Vol. 64) (1999)

1648
Mindl, Kaválek, Straková, Štěrba:
In th e pH ran ge of 6–8, th e n on -proton ated substrate can react with wa-
ter. Th en th e reaction rate can be defin ed by Eq. (4).
v = k0S [S]
(4)
A kin etically equivalen t, m ore probable, altern ative ist th e reaction of th e
proton ated substrate with h ydroxyl ion . In such a case th e reaction rate is
given by Eq. (5).
SH +
OH
SH +
OH
v = k [SH+]aOH = k (Kw/(aH + KA))[S]
(5)
Th is altern ative can be preferred for th e followin g reason s.
+
1. Th e differen ce between th e rate con stan ts k0S an d k0SH is on e order of
m agn itude on ly. Th e proton ation of substrate in creases th e rate of reaction
with water by at least two orders due to th e electrostatic effect of th e posi-
tive ch arge. At th e sam e tim e delocalisation of th e electron pair at th e oxy-
gen of N–O group is elim in ated, wh ich substan tially in creases th e reactivity
of th e carbon yl carbon atom (Sch em e 5).
NH2
NH2
Ar1
OAr2
O
Ar1
OAr2
O
HN O C
HN O C
SCHEME 5
2. Esters with good leavin g groups11 sh ow a break in th e log k vs pH de-
pen den ce due to th e ch an ge of reaction path way from [substrate +
h ydroxyl ion ] to [substrate + water] at pH 6–7. With am idoxim e carbon ate
2d , th is ch an ge takes place at about pH 9; h owever, at th is pH, th ere is n o
h ydrolysis but cyclisation to product 5, wh ich m ean s th at th e h ydroxyl
ion -catalysed h ydrolysis takes place at pH ≥ 10.
3. If a n eutral substrate of RCOOAr type reacts with water, th en th is reac-
tion is subject to gen eral base catalysis or n ucleoph ilic catalysis12. Th e h y-
drolysis of am idoxim e carbon ate 2d exh ibits in depen den ce of kobs on th e
con cen tration of acid ph osph ate buffer. Th e resultin g equation (6) for th e
values k h as th e form :
+
SH +
OH
Kw
Kw
aH2
k0SH + k
+ kOS H KA
aH +
k =
,
(6)
KA
1 +
aH +
Collect. Czech. Chem. Commun. (Vol. 64) (1999)

Base-Catalysed Hydrolysis
1649
+
wh ere k0SH = (1.01 ± 0.02) · 10–3 is th e rate con stan t of reaction of th e
proton ated substrate with water, k0S = (1.18 ± 0.01) · 10–4 is th e rate con stant
of n eutral substrate with water calculated from Eq. (4); kOS H = 17.5 ± 0.9
l m ol–1 s–1 is th e rate con stan t of reaction of th e n eutral substrate with
SH +
OH
h ydroxyl ion , k
= (2.82 ± 0.02) · 105 l m ol–1 s–1 is th e rate con stan t of re-
action of th e proton ated substrate with h ydroxyl ion , KA = (2.4 ± 0.4) · 10–5
m ol l–1 is th e dissociation con stan t of th e substrate.
Th e rate con stan ts kOH of cyclisation of com poun ds 1a–1e (substituen t X
in ben zam idoxim e) an d 2a–2d , 1e–1h (substituen t Y in ph en oxy group)
were correlated with σ0 con stan ts.
Th e con stan t ρ for com poun ds 1a–1e (substituen t X in ben zam idoxim e)
is 0.52 ± 0.02, for splittin g off th e substituted ph en ols (n ot in cludin g
4-n itro derivatives 1a an d 2d ), 0.96 ± 0.03 for com poun ds 2 an d 1.04 ± 0.03
for com poun ds 1. Th e experim en tally foun d values of σ con stan ts for
4-n itro group in com poun d 1e was 0.81 (th e sam e as in its m eth an olysis2)
an d 0.9 for com poun d 2d . Th is is due to th e im balan ce between th e ch an ge
in th e ch arge at th e ph en oxy group oxygen in th e tran sition state an d th e
degree of delocalisation of th e π electron s because delocalisation of π elec-
tron s lags beh in d th e ch arge tran sfer in th e tran sition state an d does n ot
occur to a sufficient extent until the C–O bond is broken to a large extent13–16
.
