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 section . 
;
?
;
 section 
;
Introduction
; 
;\
The dibenzo[b,e]azepine ring is an important pharmacophore in 
drug discovery and many of its derivatives exhibit a broad spectrum of 
biological activities (Van der Burg et al., 1970; Brogden 
et al., 1978; Nickolson & Wieringa, 1981; Berger et al., 1989; 
De Boer et al., 1996; Roeder et al., 1998; 
Andrés et al., 2002; Wikström et al., 2002). Consequently, 
a significant number of synthetic methods have been developed for the 
synthesis of new derivatives of this heterocyclic system (Moriconi & 
Maniscalco, 1972; Sasakura & Sugasawa, 1981; Stappers et al., 2002). 
In this context, we have recently developed a simple and practical synthetic 
route to obtain novel series of 6,11-dihydrodibenzo[b,e]azepines 
from readily available 2-allyl-N-benzyl-substituted anilines (Palma 
et al., 2004, 2010). To broaden the scope of this route, and in 
continuation of our research programme on the preparation of new potentially 
bioactive molecules containing the dihydrodibenzo[b,e]azepine 
nucleus, we have achieved a simple synthesis of three previously unknown
5-acetyl-11-ethyl-6,11-dihydro-5H-dibenzo[b,e]azepine-6-\
carboxylic acids. Here we report the molecular structures and supramolecular
assembly of three closely related compounds, namely
(6R*,11R*)-5-acetyl-11-ethyl-6,11-dihydro-5H-\
dibenzo[b,e]azepine-6-carboxylic acid, (I) (Fig. 1),
(6RS,11SR)-5-acetyl-11-ethyl-2-methyl-6,11-dihydro-5H-
dibenzo[b,e]azepine-6-carboxylic acid, (II) (Fig. 2), and
(6RS,11SR)-5-acetyl-11-ethyl-1,3-dimethyl-6,11-dihydro-
5H-dibenzo[b,e]azepine-6-carboxylic acid, (III) (Fig. 3),
the constitutions of which differ only in the presence of one methyl
substituent in (II) and two in (III), while there are none in (I). The
synthesis of compounds (I)--(III) was achieved by intramolecular
Friedel--Crafts alkylation of the corresponding methyl
2-[N-(2-allylaryl)acetamido]-2-phenylacetates using concentrated
sulfuric acid at 373 K (see scheme).
;
 section Experimental 
;
?
;
 subsection 'Synthesis and crystallization'
;
For the synthesis of each of (I)--(III), a suspension of the appropriately
substituted racemic methyl 2-[N-(2-allylaryl)acetamido]-2-phenylacetate
(see scheme) (1.0 g) in concentrated sulfuric acid (3 ml) was stirred at 373 K
for 7 min. The reaction mixture was cooled to ambient temperature by the
addition of ice and then extracted with ethyl acetate (3 × 50 ml). The
combined organic extracts were dried over anhydrous sodium sulfate and the
solvent was removed under reduced pressure. The resulting crude products were
subjected to column chromatographic purification over silica gel using
heptane--ethyl acetate--acetic acid (1:2:0.04 v/v/v).
Crystallization from ethyl acetate--ethanol (30:1 v/v) at
ambient temperature and in the presence of air gave colourless crystals of
(I)--(III), suitable for single-crystal X-ray diffraction. Compound (I): yield
35%, m.p. 449--450 K, HRMS m/z [M]⁺ found 309.1366,
C₁₉H₁₉NO₃ requires 309.1365. Compound (II): yield 20%, m.p. 460--462 K,
HRMS m/z [M]⁺ found 323.1525, C₂₀H₂₁NO₃ requires
323.1521. Compound (III): yield 41%, m.p. 497--499 K, HRMS m/z
[M]⁺ found 337.1653, C₂₁H₂₁NO₃ requires 337.1678.
;

