Indi an Journal of Chemistry
Vol. 40B, January 200 I, pp. 20-24
Preparation of isomeric hydrazones : Role of lone electron pair of nitrogen in
controlling the stability
Alaka Srivastava, Vandana Srivastava & Shiva M Verma*
Department of Chemistry, Banaras Hindu University, Varanasi-221 005
and
Anil K Saxena
Medicinal Chemi stry Divi sion, Central Drug Research Institute, Lucknow 226 00 I
Received 23 Jllll e 1999: accepted (revised) 29 JUli e 2000
Isomeric hyd razo nes (£ and Z) deri ved from N-aminoimide of anthracene-maleic anhydride adduct and alkyl aryl ketones ha ve been iso lated and characteri sed by iH, iJC NMR and IR spectral data. The di ssy mmetric cage moiety has demonstrated restricted rotation about N-N bond and the ketimino gro up (R,R1C=N-) in orthogonal geometry to the .> uccinimidyl
plane. The electronic interacti on of the lone electro n pair of ketimino nitroge n with the cage phenyl ring restri cts in version
of nitroge n lone pair and provides stability to the stereoi somers. The phenomenon supports the lateral shift m ~ chan i s m reported for the less enthalpy of ac ti vation for £-Z isomeri zation. Sterically crowded configuration in case of alky l aryl hydrazo nes has been found to be thermodynam ica ll y more stable as compared to its isomeric product. Conformational energy
analysis also suggesll:d the Z-i somer to be the lower energy conformer.
Hydrazones offer a good example of a system for
stereochem ical inves ti gati ons, where different stereochem ical processes viz., isomerizati on about C=N
bond. in version in vo lving the nitroge n atoms (sp3an d
I
sp") and rotatt on abo ut N-N bond may take place. A
great deal of work has been reported on th e stereochemi stry of hydrazo nes in various systems2.3 . Substituted imines have available a pathway of substanti all y lower enthalpy of activation fo r uncatalysed £-Z
iso merization , through th e lateral shi ft mech ani sm
hav ing the transition state of in ve rsion at imino nitroge n (1)4.5. Placement of a heteroatom parti cularly nitrogen on imino nitrogen leads to red uced ~G # values
and the config urati onal isomers have been successfull y inves ti gated by IH NMR spectroscopl. In an
atte mpt to substantiate the proposed mechanism we
have designed a system hav ing restricted inversion of
imi no nitrogen lone pair and have succeeded in isolat ing the co nfi gurat ional isomers.
Molecul ar engi neerin g with a dissymmetric cage
system showed that the lone electron pair of pyridyl
nitrogen in 2 has a stro ng repul sion from a phenyl
ring of th e cage moiety and a prefe rred non-planar
co nfo rmation hav ing th e pyridyl nitrogen in olltiori entati on (away from th e cage) has been demonstrated 7 . The addition prod uct obtained from
N-amino-3, 4- (9', 1O'-dihydroanthracene-9',IO'-diyl)
~
.
succinimide and diethyl acetylenedi carbox ylate has
been shown to be an azomethine 3 hav ing restri cted
rotation about N-N bond and the lone electron pair of
imino nitrogen in allti-orientation in the solution as
well as in solid state8. Stereodynamics of 7-azanorbornene s.ystem have demonstrated th at the lone
electron pair of nitrogen preferentiall) occupy an allti
position with respect to the electron rich n-bond in Nmethyl-7-aza-norbornene 4 and the populati on of SYII
and al/.ti invertomers in the rati o of bO:20 have been
demonstrate 9 . Considering these observations on
electrostati c irepulsion of the lone electron pair of ni trogen from a phenyl ring, a system 5 has been designed for the restriction of atomic inversion of
imino-nitrogen. Some hydrazones 6a-f have been prepared and their stereochemistry has bee n discussed in
this communicat ion.
Results and Discussion
Restricted rotation about N-N bond and the ketimine part -N=C (CH3 h orthogonal to the succinimidyI plane have been show n in compound Sa
through iH NMR spectroscop/ o. VT NMR studi es of
Sa provided some valuable information about the rate
processes involved in the system. The two methyl
signals of Sa remained sharp and moved slowly on
rai sing the temperature whi ch could on ly resu lt fro m
SRIVASTAVA et al. : PREPARATION OF ISOMERIC HYDRAZONES
X" C/ y
"
C::> N g
/~"
(I)
(2)
~
(3)
/
CH 3
C
H3
~
"'- J?
