Stereochemistry of products of reactions between 3-diazo-naphthalene-1,2,4- trione and β-dicarbonyl compounds. structure of ethyl 2-[(3-hydroxy- 1, 4-dioxo-1, 4-dihydro-naphthalen-2-yl)-hydrazono]-3-phenyl-3-oxopropionate

Article abstract of DOI:10.3184/030823409X440850

3-Hydroxy-2-[(R¹CO)(R²CO)]C=NNH-1,4-naphthoquinones, obtained from reactions of 3-diazonaphthalene-1,2,4-trione with β-diketones, R¹C(O)CH₂COR², have been previously found to have high antibacterial a

Full text of DOI:10.3184/030823409X440850

308 RESEARCH PAPER
MAy, 308–311
JOURNAL OF CHEMICAL RESEARCH 2009
Stereochemistry of products of reactions between 3-diazo-naphthalene-
1,2,4-trione and β-dicarbonyl compounds. Structure of ethyl 2-[(3-hydroxy-
1,4-dioxo-1,4-dihydro-naphthalen-2-yl)-hydrazono]-3-phenyl-3-oxo-
propionate
Fernando de C. da Silvaa, Vitor F. Ferreiraa, Patrícia de O. Lopesa, James L. Wardellb,c and
Solange M. S. V. Wardelld
aUniversidade Federal Fluminense, Instituto de Química, Departamento de Química Orgânica-PQO, 24020-150 Niterói,
Rio de Janeiro, Brazil
bCentro de Desenvolvimento Tecnológico em Saúde (CDTS), Fundação Oswaldo Cruz (Fiocruz), Casa Amarela,
Campus de Manguinhos, Av. Brazil 4365, 21040-900, Rio de Janeiro, RJ, Brazil
cDepartment of Chemistry, University of Aberdeen, Old Aberdeen AB24 3UE, UK
dDepartamento de Síntese, Farmanguinhos – Fiocruz, Instituto de Tecnologia em Fármacos, R. Sizenando Nabuco 100,
21041-250 Manguinhos, Rio de Janeiro, RJ Brazil
1
2
=
3-Hydroxy-2-[(R CO)(R CO)]C NNH-1,4-naphthoquinones, obtained from reactions of 3-diazonaphthalene-1,2,4-
trione with b-diketones, R1C(O)CH2COR2, have been previously found to have high antibacterial activity. However,
=
confirmation of the stereochemistry about the C N bond could not be achieved by spectroscopic means for products
having different R1 and R2 groups, thereby limiting the utility of the reaction. Full characterisation of the product
isolated from reaction of 3-diazonaphthalene-1,2,4-trione with PhC(O)CH2CO2Et is now reported, from a single
=
crystal X-ray structure determination: the product, 3-hydroxy-2-[(PhCO)(EtCO2)]C NNH-1,4-naphthoquinone has a
(Z)-stereochemistry. The Z-isomer is obtained rather than the E form due to the preferred formation of the stronger
intramolecular N–H---O hydrogen-bond with the ester carbonyl oxygen rather than a weaker one with the ketone
oxygen. Weaker C–H---O hydrogen bonds link the molecules into columns. It is suggested that similar Z geometries
will arise from other RC(O)CH2CO2Ri reactants.
Keywords: 1,4-naphthoquinones, lapachol derivatives, hydazones, antibacterial activity
O
Quinones have been the subject of considerable interest for
many years as a result of their biological activities. It has
been over 60 years since Wendel initially showed that certain
2-hydroxy-3-alkyl-naphthoquinones inhibited the growth of
Plasmodium.1 Further studies have proven that the toxicity of
naphthoquinones to Plasmodium sp. is due to interaction with
the mitochondrial respiratory chain.2,3
O
O
O
O
H
H
O
O
O
O
1
3
2
Among the family of naphthoquinones, lapachol, 1,
(a naturally occurring compound), and its derivatives have
been particularly well investigated over the past decades for
their antibacterial,4-6 antifungal7 and anticancer8-12 activities.