 subsection Refinement
;
Crystal data, data collection and structure refinement details are summarized
in Table 1. All H atoms were located in difference maps and subsequently
treated as riding atoms. C-bound H atoms were permitted to ride in
geometrically idealized positions, with C---H = 0.95 (aromatic), 0.98 (CH₃),
0.99 (CH₂) or 1.00 Å (aliphatic C---H), and with Uiso(H) =
kUeq(C), where k = 1.5 for the methyl groups, which were
permitted to rotate but not to tilt, and 1.2 for all other C-bound H atoms.
O-bound H atoms were permitted to ride at the positions located in difference
maps with Uiso(H) = 1.5Ueq(O), giving the O---H distances
shown in Table 3. Several low-angle reflections, which had been wholly or
partially attenuated by the beam stop, were omitted from the final
refinements. The value of the Flack x parameter (Flack, 1983)
for (I)
was indeterminate (Flack & Bernardinelli, 2000); accordingly,
Friedel-equivalent reflections were merged prior to the final refinements.
Examination of the refined structures using PLATON (Spek, 2009)
showed
the presence of two small cavities in the structure of (II), centred at (1/2,
0, 1/2) and (1/2, 1/2, 0) and each of volume 24 Å³; these cavities are far
too small to contain any plausible solvent molecule but, nonetheless, the
largest peak in the difference map, 0.68 e Å⁻³ at (0.523, 0.482, 0.064),
was very close to one of the cavities. However, application of the SQUEEZE
procedure in PLATON revealed only one excess electron per cavity.
Accordingly, we regard both the difference peak and the excess electron count
as minor artefacts of the data.
;

 subsection 'Analysis of spectral data'
;

;


 section 'Results and discussion'
;
;

 subsection 'Stereogenic centres in the title compounds'
;
The molecules of (I)--(III) all contain two stereogenic centres at atoms C6 and
C11 (Figs. 1--3). In (I), the exocyclcic substituents at atoms C6 and C11 have
a cis arrangement relative to the azepine ring, while those in (II) and
(III) have a trans arrangement. For each compound, the reference
molecule was selected as one having the R configuration at atom C6. On
this basis, the reference molecule of (I) has the R configuration at
atom C11, while those of (II) and (III) have the S configuration at
atom C11. Compounds (II) and (III) crystallize as racemic mixtures, as shown
by the centrosymmetric space group, but (I) crystallizes in the Sohnke space
group P2₁. Hence in the absence of twinning, for which no evidence
was found, each crystal of (I) contains only one enantiomorph. It was not
possible to determine the absolute configuration of the molecules in the
crystal of (I) which was selected for data collection, and hence the
configuration of the reference molecule was set to have the R
configuration at atom C6, just as for (II) and (III).
;

 subsection 'Three-dimensional structures of the title compounds'
;
The molecules of (III) are linked into a three-dimensional framework structure
by a combination of O---H...O, C---H...O and C---H...π(arene) hydrogen bonds
(Table 3). The O---H...O hydrogen bond links molecules related by the
n-glide plane at y = 3/4 to form a C(7) chain running
parallel to the [101] direction (Fig. 6), and the C---H...O hydrogen bond
links molecules related by a 2₁ screw axis along (3/4, y, 1/4) to
form a C(8) chain running parallel to the [010] direction (Fig. 6). The
combination of these two chains generates a sheet lying parallel to (10\=1)
and built from a single type of centrosymmetric R₄⁴(30) ring (Fig.
6). Sheets of this type are linked to form a continuous three-dimensional
framework structure by the C---H...π(arene) hydrogen bond, which links
molecules related by translation along the [100] direction (Fig. 7). The
combination of chains along [100], [010] and [101] is sufficient to form a
three-dimensional structure.
;
 subsection 'Hydrogen bonding in the title compounds'
;
It is thus striking that none of (I)--(III) exhibits the R₂²(8)
dimer motif so characteristic of simple carboxylic acids. Instead, all utilize
atom O51 of the N-acetyl group as acceptor in an O---H...O hydrogen
bond, and it is of interest briefly to compare the substructures which can be
identified in the supramolecular assemblies of (I)--(III). In each of the
structures, a C(7) chain motif can be identified built from O---H...O hydrogen
bonds. However, these chains differ in that those in (I) and (II) contain
molecules related by a 2₁ screw axis, whereas that in (III) contains
molecules related by an n-glide plane. Similarly, sheets built from a
combination of O---H...O and C---H...O hydrogen bonds can be identified in the
structures of (I) and (III) (Figs. 5 and 6). Both sheets exhibit (4,4)
topology (Batten & Robson, 1998). The ring sizes in the sheets in (I)
and
(III) differ, as do the numbers of hydrogen-bond acceptors within these rings,
since in (I) amide atom O51 acts as a double acceptor of hydrogen bonds,
unlike that in (III). However, within the sheet in (III) the constituent rings
are centrosymmetric, while those in (I) are not centrosymmetric. Chain
formation by means of O---H...O hydrogen bonds has been extensively studied in
keto acids, where the chain motif follows directly from the mutual disposition
of the carboxyl and keto groups. Thus, γ-keto-acids form C(7) chains
(e.g. Thompson et al., 2004; Malak et al.,
2006), δ-keto
acids form C(8) chains (e.g. Davison, Kikolski et al.,
2004) and ε-keto acids form C(9) chains (e.g. Davison,
Thompson
et al., 2004), while longer chain motifs are generated in
steroidal
keto acids (e.g. Kikolski et al., 2006).
;

 section Conclusions
;