~
Syn
(4)
(5)
(a)
R = CH3
(b) R = CH2-CH3
(6)
(a) Rl = CH3,
R2 ~
(b) Rl=-Q R2 = CH3,
(c) Rl= CH3,
=-00
R2
(d) Rl~ R2 = CH3 ,
(c) RJ= CH3,
(f)
Rl~Q
R2
R2
=-Q
=
CH3~
the rotation about C=N bond and an activation energy,
= 28.5 kcal mor l has been eva luated . Thi s behaviour eliminated the possibility of nitrogen in version and rotation about N-N bond where an entirely
different magnetic environment would be attai ned .
Hydrazone .5b obtained from 2-butanone and
~G#
21
N-ami no- 3 ,4-(9', 10' -dih ydroan threcene-9', 10' -di y 1)succinimide exhibited a single spot on TLC plate.
IH NMR showed the E-configuration with the -CH3 in
syn (~8= I ppm) and -CH 2CH 3 in anti orientation . This
iso mer is fairly stable and does not isomerize in boilll
ing xylene .
Condensation of N-amino-3 ,4- (9', I 0' -dihydroanthracene-9', 10'-diyl)succinimide with acetophenone
in ethanol yielded a product 6a, mp 285°. Another
iso meric product 6b, mp 230 0 was obtained when the
same condensation was carried out in boiling xy lene.
IH NMR spectrum of 6a ex hibits magnetic
equivalance of 3,4-protons and shi elding parameter of
methyl protons indicates a geometry similar to Sa
with restricted rotation about N-N bond having the
ketimine part orthogonal to the succinimidyl plane
and -CH3 in syn orientation to the cage (Econfiguration).
IH NMR of the iso meric product 6b suggests a Zconfiguration of the ketimine moiety having the
methyl away from the cage. ]n the absence of shi eldin g on any proton of the phenyl ring, a sand wiched
geo metry of the phenyl with the cage is proposed.
Similar geometry has been reported for the N'N-amino-3,4- (9'-10'benzoyl
in N'-benzoyl
dihydroanthracene-9' , 10' -di y I) succinimide 12.Variable
temperature spectral studies showed th at on heatin g
6a in DMSO-ch gets transformed into 6b and at 180°,
the configurational population of 6a : 6b has been
evaluated to be in the ratio of 1:5. Thi s indicated th at
the Z-isomer has attained hi gher stability as compared
to the E-isomer by sandwi ching of the phenyl rings.
I3C NMR spectra of the isomeric product show that
the methyl of 6a resonates upfi eld (~8 = 10.68 ppm)
as compared to the methyl of 6b. This shi elding may
l3
be attributed to the steric compress ion effect of the
cage phenyl on the methyl carbon in 6a.
The confor mati o nal energy analysis carri ed out
us ing Search -Compare (Ver. 2 .3.0) of Insigh t - II
(Ver. 2.3.0) and Di scover Ver. 3. 1.0 module of 810SYM software (2 .3 .0)14 also suggested the Z conformer to be the lowest energy conformer (Vdw =
118 .642; Elec. = 14.2401; Total = 132.882)
(Figure 1, 6b) . Th e minimum energy conformer
obta ined by minimizing the E-isomer has hi gher energy ( Vdw = 123.620; Elec. = 14.290; Total =
137.952) (Figure 1, 6a) than the for mer. Th e stabilization of th e conformer 6b may be due to the n-n
(p i-pi) interaction of the phenyl group with o ne of
the cage benzo rin g.
22
INDIAN J CHEM , SEC 13, JANUARY 200 1
(6a)
vdW. 123.662 : Elect. 14 .29 : TotAl. 137.952
(6b)
vdW. 119.642 : Elect. • 14.2401 : TotRI. 132.882
Figure l --Conform ati onal energy analysis carried out using Search-Compare (Ver. 2.3.0) and Discover Ver. 3.1 .0 module of BIOSYM
soft ware (2.3.0)
Reduction of 6a and 6b with excess of sod ium
borohydride in methanol gave a single product which
has been characterised as 7. One of the carbonyl s of
the succi nimidyl ring has been reduced to -CHOH and
the -C=N is transformed into -CH-NH groupi 5. An s/
non-inverting geometry of nitrogen in N- (isopropyIideneamino)- imide 8 stabi li zed by the 7t- electronic
system and restricted rotation about NSp 3_CSp 3 bond
has been demonstrated by iH NMR and X-ray crystallography lO. The methyl reso nances of 7 indicates
that the benzylic phenyl is sand wiched with the cage.
This observation is an additional evidence in conformity with the stable Z-configuration of 6b.