The anti-cancer activity of b-lapachone, 2, an isomer of
lapachol 1, has also been intensely investigated.13-16 Studies
with substituted lapachol derivatives have indicated certain
correlations between structure and biological activity. For
example, a relationship was established between the length
of the side chain at site 3 in 2-hydroxy-3-alkyl-substituted-
1,4-naphthoquinones and the toxic effects on several
microorganisms.17,18 Fieser and Richardson showed that, as
the alkyl side chain in hydrolapachol, 3, is lengthened by the
insertion of methylene units, the activity against P. lophurae
in duck increases up to a C9-side chain, but then falls away.19
Ferreira and co-workers20 have reported the synthesis and
antibacterial activity of the 2-hydroxy-3-hydrazino-1,4-
naphthoquinones, 4a–e, obtained from 3-diazo-naphthalene-
O
O
O
H
N
N
H
R1
O
O
R2
4: (a) R1 = R2 = Me
(b) R1 = Me, R2 = OEt
(c) R1 = Me, R2 = OBut
(d) R1 = R2 = OCMe 2O
(e) R1 = R2 = OEt
(f) R1 = Ph, R 2 = OEt
Fig. 1 Selected 1,4-naphthoquinones.
1,2,4-trione following a procedure published by Reid et al.,21
see Scheme 1 and Fig. 1. Compounds 4 can be considered
as analogues of the 2-hydroxy-3-alkyl-substituted-1,4-
O
O
O
O
R1
R2
O
H
COR 1
COR 2
O
N
C
1
K2CO3 ,Me2CO
N2
N
H
O
O
Scheme 1
* Correspondent. E-mail: j.wardell@abdn.ac.uk

JOURNAL OF CHEMICAL RESEARCH 2009 309
naphthoquinones. The most active of these compounds,
4b, in preliminary susceptibility testing in discs, exhibited
a higher level of antibacterial activity than lapachol, 1.
Additional studies on the minimal inhibitory concentration
(MIC) for Staphylococcus aureus showed that 4b has shown
an activity twice that of lapachol. The stereochemistry about
the hydrazone C=N bond for compounds, 4, having different
R1 and R2 groups, could not be established by spectroscopic
means. Without confirmation of the stereochemistry, the
scope of this reaction is somewhat limited to symmetrical
compounds. Thus we have turned to X-ray crystallography
to help solve the stereochemical problem. The unsymmetrical
hydrazono compound, ethyl 2-[(3-hydroxy-1,4-dioxo-
1,4-dihydro-naphthalen-2-yl)hydrazono]-3-phenyl-3-oxo-
propionate (4f), containing an ester and a ketone groups
produced suitable crystals for the X-ray study.
shown in Fig. 2a, while selected bond lengths and angles are
listed in Table 1.
There are several possible combined stereochemical and
conformational forms for 4f, some of which are drawn in
Fig. 3. The form actually determined was the [(Z)-4f-I] form,
i.e. with a (Z) stereochemistry at C(9)) = N(2), see Figs 2a and 3.
This geometry is cemented by the N1–H1---O6 (involving the
ester group) and the O–H---N intramolecular hydrogen bonds.
The corresponding (E)-4f-I form would have the ketone
carbonyl oxygen atom, O3, H-bonded to NH- a less favourable
situation due to the reduced H-bond ability of keto compared
to ester carbonyl groups. It is noticeable that the Z-form
adopted in the solid state is the [(Z)-4f-I] form rather than the
[(Z)-4f-II] form. The (Z)-form, [(Z)-4f-II], would also allow
the strong N1–H1---O6 intramolecular hydrogen-bonding and
additionally an O2–H2---O3 intramolecular H-bond. However
this is not favoured in the solid state. Instead of being
involved in an intramolecular H–bond, the PhCO oxygen, O3,
takes part preferentially in intermolecular hydrogen bonding.
This C5–H5---O3i intermolecular hydrogen bond, as well as
C18–H18b---O2ii, link the molecules into columns: symmetry
codes: i: –1/2–x, –1/2 + y, –3/2 + z, ii: –1/2–x, 1/2 + y, 1/2 + z,
see Fig. 2b and Table 1.
Geometric parameters for the hydrogen bonds, recognised
by PLATON,22 are listed in Table 1. The intramolecular
hydrogen bonds, O2–H2---N2 and O2–H2---N1, would occur
irrespective of the nature of the stereochemistry at the C=N
bond. In addition to the intermolecular H-bonds, there are also
π–π stacking intermolecular interactions linking molecules,
see Table 1. The most significant of these are shown in Fig. 2c.