For determ in ation of m ech an ism of cyclisation of am idoxim e carbon ates
1 an d 2, th e decisive effect is th at of substituen ts in th e ben zen e rin g of
com poun ds 1a–1e. With very weak n ucleoph iles such as weakly-basic
am in es, it is possible to presum e two m ech an ism s for th e base-catalysed re-
action . Th e first in volves gen eral base-catalysed rem oval of th e proton from
am in o group in th e tran sition state an d with form ation of a tetrah edral in -
term ediate12 (Sch em e 6).
-δ
O
O
C
R1
R2
C
O Ar
H B
O
R1
O Ar
R2NH2
R1
C
B
BH
ArO
+
+
+
+
+δ
HN R2
N
H
SCHEME 6
Th e am in o group carries a partial positive ch arge in th e tran sition state,
h en ce an electron -with drawin g substituen t in th e R2 group will slow down
th e reaction , an d th e ρ con stan t h as n egative sign .
Th e secon d m ech an ism presum es th at th e proton is split off from th e
am in o group in a pre-equilibrium step, an d th e activated com plex of th e
Collect. Czech. Chem. Commun. (Vol. 64) (1999)

1650
Mindl, Kaválek, Straková, Štěrba:
subsequen t rate-lim itin g step h as a partial n egative ch arge at th e n itrogen
atom (Sch em e 7).
R2NH2
R2NH
B
BH
+
+
O
O
O
-δ
H
N
-δ
R1 C O Ar
R2
C O Ar
R1
ArO
R1
C
R2NH
+
+
NH
R2
SCHEME 7
Th e first step of th is m ech an ism will be en h an ced by electron -
with drawin g R2 groups an d th e ρ con stan t will h ave positive sign . Th e sec-
on d step will be retarded by electron -with drawin g groups (n egative ρ).
However, th e experim en tally determ in ed ρ value of 0.52 is on ly con sisten t
with th is m ech an ism an d in dicates th at th e pre-equilibrium h as th e larger ρ
value.
In carbon ate an d basic ph osph ate buffers, th e kobs con stan ts of reaction s
of com poun ds 2a–2d in creased lin early with in creasin g con cen tration of
th e basic buffer com pon en t, wh ich could in dicate a gen eral base catalysis
by CO 23 – an d PO43– ion s, i.e. m an ifestation of th e first m ech an ism m en -
tion ed (or sim ultan eous operation of both th e m ech an ism s) for th ese bases.
Th e sm all or n o in crease of kobs with carbon ate an d ph osph ate buffers for
com poun ds 1a–1h m ay be due to th eir greater reactivity with HO– ion s.
Beside th e determ in ation of reaction m ech an ism of cyclisation , th e study
of substituen t effects also en ables an estim ate of th e exten t of form ation of
a n ew bon d to n ucleoph ile an d splittin g of th e bon d to th e leavin g group
in th e tran sition state. Suitable pieces of in form ation 17 can be obtain ed
from th e βn uc an d βlg values of th e rate-lim itin g step (Eqs (7) an d (8)).
βn uc = d log kn uc/dpKA,n uc
(7)
(8)
βlg = d log klg/dpKA,lg
In th e case of am idoxim e carbon ates, th e n ucleoph ilic group form s a part
of th e substrate with th e substituted ben zen e rin g (th e reaction is in tram o-
lecular), an d th e leavin g group is a substituted ph en ol.
Collect. Czech. Chem. Commun. (Vol. 64) (1999)

Base-Catalysed Hydrolysis
1651
In th e cyclisation reaction , th e kOS H value is a product of th e dissociation
con stan t KAS of th e n eutral substrate an d th e rate con stan t kn uc of th e rate-
lim itin g step (Eq. (9)).
kOS H = kn ucKAS /Kw
(9)
an d ρ = ρn uc + ρK
.