Iso meric products have been obtained in the reacti on of N-amino-3,4- (9', 10' - dihydroanthracene9',10'-diyl)succinimide with 2-acetonaphthalene (6c
and 6d) and 2-acetothiophene (6e and 6f). Compounds 6c and 6e have bee n isolated from the reaction in ethanol medium while 6d and 6f were obtained from boiling xy lene solution. Methyl resonances in iH NMR are quite characteri stic in demonstrating the geo metry of the hyd razones. £configurat ion has been assig ned to 6c and 6e while
Z-configuration to 6d and 6f. DC NMR spectra of
compo unds 6c and 6f are in agreement with th e proposed structures.
iH NMR spectrum of p-benzoquinone hydrazo ne 9
is interesting. A characteristic shieided reso nance for
one of th e p-benzoquinone protons indicates an
orth ogo nal geometry of th e p-benzoq uino ne moiety to
the succinimidyl plane i6 . Molecular model also
sup ports the syn-geo metry of th e fJ-benzoq ui none
moiety .
(~)
(9)
Experimenta l Section
All th e melting points reported are uncorrected .
iH NMR spectra were recorded on a lEOL 90Q
multinuclear spectrometer at 25°C in CDC b with
TMS as the internal standard (chemical shift in 8,
ppm) . IR spectra were recorded in KBr on a JAS CO
Ff/IR 5300 s ectrometer. Elemental analys is of the
compounds were determined on Perki Il-Elmer model
240C.
Molecular modelling : The molecuk 6 "vas constructed on silicon graphics workstation (I -DY ) using.
BIOSYM molec ul ar modelling software (Ver.2 .3.0(1.
The mo lecul e was minimised in Discover module of
SRI VASTAVA et al.: PREPARATION OF ISOMERI C HYDRAZONES
the software giving the parameter iteration ( 1000) and
deri vatives (0.00 I). A conformational analysis was
carri ed out rotati onal bond (C=N) giving the rotational bond mode as user defined, range (0 to 360),
increment (30.00), max imum conformers ( 100), energy threshold ( 10.00), mode (charge) and anchor atoms as nitrogen (N 20 ) of the (C=N) to get the lowest
energy conformer 6b (Figure 1). In order to have the
low energy co nformer corresponding to (6a) the energy of the con former was minimized to get the local
minimum energy conformer corresponding to Eiso mer 6a (Figure 1).
N- (Acetophenoneimino)-3, 4-endo (9',10'dihydro-anthracene-9',10'-diyl)succinimide
(Eisomer) 6a. It was prepared by refiu xing the Nami noimide l 7 of the anthracene-maleic anhydride adduct with equimolar amount of acetophenone and a
pinch of p-toluenesulphoni c acid in EtOH for 3 hr. On
cooling the reacti on mixture, the product separated
out which was recrystallized fro m ethanol, mp 28587°; IR (KBr): 1765 m, 1710 s, 1630 w, 760 m cm-I;
IH NMR: 8 1.08 (3 H, s), 3.50 (2 H, bs), 5.09 (2 H, bs),
7.04-8. 14 ( 13H, m). I3C NMR: 8 15 .87, 45 .56,45. 88,
124.28 , 125.36, 125.82, 126.82, 127 .31 , 127.64,
128 .28, 13 1.59, 139.23 , 14 1.50, 174.09. Anal. Ca\cd
for C26H200 2N2: C, 79.55 ; H, 5.15 . Found : C, 79.48;
H, 5.1 0%.
N(Acetophenoneimino)-3,4-endo
(9', 10'dihydro-anthracene-9' ,10'-diyl) succinimide (Zisomer) 6b. It was obtained by refluxin g the N-amino
imide of the anthracene-maleic anhydride adduct with
equimolar amount of acetophenone and a pinch of ptoluenesulphoni c acid in p-xylene for 3 hr. On cooling
the reaction mi xture, the product separated out which
was recrystalli zed fro m xy lene, mp 230-32°; IR (KBr)
1765 m, 1700 s, 1620 w, 750 m cm-I; IH NMR : 8 2.77
(3 H, s), 3.36 (2 H, bs), 5.02 (2 H, bs), 7.16-8.36 (l3H ,
m). 13C NMR : 8 26.55 , 45.29, 45 .89, 124 .28, 124.99,
125.30, 126.17 , 126.28, 127.20, 127.60, 128.29,
128.56, 128.94, 133.05, 174.09. An al. Ca\cd fo r
e 26H200 2N2: e , 79.55 ; H, 5.15 . Found: C, 79.40; H,
5.20%.
N- (2-Acetonaphthaleneimino)-3,4-elldo (9',10'di-hydroanthracene-9' ,10'-diyl) succinimide (Eisomer) 6c. It was obtained from N-amino imide of
the anthracene-maleic anhydride adduct with equimolar amount of 2-acetyl naphthalene in the sa me
way reported for 6a, mp 290-92°; IR (KBr): 1770m,
1710 s, 1625 w, 730 m c m-I; IH NMR : 8 1.40 (3H, s),
3.52 (2H. bs), 5.14 (2 H, bs), 7.45-8.50 (I SH , m).