The stereochemistry about the C=N bond is significant while
the conformation found in the solid state really has relevance
only for the solid state as thermal motions and solvation effects
Results and discussion
The isolated yields of 4a–4e, as pure single-component solids,
were reported to be in the range 55–68%,20 while that for the
new derivative, purple 2-[(3-hydroxy-1,4-dioxo-1,4-dihydro-
naphthalen-2-yl)-hydrazono]-3-phenyl-3-oxo-propinoate (4f),
obtained from ethyl benzoylacetate, was found to be lower at
27%, after two recrystallisations. While no product balance
was carried out, there were no indications of other isomeric
products: starting materials had been totally consumed.
No other products were isolated or identified in the reaction
residue despite attempts to do so. Spectral and other data were
consistent with the formula for 4f, but could not distinguish
between the possible geometric isomers. The sample of 4f
used in the crystallographic study was recrystallised from
EtOH. The atom arrangement and numbering scheme are
a
b
b
c
a
Fig. 2 (a) Atom arrangements and numbering scheme for 4f, probability ellipsoids of atoms are drawn at the 50% level,
hydrogen atoms are drawn as spheres of arbitrary radius; intramolecular H-bonds drawn as dashed lines; (b) molecules linked
by intermolecular H-bonds, C5–H5---O33 and C183–H18b3---O2; (c) molecules indicating the p–p stacking interactions involving the
quinone ring [C(5)–C(8), C(8A), C(4A)] and the terminal aryl ring [C(1)–C(4), C(4A), C(8A)]: symmetry codes are listed in Table 2.

310 JOURNAL OF CHEMICAL RESEARCH 2009
Table 1 Geometric parameters for 4f
(a) Selected bond lengths and angles [Å,°]
O(4)–C(4)
O(2)–C(3)
O(5)–C(18)
1.211(8)
1.355(8)
1.443(8)
O(1)–C(1)
O(5)–C(17)
O(6)–C(17)
1.210(8)
1.321(9)
1.221(9)
N(1)–N(2)
N(2)–C(9)
C(10)–C(11)
1.341(7)
1.300(9)
1.472(10)
N(1)–C(2)
C(9)–C(10)
O(3)–C(10)
1.395(9)
1.481(10)
1.239(8)
C(4)–C(4A)
C(1)–C(8A)
C(3)–C(2)
1.509(10)
1.495(10)
1.361(9)
C(8A)–C(4A)
C(2)–C(1)
C(4)–C(3)
1.405(10)
1.481(10)
1.469(10)
N(2)–N(1)–C(2)
N(2)–C(9)–C(10)
119.2(6)
113.1(7)
C(9)–N(2)–N(1)
C(11)–C(10)–C(9)
122.5(6)
119.0(5)
C(3)–C(4)–C(4A)
C1–C(8A)–C(4A)
C(3)–C(2)–C(1)
116.1(7)
120.3(7)
122.1(7)
C(8A)–C(4A)–C(4)
C(2)–C(1)–C(8A)
C(2)–C(3)–C(4)
121.4(7)
117.0(7)
122.9(7)
(a) Hydrogen bonds (Å,°)
D–H---A
D–H
H---A
D---A
–D–H---A
N1–H1---O6
O2–H2---N1
O2–H2---N2
C5–H5---O3i
C18–H18B---O2ii
1.05
0.82
0.82
0.95
0.99
1.88
2.45
1.91
2.39
2.56
2.632(6)
2.923(6)
2.647(7)
3.207(8)
3.183(8)
125
117
150
144
121
Symmetry codes: i = –1/2–x, –1/2 + y, –3/2 + z; ii = –1/2–x, 1/2 + y, 1/2 + z
(b) p–p- stacking interactions (Å,°)a
Cg(I)---Cg(J)
Cg∙∙Cg
a
b
g
Cgperp
Slippage
Cg(1)---Cg(2)iii
Cg(2)---Cg(1)iv
4.282(5)
4.281(5)
1.3(4)
1.3(4)
38.57
39.65
39.65
38.57
3.297(3)
3.347(3)
3.348(3)
3.297(3)
aCg(1) is the centroid of the ring defined by C(1)–C(4), C(4A), C(8A) and Cg(2) is the centroid of the ring defined by C(5)–C(8),
C(8A), C(4A); a is the dihedral angle between the overlapping rings; b is the angle at either Cg between the vectors Cg∙∙Cg and
Cgperp; Cg∙∙Cg is the distance between the ring centroids; Cgperp is the perpendicular between the ring planes and slippage,
or lateral displacement, is the distance between Cg(I) and perpendicular projection of Cg(J) on ring I. [Symmetry codes:
(iii) x,y,1 + z (iv) z, y,–1 + z]
O
O
O
O
O
H
N
H
N
N
H
N
H
O
O
O
O
OEt
O
OEt
(Z)-4f-I
(Z)-4f-II
O
O
O
O
O
H
H
N
OEt
O
N
OEt
N
H
O
N
H
O
O
O
(E)-4f-I
Fig. 3 Selected stereoisomers and conformers of 4f.