As the dissociatAion of neutral substrates is very sim ilar to that of substituted
benzoic acids, its ρ constant will be sim ilar identical with the value ρ = 1 of
ben zoic acids.
Th erefrom it follows th at th e ρ con stan t of th e rate-lim itin g step is ρn uc
0.52 – 1 ≈ –0.48, an d βn uc = –ρn uc ≈ 0.48.
≈
Th e con stan t for splittin g off of th e substituted ph en ols was determ in ed
in com poun ds 1e–1h (ρ = 1.04). Th is con stan t can be tran sform ed in to βlg
by division by –2.23, wh ich is th e n egative value of ρ con stan t for dissocia-
tion of substituted ph en ols18, βlg = –0.47.
Th e values foun d for βn uc (0.48) an d βlg (–0.47) express th e exten t of
ch an ge of ch arge in th e reaction cen tre in th e activated com plex of th e
rate-lim itin g step of reaction in volvin g an attack of th e n eutral substrate by
n egatively ch arged n ucleoph ile with form ation of a n eutral reaction prod-
uct an d a n egatively ch arged n ucleofuge. Com parison of βn uc an d βlg sh ows
th at in th e tran sition state, th e ch an ge in ch arge at both th e reactin g atom s
(N an d O) is approxim ately th e sam e.
In m eth an olic solution 2, m eth oxide reacts as a n ucleoph ile with th e car-
bon yl group of substrate 1. On th e oth er h an d, in aqueous solution , wh ere
th e depen den ce of log k on pH h as th e slope 1, th e reaction in volves an
acid-base reaction of h ydroxyl ion with th e substrate an d subsequen t
in tram olecular attack at th e carbon yl group by th e NH an ion form ed to
give th e cyclic product. Th is differen ce in m ech an ism lies in th e far h igh er
n ucleoph ilicity of m eth oxide ion as com pared with th at of h ydroxyl ion .
For exam ple, m eth oxide reacts with aryl acetates in aqueous solution al-
m ost two orders faster th an h ydroxyl ion 19 alth ough th e pKA value of m eth -
an ol in water is alm ost th e sam e as th e pKA of water20
.
Th e decisive reason lies in th e substan tially lower en ergy n eeded for par-
tial desolvation of m eth oxide ion in water as com pared with h ydroxyl ion
in water. Sin ce th e solvation en ergy of m eth oxide ion in m eth an ol is m uch
lower th an th at in water (its value is n ot kn own at presen t but th e differ-
en ce of solvation en ergies will be th e sam e as, or larger th an , th at of ch lo-
Collect. Czech. Chem. Commun. (Vol. 64) (1999)

1652
Mindl, Kaválek, Straková, Štěrba:
ride an d acetate ion s, i.e., 13.2 an d 16.0 kJ m ol–1, respectively21), th e
in crease in its n ucleoph ilicity as com pared with its basicity will be even
m ore distin ct th an th at in water.
CONCLUSION
In con trast to th e reaction of com poun d 1 with m eth oxide in m eth an ol,
wh ere m eth an olysis is th e on ly process2, th e products of reaction of
n on -proton ated com poun ds 1 an d 2 with h ydroxyl ion in aqueous m edia
are th e cyclic com poun ds 3 an d 5, respectively. Th is appears due to th e
m uch h igh er en ergy n eeded for partial desolvation of h ydroxyl ion in its at-
tack on carbon yl group, h en ce th e cyclisation reaction becom es m ore ad-
van tageous en ergetically. Th e cyclisation reaction proceeds via two steps:
th e first, reversible, step in volves loss of a proton from th e am in o group,
an d th e secon d, con certed, step in volves N–C bon d form ation an d C–O
bon d cleawage (Sch em e 7). Com poun d 2d at pH < 7.5 exclusively un der-
goes h ydrolysis of th e proton ated substrate with h ydroxyl ion , an d in m od-
erately acid m edia, it reacts with water.
This work was supported by the Grant Agency of the Czech Republic (grant No. 203/97/0545).