23
Anal. e a\cd fo r e 30H220 2N2: e , 8 1.40; H, 5.02.
Found: C, 8 1.51 ; H, 5.10%.
N-(2-Acetonaphthaleneimino)-3,4-elldo (9' ,10'di-hydroanthracene-9' ,10'-diyl) succinimide (Zisomer) 6d. It was prepared from N-amino imide of
the anthracene-maleic anhydride adduct with equimolar amount of 2-acetyl naphthalene in the same
way reported for 6b, mp 260-6 1°; IR (KBr): 1770 m,
1630 w, 1700 s, 1630 w, 730 m cm-I; IH NMR:
8 2. 86 (3 H, s), 3.36 (2 H, bs), 5.02 (2 H, bs), 7.36-8.8 1
( ISH, m). Anal. e a\cd for C30H220 2N2: e , 8 1.40; H,
5.02. Found : e , 8 1.46: H, 4.95%.
N- (2-Acetothiopheneimino)-3, 4-endo (9', lO'-dihydroanthracene-9' ,10' -diyl)
succinimide
(Eisomer) 6e. It was obtained in the same way as 6a
fro m N-amino imide of the anthracene-maleic anhydride adduct with equimolar amount of 2-acetyl th iophene: mp 295-97°C; IR (KBr): 1760 m, 17 10 s,
1630 w, 750 m em-I; IH NMR : 8 1.31 (3 H, s), 3.45
(2 H, bs), 5.04 (2 H, bs), 7.27-7 .77 (11H , m). Anal.
e a\cd. for C 24 H IS0 2N2S: e , n .3 1; H, 4.63 . Found: e ,
n.20; H, 4.78%.
N- (2-Acetothiopheneimino)-3, 4-elldo (9', 10'-dihydroanthracene-9' ,10'-diyl)
succinimide
(Zisomer) 6f. It was obtained in the same way as. menti oned for 6e by refiuxin g the mi xture in p-xy lene for
3 hr. mp 250-51 °C; IR (KBr): 1735 m, 1700 s,
1630 w, 750 m em-I; IH NMR : 8 2.68 (3H, s), 3.50
(2 H, bs), 5.00 (2 H, bs), 7.3 1-8.04 (lIH, m). Anal.
e alcd. for e 24HIS0 2N2S: C, n. 31; H, 4.63. Found : e ,
n.50; H, 4.55 %.
N- (1-Methylbenzylamino)-3, 4-endo (9', 10'-dihydroanthracene-9',10'-diyl)5-exo hydroxy-2-pyrrolidone 7. It was obtained by the reaction of 6a with
excess of NaBH4 (3 mole) in methanol at 25°C. The
mi xture was stirred over a peri od of 30 min . After
6 hr, the borate complex was hydrolyzed with water
and extracted with Et 20 . The ether extract was dried
(Na2S04) and concentrated to give the crystalline
product: mp 171-n oe ; lR (KEr): 3250 b, 3 100 w,
1680 s, 750 m em-I ; IH NMR: 80.9 (3 H, d), 2.45 (l H,
d), 2.51 (I H, S, 0 20 exchangeable), 2.95 (I H, dd), 3. 1
(1 H, q), 4.1 (1 H,S, 0 20 exchangeable) 4.43 ( I H, d),
4.6 (lH, s), 4.67 (lH , d), 6.95-7 .50 (l 3H, m). Anal.
e a\cd. for e 26H240 2N2: C, 78.79 ; H, 6.06 Found: e ,
.
78. 88; H, 6.11 %.
N- (p-Benzoquinoneimino)-3, 4-elldo (9', 10'-dihydroanthracene-9',10'-diyl) succinimide 9. It was
obtained from N-aminoimide of the anthracenemaleic anhydride adduct and p-benzoquinone in cth a-
24
INDIAN J C HEM, SEC B, JANUARY 2001
nol medium as repo rted for 6a . On cooling the reacti on mi xture, the produ ct separated out which was
recrysyallized from ethanol, mp 260-6 1°; IR ( KBr):
1790 w, 1730 s, 765 m cm-I; IH NMR : <5 3.44 (2H ,
bs), 5.00 (2 H, bs), 5.15 (1 H, dd , J=9Hz and J=3Hz ),
6.37 (dd , tH ) 6.71 ( tH , dd), 7.24-7 .68 (9H, m). Anal.
Calcd fo r C24 H1 60 3N2: C, 77 .80 ; H, 4 .22. Found: C,
77 .62; H, 4.20%.
Acknowledgement
Authors are thankful to the Council of Scientific
and Industri al Research, New Delhi for the support of
the research project No .2 1 (279)/93 -EMR II.
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