;

#=============================================================

_audit_creation_date        'June 17, 2013'
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#===================================================================
# 1. SUBMISSION DETAILS

_publ_contact_author_name       'Professor Christopher Glidewell'
_publ_contact_author_address
;
University of St Andrews
Fife KY16 9ST
Scotland
;

_publ_contact_author_phone      '+1334-463839'
_publ_contact_author_fax        '+1334-463808'
_publ_contact_author_email      cg@st-andrews.ac.uk

_publ_requested_journal         'Acta Crystallographica C'
_publ_requested_category        FA
_publ_requested_coeditor_name   ?

_publ_contact_letter
;
January 30, 2014

Please consider this CIF submission for publication in Acta Crystallographica
Section C.  All authors have seen and approved this submission.

The CIF has passed the Chester CHECKCIF routines and gives a 
satisfactory PRINTCIF file.  

Christopher Glidewell
;

#=====================================================================
# 2. PROCESSING SUMMARY  (IUCr Office Use Only)

_journal_date_recd_electronic     ?
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_journal_date_from_coeditor       ?
_journal_date_accepted            ?
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_journal_paper_category           FA
_journal_coeditor_notes           ?
_journal_techeditor_code          ?
_iucr_compatibility_tag           ACTA95
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_journal_coden_ASTM               ACSCGG
_journal_name_full                'Acta Crystallographica, Section C'
_journal_year                     ?
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#=====================================================================
# 3. TITLE AND AUTHOR LIST

_publ_section_title
;
Three closely related dibenzazepine carboxylic acids: hydrogen-bonded
aggregation in one, two and three dimensions
;

loop_
_publ_author_name
_publ_author_address
_publ_author_email
_publ_author_footnote
'Sanabría, Carlos M.'
;  
Laboratorio de Síntesis Orgánica
Escuela de Química
Universidad Industrial de Santander
AA 678 Bucaramanga
Colombia
;
carmasasa@gmail.com
?
'Palma, Alirio'
;
Laboratorio de Síntesis Orgánica
Escuela de Química
Universidad Industrial de Santander
AA 678 Bucaramanga
Colombia
;
apalma@uis.edu.co
?
'Cobo, Justo'
;
Departamento de Química Inorgánica y Orgánica
Universidad de Jaén
23071 Jaén
Spain
;
jcobo@ujaen.es
?
'Glidewell, Christopher'
;
School of Chemistry
University of St Andrews
Fife KY16 9ST
Scotland
;
cg@st-andrews.ac.uk
?

#======================================================================
# 4. TEXT

_publ_section_synopsis
;\
In three
5-acetyl-11-ethyl-6,11-dihydro-5H-dibenzo[b,e]azepine-6-\
carboxylic acids, which differ only in the presence of zero, one or two
methyl substituents in one of the aryl rings, the hydrogen-bonded
supramolecular aggregation is respectively, two-, one- and three-dimensional.
;

_publ_section_keywords
;
crystal structure, dibenzo[b,e]azepine-6-carboxylic acid,
hydrogen bonding, hydrogen-bonded supramolecular aggregation
;

_publ_section_related_literature
;
For related literature, see: Allen et al. (1987);
Andrés et al. (2002);
Batten & Robson (1998);
Berger et al. (1989);
Bernstein et al. (1995);
Bondi (1964);
Brogden et al. (1978);
Cremer & Pople (1975);
Davison, Kikolski, Lalancette & Thompson (2004);
Davison, Thompson & Lalancette (2004);
De Boer, Nefkens, van Helvoirt & van Delft (1996);
Entrena et al. (1997);
Evans & Boeyens (1989);
Ferguson et al. (1998a, 1998b);
Flack (1983);
Flack & Bernardinelli (2000);
Gregson et al. (2000);
Kikolski et al. (2006);
Malak et al. (2006);
Moriconi & Maniscalco (1972);
Nickolson & Wieringa (1981);
Palma et al. (2004, 2010);
Roeder et al. (1998);
Rowland & Taylor (1996);
Sasakura & Sugasawa (1981);
Spek (2009);
Stappers et al. (2002);
Thompson et al. (2004);
Van der Burg, Bonta, Delobelle, Ramon & Vargaftig (1970);
Wikström et al. (2002);
Wood et al. (2009).
;