REFERENCES
1. a) Kaválek J., Kotyk M., Said El Bahaie, Štěrba V.: Collect. Czech. Chem. Commun. 1981,
46, 246; b) Kaválek J., Hruška J., Štěrba V.: Collect. Czech. Chem. Commun. 1982, 46, 518;
c) Kaválek J., Potěšil T., Štěrba V.: Collect. Czech. Chem. Commun. 1983, 48, 578;
d) Kaválek J., Macháček V., Svobodová G., Štěrba V.: Collect. Czech. Chem. Commun.
1986, 51, 375; e) Macháček V., Svobodová G., Štěrba V.: Collect. Czech. Chem. Commun.
1987, 52, 140; f) Mindl J., Šěrba V.: Collect. Czech. Chem. Commun. 1987, 52, 156;
g) Kaválek J., Macháček V., Svobodová G., Štěrba V.: Collect. Czech. Chem. Commun.
1989, 54, 1005; h) Kaválek J., Macháček V., Sedlák M., Štěrba V.: Collect. Czech. Chem.
Commun. 1992, 57, 1282; i) Kaválek J., Macháček V., Sedlák M., Štěrba V.: Collect. Czech.
Chem. Commun. 1993, 58, 1122; j) Sedlák M., Hladůvková J., Kaválek J., Macháček V.:
Org. Reactiv. 1995, 29, 79; k) Sedlák M., Kaválek J., Mitaš P., Macháček V.: Collect. Czech.
Chem. Commun. 1998, 63, 394; l) Hrabík O., Mindl J., Kaválek J., Štěrba V.: Unpublished
results.
2. Dušek L., Kaválek J., Štěrba V.: Collect. Czech. Chem. Commun. 1999, 64, 265.
3. Buzle R., Lenaers R., Eloy F.: Helv. Chim. Acta 1963, 46, 1073.
4. Grambal F., Lasovský J.: Collect. Czech. Chem. Commun. 1983, 48, 596.
5. Eloy F., Lenaers R.: Bull. Chim. Therap. 1966, 347.
6. Sterne J., Hirsch C.: Therapie 1965, 20, 95.
7. Hangwitz R. D., Martinez A. S., Venslavsky J.: J. Med. Chem. 1985, 28, 1234.
8. Hurd C. D.: Inorg. Synth. 1939, 1, 87.
Collect. Czech. Chem. Commun. (Vol. 64) (1999)

Base-Catalysed Hydrolysis
1653
9. Hussein A. Q.: J. Chem. Eng. Data 1987, 32, 127.
10. Hurd C. D., Andriech L. F., Napelski L. A.: Inorg. Synth. 1939, 2, 87.
11. Euranto E. K. in: The Chemistry of Carboxylic Acid and Esters (S. Patai, Ed.), Ref. 1, Chap.
11. Wiley-Interscience, London 1992.
12. Kirby A. J. in: Comprehensive Chemical Kinetics (C. H. Bamford and C. H. Tipper, Eds),
Vol. 10, Chap. 2. Elsevier, Amsterdam 1972.
13. Stefanidis D., Cho S., Pafanon S. D., Jencks W. P.: J. Am. Chem. Soc. 1993, 115, 1650.
14. Bernasconi C. F.: Adv. Phys. Org. Chem. 1992, 27, 119.
15. Bernasconi C. F.: Acc. Chem. Res. 1992, 25, 9.
16. Ba-Saif S. A., Colthurst M., Waring M. A., Williams A.: J. Chem. Soc., Perkin Trans. 2
1992, 1901.
17. Wiliams A.: Advances in Physical Organic Chemistry, Vol. 27, Chap. 2. Academic Press,
London 1992.
18. Exner O.: Correlation Analysis of Chemical Data, p. 73. SNTL, Prague 1988.
19. Jencks W. P., Gilchrist M.: J. Am. Chem. Soc. 1968, 90, 2622.
20. Ballinger P., Long F. A.: J. Am. Chem. Soc. 1960, 82, 795.
21. Marcus Y.: Pure Appl. Chem. 1983, 55, 977.
Collect. Czech. Chem. Commun. (Vol. 64) (1999)