(E)-4f-II
are significant in solution and can affect the conformational
equilibrium. The atoms, O2, C3, C2, C1, O1, C8A, C8, C7, C6,
C5, C4A, C4, O4, N1, N2, C10 are essentially co-planar, with
atoms O1 and O4, being the furthest out of the best plane by
0.096(4) and 0.098(4) Å, respectively. The angles between this
best plane and that of the C11-C16 phenyl plane is 59.02 (12)°.
It has to be stated that (Z)-4f-I was isolated in a low yield.
While no product balance was undertaken, no indication of an
(E)-4f product was obtained. However, it remains a possibility
that a (E)-4f stereoisomer had been formed, but had escaped
detection and isolation. No indication of a tautomer of 4f
either was found.
The crystallographic findings, with respect to the
stereochemistry for 4f, are clear, and suggest that similar
Z-configurations will apply to other keto-ester compounds,
such as 4b and 4c, shown in Fig. 1.

JOURNAL OF CHEMICAL RESEARCH 2009 311
Crystallography
Experimental
The sample was recrystallised from EtOH. Data were obtained at
120 K with Mo-K– radiation by means of the Enraf Nonius
KappaCCDareadetectordiffractometeroftheEPSRCcrystallographic
service, based at the University of Southampton. Data collection
was carried out under the control of the program COLLECT23 and
data reduction and unit cell refinement were achieved with the
COLLECT23 and DENZO programs.24 Correction for absorption,
by comparison of the intensities of equivalent reflections, was
applied using the program SADABS.25 The program ORTEP-
3 for Windows26 was used in the preparation of the figures and
SHELXL-9727 and PLATON22 in the calculation of molecular
geometry. The structure was solved by direct methods using
SHELXS-9728 and fully refined by means of the program
SHELXL-97.27 In the final stages of refinement hydrogen atoms
were introduced in calculated positions and refined with a riding
model. Crystal data and structure refinement details are listed in
Table 2. CCDC 676187 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif”.
NMR spectra were run in CDCl3 solutions on a Varian Unity 300 MHz
Plus Spectrometer, infrared spectra were recorded on a Perkin-Elmer
FT-IR Spectrum One spectrophotometer calibrated relative to the
1601.8 cm-1 absorbance of polystyrene, thin layer chromatography on
silicagel 60F-254 (5554 MERCK), 0.2 mm thick, and with spraying
with aqueous ammonium sulfate (25% m/v), column chromatography
on silicagel 60 (0.063–0.200 mm ref. Merck. 1.05554). Melting points
were measured on Reichert micro hot stage and are uncorrected.
Solvents were dried by standard methods.
Preparation of 2-[(3-hydroxy-1,4-dioxo-1,4-dihydro-naphthalen-2-
yl)-hydrazono]-3-phenyl-3-oxo-propionate (4f)
A mixture of ethyl benzoylacetate (0.38 mmol) and anhydrous
K2CO3 (57 mg, 0.4 mmol) in dry acetone (15 mL) was stirred for
15 min under a nitrogen atmosphere. To this mixture was added
slowly through a syringe, a solution of 3-diazo-naphthalene-1,2,4-
trione (5, 77 mg, 0.38 mmol) in dry acetone (5 mL) during 15 min.
After stirring for 2 h the reaction was acidified with 5% (v/v) HCl
(40 mL), the solid material was collected by filtration gave (Z)
2-[(3-hydroxy-1,4-dioxo-1,4-dihydro-naphthalen-2-yl)-hydrazono]-
3-phenyl-3-oxo-propinoate (4f) as a purple solid (m.p. 178–179°C)
in 27% yield.
The authors thank the EPSRC X-Ray Crystallography Service,
based at the University of Southampton, England for the data
collection.
O
5
4
4a
O
6
7
H
N
3
Received 28 December 2008; accepted 1 Fenruary 2009
Paper 08/0363 doi: 10.3184/030823409X440850
Published online: 20 May 2009
2 N
H
O
8a
1
8
O
O
O
IR nmax:1736, 1676, 1668, 1651, 1618, 1595, 1530, 1466, 1447,
1370, 1335, 1293, 1272, 1258, 1214, 1202, 1149, 959, 713 cm-1.