_publ_section_abstract
;\
In the structure of
(6R*,11R*)-5-acetyl-11-ethyl-6,11-dihydro-5H-\
dibenzo[b,e]azepine-6-carboxylic acid, C₁₉H₁₉NO₃, (I),
the molecules are linked into sheets by a combination of O---H...O and
C---H...O hydrogen bonds; in the structure of the monomethyl analogue
(6RS,11SR)-5-acetyl-11-ethyl-2-methyl-6,11-dihydro-5H-\
dibenzo[b,e]azepine-6-carboxylic acid, C₂₀H₂₁NO₃, (II),
the molecules are linked into simple C(7) chains by O---H...O hydrogen
bonds; and in the structure of the dimethyl analogue
(6RS,11SR)-5-acetyl-11-ethyl-1,3-dimethyl-6,11-dihydro-\
5H-dibenzo[b,e]azepine-6-carboxylic acid,
C₂₁H₂₃NO₃, (III), a combination of O---H...O, C---H...O and
C---H...π(arene) hydrogen bonds links the molecules into a three-dimensional
framework structure. None of these structures exhibits the R₂²(8)
dimer motif characteristic of simple carboxylic acids.
;

_publ_section_references
;
Allen, F. H., Kennard, O., Watson, D. G., Brammer, L., Orpen, A. G. & 
Taylor, R. (1987). J. Chem. Soc. Perkin Trans. 2, pp. S1--S19.

Andrés, J. I., Alcázar, J., Alonso, J. M., Díaz, A., Fernández, J.,
Gil, P., Iturrino, L., Matesanz, E., Meert, T. F., Megens, A. & Sipido, 
V. K. (2002). Bioorg. Med. Chem. Lett. 12, 243--248.

Batten, S. R. & Robson, R. (1998). Angew. Chem. Int. Ed. 37,
1460--1494.

Berger, J. G., Chang, W. K., Clader, J. W., Hou, D., Chipkin, R. E. & McPhail,
A. T. (1989). J. Med. Chem. 32, 1913--1921.

Bernstein, J., Davis, R. E., Shimoni, L. & Chang, N.-L. (1995). Angew. 
Chem. Int. Ed. Engl. 34, 1555--1573.

Bondi, A. (1964). J. Phys. Chem. 68, 441--451.

Brogden, R. N., Heel, R. C., Speight, T. M. & Avery, G. S. (1978).
Drugs, 16, 273--301.

Burla, M. C., Caliandro, R., Camalli, M., Carrozzini, B., Cascarano, G. L., 
De Caro, L., Giacovazzo, C., Polidori, G. & Spagna, R. (2005). J. Appl.
Cryst. 38, 381--388.

Cremer, D. & Pople, J. A. (1975). J. Am. Chem. Soc. 97,
1354--1358.

Davison, M., Kikolski, E. M., Lalancette, R. A. & Thompson, H. W. (2004).
Acta Cryst. C60, o449--o451.

Davison, M., Thompson, H. W. & Lalancette, R. A. (2004). Acta Cryst.
C60, o242--o244.

De Boer, T. H., Nefkens, F., van Helvoirt, A. & van Delft, A. M. L. (1996).
J. Pharmacol. Exp. Ther. 277, 852--860.

Duisenberg, A. J. M., Hooft, R. W. W., Schreurs, A. M. M. & Kroon, J. (2000).
J. Appl. Cryst. 33, 893--898.

Duisenberg, A. J. M., Kroon-Batenburg, L. M. J. & Schreurs, A. M. M. (2003).
J. Appl. Cryst. 36, 220--229.

Entrena, A., Campos, J., Gómez, J. A., Gallo, M. A. & Espinosa, A. (1997).
J. Org. Chem. 62, 337--349.

Evans, D. G. & Boeyens, J. C. A. (1989). Acta Cryst. B45,
581--590.

Ferguson, G., Glidewell, C., Gregson, R. M. & Meehan, P. R. (1998a).
Acta Cryst. B54, 129--138.

Ferguson, G., Glidewell, C., Gregson, R. M. & Meehan, P. R. (1998b).
Acta Cryst. B54, 139--150.

Flack, H. D. (1983). Acta Cryst. A39, 876--881.

Flack, H. D. & Bernardinelli, G. (2000). J. Appl. Cryst. 33,
1143--1148.

Gregson, R. M., Glidewell, C., Ferguson, G. & Lough, A. J. (2000). Acta
Cryst. B56, 39--57.

Kikolski, E. M., Thompson, H. W. & Lalancette, R. A. (2006). 
Acta Cryst. C62, o397--o398.

Malak, M. H., Baker, D., Brunskill, A. P. J., Thompson, H. W. & Lalancette, R.
A. (2006). Acta Cryst. C62, o669--o670.

