96 J. CHEM. RESEARCH (S), 1997
J. Chem. Research (S),
1997, 96–97†
Reactions of Carbonyl Compounds in Basic Solutions. Part
27.1 Alkaline Hydrolysis of Bridged Benz[de]isoquinolin-
1-ones: Torsionally Distorted Lactams†
Keith Bowden* and Simon P. Hiscocks
Department of Biological and Chemical Sciences, Central Campus, University of Essex,
Wivenhoe Park, Colchester, Essex CO4 3SQ, UK
Rate coefficients have been measured for the alkaline hydrolysis of 2,3-ethanoxy- and 2,3-propanamino-2,3-dihydro-
1H-benz[de]isoquinolin-1-ones‡ in 70% (v/v) dimethyl sulfoxide–water at several temperatures and of N,N-dimethyl-
1-naphthamide in water: the relative rates of hydrolysis, activation parameters and other studies indicate the importance
of the torsional distortion of the lactam nitrogen and steric ‘bulk’ factors in controlling reactivity.
There have been a number of studies of the alkaline hydro-
lysis of strained lactams2–4 and amides.5 Structural distortion
of an amide or lactam group from planarity has been demon-
strated to increase the reactivity towards alkaline hydrolysis.
Several bicyclic lactams have been used to establish a rela-
tionship between the degree of distortion and the susceptibil-
ity towards hydrolysis.3,4 However, these lactams all involve
alkyl–carbonyl and aryl–amine linkages.
The present study is an investigation of the alkaline hydro-
lysis of the torsionally distorted lactams, the 2,3-bridged
2,3-dihydro-1H-benz[de]isoquinolin-1-ones 1, in which the
lactams have aryl–carbonyl and alkyl–amine linkages, while
being locked by a 1,8-naphthalene template. The effects of
structure and substitution on the rates of reaction, as well as
the activation parameters, are considered to enable an analy-
sis of the reactivity and reaction mechanism.
10,11,12,12a-Tetrahydro-9H-benzo[de]pyrimidino[1,2-b]isoquino-
lin-7-one (1b) (32%), mp 155–158 °C (colourless needles from
ethyl acetetate); vmax/cmꢀ1 (CHCl3) 1649 (CtO); ([2H6]Me2SO)
3.51–4.20 (m, 6 H, CH2), 4.88 (1 H, NH), 6.11 (s, 1 H, CH),
7.63–8.21 (m, 6 H, arom.); m/z (70 eV) 238 (Mǹ) (Found: C, 75.2;
H, 6.2; N, 11.65%). C15H14N2O requires C, 75.6; H, 5.9; N,
11.75%).
11a-Phenyl-9,10-dihydro-11aH-benzo[de][1,3]oxazolo[3,2-b]iso-
quinolin-7-one (1c) (13%), mp 151–153 °C (colourless needles
from ethyl acetate); vmax/cmꢀ1 (CHCl3) 1648 (CtO); dH (CDCl3)
3.28–4.60 (m, 4 H, CH2), 7.13–8.52 (m, 11 H, arom.); m/z (70 eV)
301 (Mǹ) (Found: C, 79.4; H, 4.95; N, 4.55. C20H15NO2 requires C,
79.7; H, 5.0; N, 4.65%).
12a-Phenyl-10,11,12,12a-tetrahydro-9H-benzo[de]pyrimidino[1,2-
b]isoquinolin-7-one (1d) (5%), mp 255–256 °C (colourless needles
from ethyl acetate); vmax/cmꢀ1 (CDCl3) 1647 (CtO); dH (CDCl3)
1.58–2.96 (m, 6 H, CH2), 7.14–8.53 (m, 11 H, arom.); 5.05 (1 H,
NH); m/z (70 eV) 314 (Mǹ) (Found: C, 80.25; H, 5.75;l N, 8.9.
C21H18N2O requires C, 80.25; H, 5.75; N, 8.9%).
The solvents were purified as described previously.8
Measurements.sRate coefficients for the alkaline hydrolysis of
the lactams and amide were determined by use of a Perkin-Elmer
Lambda 5 or 16 UV–VIS spectrometer. The cell temperature was
controlled to within <0.05 °C by means of a Haake DC3 circulator.