1H NMR (300.00 MHz, CDCl3) d 1.35 (3H, t, J = 7.1 Hz, OCH2CH3),
4,43 (2H, q, J = 7.1 Hz, OCH2CH3), 7.53–7.48 (2H, m, meta-Ph),
7.53–7.48 (1H, m, H-6); 7.69–7.75 (1H, m, para-Ph); 7.69–7.75 (1H,
m, H-7), 7.86 (1H, d, J = 9.0 Hz, H-8); 7.93–7.97 (1H, m, ortho-Ph),
8.09 (1H, d, J = 9.0 Hz, H-5) ppm; 13C NMR (75.0 MHz, CDCl3)
d 13.7 (OCH2CH3), 62.3 (OCH2CH3), 122.4 (C-2), 126.0 (C-5), 126.4
(C-8), 128.3 (Cmeta-Ph), 128.7 (Cortho-Ph), 129.3 (Cpara-Ph), 129.5
(C=N), 130.6 (C-4a), 133.6 (C-7), 134.1 (C-6), 135.8 (C-8a), 142.5
(Ph), 144.6 (C-3), 162.4 (CO2Et), 168.7 (C-4), 174.4 (C-1), 178.9
(PhC=O) ppm. Found: C, 64.1; H, 4.3; N, 7.2. C21H16N2O6 requires:
C, 64.28; H, 4.11; N, 7.14%
References
1
2
3
4
W.B. Wendel, Fed Proc., 1946, 5, 406.
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Table 2 Crystal data and structure refinement for 4f
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39, 2472.
Empirical formula
Formula weight
C21H16N2O6
392.36
Temperature
120(2) K
Wavelength
0.71073 Å
Crystal system, space group
Unit cell dimensions
Orthorhombic, Pna21
a = 20.5630(9)Å
b = 14.633(2) Å
c = 6.011(3) Å
1808.7(9) Å 3
4
Volume
Z
Density (calculated)
Absorption coefficient
F(000)
1.441 Mg m-3
0.107 mm–1
816
Crystal size
0.60 ¥ 0.05 ¥ 0.03 mm
Theta range for data collection 2.96 to 25.00 deg.
18 R.J.Weaver, M. Dickins and M.D. Burke, Biochem Pharmacol., 1993,
46, 1183.
Index ranges
–17< = h< = 24;
19 L.F.Fieser and A.P. Richardson, J Am Chem Soc., 1948, 70, 3156.
20 G.T. Oliveira, F.F. Miranda, V.F. Ferreira, C.C. Freitas, R.F. Rabello,
J.M. Carballido and L.C.D. Correa, (2001) J Braz Chem Soc., 2001,
12, 339.
21 W. Reid and E. Kahr, Liebigs Ann Chem., 1969, 725, 228.
22 A.L. Spek, J. Appl. Cryst., 2003, 36, 7.
23 R.W.W. Hooft, COLLECT. Nonius BV, Delft, The Netherlands. 1998.
24 Z. Otwinowski and W. Minor, Methods in Enzymology, Vol. 276,
Macromolecular Crystallography, Part A, eds C.W. Carter Jr and
R.M. Sweet, pp. 307-326. New York: Academic Press. 1997.
25 G.M. Sheldrick, SADABS. Version 2.10. Bruker AXS Inc., Madison,
Wisconsin, USA. (2003).
26 L.J. Farrugia, J. Appl. Cryst., 1999, 32, 837.
27 G.M. Sheldrick, SHELXL-97. Program for Crystal Structure Refinement.
University of Göttingen, Germany, 1997.
–17< = k< = 17; –7< = l< = 7
9888
Reflections collected
Independent reflections
1719 [R(int) = 0.1350]
Reflections observed (>2 sigma) 1050
Data Completeness
Absorption correction
Refinement method
0.976
None
Full–matrix least–squares
on F2
Data/restraints/parameters
Goodness–of–fit on F@2
Final R indices [I>2 sigma(I)]
R indices (all data)
Absolute structure parameter
Largest diff. peak and hole
CCDC deposit number
1719/1/266
1.099
R1 = 0.0911 wR2 = 0.1385
R1 = 0.1599 wR2 = 0.1631
0.00 (10)
0.259 and –0.265 e Å 3
676187
28 G.M. Sheldrick, SHELXS-97. Program for the Solution of Crystal
Structures. University of Göttingen, Germany, 1997.