Moriconi, E. J. & Maniscalco, I. A. (1972). J. Org. Chem. 37,
208--215.

Nickolson, V. J. & Wieringa, J. H. (1981). J. Pharm. Pharmacol.
33, 760--766.

Nonius (1998). COLLECT. Nonius BV, Delft, The Netherlands.

Palma, A., Galeano, N. & Bahsas, A. (2010). Synthesis, pp. 1291--1302.

Palma, A., Jaimes-Barajas, J., Kouznetsov, V. V., Stashenko, E., Bahsas, A. &
Amaro-Luis, J. (2004). Synlett, pp. 2721--2724.

Roeder, T., Degen, J. & Gewecke, M. (1998). Eur. J. Pharmacol.
349, 171--177.

Rowland, R. S. & Taylor, R. (1996). J. Phys. Chem. 100,
7384--7391.

Sasakura, K. & Sugasawa, T. (1981). Heterocycles, 15, 421--425.

Sheldrick, G. M. (2003). SADABS. University of Göttingen, Germany.

Sheldrick, G. M. (2008). Acta Cryst. A64, 112--122.

Spek, A. L. (2009). Acta Cryst. D65, 148--155.

Stappers, F., Broeckx, R., Leurs, S., Van Den Bergh, L., Agten, J., 
Lambrechts, A., Van den Heurel, D. & De Smaele, D. (2002). Org. 
Process Res. Dev. 6, 911--914.

Thompson, H. W., Coté, M. L. & Lalancette, R. A. (2004). Acta Cryst.
C60, o727--o729.

Van der Burg, W. J., Bonta, I. L., Delobelle, J., Ramon, C. & Vargaftig, B.
(1970). J. Med. Chem. 13, 35--39.

Wikström, H. V., Mensonides-Harsema, M. M., Cremers, T. I. F. H., Moltzen, 
E. K. & Arnt, J. (2002). J. Med. Chem. 45, 3280--3285.

Wood, P. A., Allen, F. H. & Pidcock, E. (2009). CrystEngComm, 
11, 1563--1571.
;


_publ_section_figure_captions  
;
Fig. 1. The molecular structure of the (6R,11R) enantiomer of
(I), showing the atom-labelling scheme. Displacement ellipsoids are drawn at
the 30% probability level.

Fig. 2. The molecular structure of the (6R,11S) enantiomer of
(II), showing the atom-labelling scheme. Displacement ellipsoids are drawn at
the 30% probability level.

Fig. 3. The molecular structure of the (6R,11S) enantiomer of
(III), showing the atom-labelling scheme. Displacement ellipsoids are drawn at
the 30% probability level.

Fig. 4. Part of the crystal structure of (II), showing the formation of a
hydrogen-bonded (dashed lines) chain parallel to [010]. For the sake of
clarity, H atoms not involved in the motifs shown have been omitted. Atoms
marked with an asterisk (*), a hash (#), a dollar sign ($) or an ampersand (&)
are at the symmetry positions (-x+1, y+1/2, -z+1/2), 
(-x+1, y-1/2, -z+1/2), (x, y+1, z) 
and (x, y-1, z), respectively.

Fig. 5. A stereoview of part of the crystal structure of (I), showing the
formation of a hydrogen-bonded (dashed lines) sheet parallel to (10\=1). 
For the sake of clarity, H atoms not involved in the motifs shown have been
omitted.

Fig. 6. A stereoview of part of the crystal structure of (III), showing the
formation of a hydrogen-bonded (dashed lines) sheet of R₄⁴(30)
rings parallel to (10\=1) and built from a combination of O---H...O and
C---H...O hydrogen bonds. For the sake of clarity, H atoms not involved in the
motifs shown have been omitted.

Fig. 7. A stereoview of part of the crystal structure of (III), showing the
formation of a chain parallel to [100] built from C---H...π(arene) hydrogen
bonds (dashed lines). For the sake of clarity, H atoms not involved in the
motif shown have been omitted.
;

_publ_section_table_legends
;
Table 1.  Experimental details

Table 2. Selected geometric parameters (Å, °) for (I)--(III)

Table 3. Hydrogen bonds and short intermolecular contacts (Å, °) for 
(I)--(III)
;
_publ_section_acknowledgements
;
The authors thank the Centro de Instrumentación Científico-Técnica of the
Universidad de Jaén and the staff for the data collection. AP and CMS thank
Colciencias for financial support (grant No. 1102-521-28229). JC thanks the
Consejería de Innovación, Ciencia y Empresa (Junta de Andalucía, Spain)
and the Universidad de Jaén for financial support.
;