The reactions were followed at the wavelengths shown in Table 1.
The procedure used as that described previously.9 The alkaline
hydrolysis of 1a, 1b and 2b is of first order in both substrate and
hydroxide anion. The rate coefficient in 70% (v/v) aqueous di-
methyl sulfoxide (DMSO) and other solvent systems are shown in
Table 1. The activation parameters are shown in Table 2. The
products of the alkaline hydrolysis of 2b are the anion of 1-naph-
thoic acid and dimethylamine, that of 1a is the anion of 8-(1,3-oxa-
zolidin-2-yl)-1-naphthoic acid 3a and that of 1b is the anion of
8-(hexahydropyrimidin-2-yl)-1-naphthoic acid 3b. Both the struc-
1
tures of 3a and 3b were determined by H NMR spectroscopy of
the solution of the product in 70% (v/v) [2H6]DMSO–D2O. The
corresponding acids could not be obtained pure on acidification, as
cyclisation occurred. Both 1c and 1d were very resistant to alkaline
hydrolysis. No significant reaction could be observed for either
substrate after 12 h at 60 °C in 70% (v/v) aqueous DMSO and 0.3
Experimental
Materials.sN,N-Dimethyl-1-naphthamide (2b) was prepared by
the reaction of 1-naphthoyl chloride with dimethylamine.6 The
2,3-bridged 2,3-dihydro-1H-benz[de]isoquinolin-1-ones 1a–d were
prepared by the reaction of 8-formyl- or 8-benzoyl-1-naphthoyl
chloride in chloroform with an excess of ethanolamine or 1,3-di-
aminopropane. The reaction products were purified by use of a
Chromatotron (dichloromethane–ethyl acetate). 1a and 2b are
known compounds6,7 and were recrystallised from ethyl acetate.
Melting points are uncorrected. IR spectra were recorded on a
mol dmꢀ3 base.
Discussion
A mechanistic pathway for the alkaline hydrolysis of lactams
under present study is shown in Scheme 1.2,4 The first step is the
addition of base to form the adduct 4, which collapses to form 5.
The latter rapidly transforms to the final product 3.
1
Zeiss Specord M-80 spectrophotometer. H NMR spectra were
recorded on a JEOL EX270 FT spectrometer with Me4Si as inter-
The lactams 1a and 1b are relatively reactive in their alkaline
hydrolysis, cf. ref. 2. The relative rate of hydrolysis in water of 1a
(extrapolated) to 2b at 60.0 °C is ca. 60. This is considerably less
than the factor of ca. 107 noted by Brown’s group4 in passing from
N-methylacetanilide to their most distorted lactam, 3,4-dihydro-
1,4-ethanoquinolin-2(1H)-one (6).
The torsional distortions in 1a and 1b are not as great as that in
6, but the effect on the rates appears to persist in systems with aryl–
carbonyl and alkyl–amino linkages. The lactam 1a has a fused ring
consisting of a five-membered ring containing nitrogen and oxygen,
whereas 1b has a six-membered ring containing nitrogen and nitro-
gen. The small difference in their rates of hydrolysis, a factor of ca.
2, indicates that the effect is achieved by ring fusion itself and does
not depend on ring size. A comparison of the activation parameters
for the hydrolysis of 1a and 1b with those for related systems
indicates that the hydrolysis of the latter shows rather large DH‡
nal reference. Chemical shifts are expressed as d/ppm. The purity
of the lactams and amide was monitored by IR and H and 13C
1
NMR spectroscopy, as well as mass spectroscopy. The mps of the
compounds, after repeated recrystallisation and drying under
reduced pressure (P2O5), were either in agreement with literature
values6,7 or are shown below, together with their spectral details
and elemental analysis.
*To receive any correspondence (email: keithb@essex.ac.uk).
†This is a Short Paper as defined in the Instructions for Authors,
Section 5.0 [see J. Chem. Research (S), 1997, Issue 1]; there is there-
fore no corresponding material in J. Chem. Research (M).
‡
9,10-Dihydro-11aH-benzo[de]oxazolo[3,2-b]- and 10,11,12,12a-
tetrahydro-9H-benzo[de]pyrimidino[1,2-b] -isoquinolin-7-ones
respectively.