(R)-4-(4-Aminophenyl)-2,2,4-tri-methyl-chroman and (S)-4-(4-aminophenyl)-2, 2,4-trimethylthiachroman

Article abstract of DOI:10.1107/S0108270111012157

The title compounds, C₁₈H₂₁NO and C ₁₈H₂₁NS, in their enantio-merically pure forms are isostructural with the enantio-merically pure 4-(4-hy-droxy-phenyl)-2,2,4- trimethyl-chroman and 4-(2,4-dihy-droxy-phenyl)-2

Full text of DOI:10.1107/S0108270111012157

organic compounds
Acta Crystallographica Section C
Crystal Structure
Communications
The absolute configuration in this instance was derived from
the purification of the (S,S)-4-(2,2,4-trimethylchroman-4-yl)-
phenyl camphonate of known stereochemistry, rather than by
anomalous dispersion methods.
ISSN 0108-2701
(R)-4-(4-Aminophenyl)-2,2,4-tri-
methylchroman and (S)-4-(4-amino-
phenyl)-2,2,4-trimethylthiachroman
Christopher S. Frampton,a* David D. MacNicolb and
Derek R. Wilsonb
aPharmorphix Solid State Services, A Sigma–Aldrich Company, 250 Cambridge
Science Park, Milton Road, Cambridge CB4 0WE, England, and bDepartment of
Chemistry, University of Glasgow, Glasgow G12 8QQ, Scotland
Correspondence e-mail: chris.frampton@sial.com
Received 22 March 2011
Accepted 31 March 2011
Online 16 April 2011
The title compounds, C18H21NO and C18H21NS, in their
enantiomerically pure forms are isostructural with the
enantiomerically pure 4-(4-hydroxyphenyl)-2,2,4-trimethyl-
chroman and 4-(2,4-dihydroxyphenyl)-2,2,4-trimethylchroman
analogues and form extended linear chains via N—HÁ Á ÁO or
N—HÁ Á ÁS hydrogen bonding along the [100] direction. The
absolute configuration for both compounds was determined
by anomalous dispersion methods with reference to both the
Flack parameter and, for the light-atom compound, Bayesian
statistics on Bijvoet differences.
The crystal structures of the two title compounds, (III) and
(IV), where the 4-hydroxy substituents of 4-(4-hydroxy-
phenyl)-2,2,4-trimethylchroman and 4-(4-hydroxyphenyl)-
2,2,4-trimethylthiachroman are replaced by a 4-amino group,
are described here. For comparison purposes, we also report
the structure of racemic ‘guest-free’ Dianin’s compound, (I),
at 100 K, since the two previously published structures were
performed at room temperature (Goldup & Smith, 1971;
Imashiro et al., 1998).
Comment
As part of our continuing studies of the structural properties
of materials that demonstrate a close relationship with
Dianin’s compound [4-(4-hydroxyphenyl)-2,2,4-trimethyl-
chroman], (I), we have focused on how small incremental
changes to the scaffold of Dianin’s compound can affect the
crystal engineering properties of this classic host–guest
material (Hardy et al., 1977, 1979; Beresford et al., 1999;
Frampton et al., 1992) [structural data for (I), together with
ellipsoid and packing plots, are available in the Supplementary
material]. In its racemic form, Dianin’s compound and its thia-
and selenachroman analogues (Hardy et al., 1979; MacNicol et
al., 1969, 1987; MacNicol & Wilson, 1971) form a series of
isomorphous and isostructural clathrates having the common
˚
space group R3 with approximate cell paramenters a = 27 A
˚
and c = 11 A. In contrast, Dianin’s compound in its enantio-
merically pure form has a packing arrangement that is
significantly different from that of the racemate and does not
form a clathrate-type structure (Brienne & Jaques, 1975). The
crystal structure of Dianin’s compound as the enantio-
merically pure S isomer has been described previously (Lloyd
& Bredenkamp, 2005) and crystallizes with one molecule in
the asymmetric unit in the orthorhombic space group P212121.
Figure 1
The molecular structure of (III), showing the atom-labelling scheme.
Displacement ellipsoids are drawn at the 50% probability level.
o188 # 2011 International Union of Crystallography
doi:10.1107/S0108270111012157
Acta Cryst. (2011). C67, o188–o191

organic compounds
Figure 3
The packing of (III), viewed down the c axis, showing the formation of the
extended linear N—HÁ Á ÁO hydrogen-bonded chain along the [100]
direction (thin lines).
Figure 2
The molecular structure of (IV), showing the atom-labelling scheme.
Displacement ellipsoids are drawn at the 50% probability level.
Compounds (III) and (IV) (Figs. 1 and 2) are isostructural
not only with each other but also, suprisingly, with the
enantiomerically pure forms of the 4-(4-hydroxyphenyl)-, (I)
(Lloyd & Bredenkamp, 2005), and 4-(2,4-dihydroxyphenyl)-
2,2,4-trimethylchroman, (II) (Beresford et al., 1999), analo-
gues. Crystals of both (III) and (IV) were obtained by spon-
taneous resolution on crystallization, yielding a 50:50 mixture
of the pure enantiomers. The heterocyclic chroman ring in
both compounds adopts an envelope conformation or E form,
with atom C2 displaced from the mean plane defined by atoms
Figure 4
The packing of (IV), viewed down the c axis, showing the formation of the
extended linear N—HÁ Á ÁS hydrogen-bonded chain along the [100]
direction (thin lines).
maximize the likelihood of success, a full sphere of data was
collected at 100 K using Cu Kꢀ radiation to a maximum
˚
resolution of 0.80 A. A total of 25 124 reflections were
˚
collected, yielding a Flack parameter x and standard uncer-
tainty u for this structure of À0.07 (18). The value of u is
beyond the limit of enantiopure sufficient distinguishing
power (Flack & Bernardinelli, 2000), and for further confir-
mation of the absolute configuration a determination using
Bayesian statistics on Bijvoet differences (Hooft et al., 2008),
as implemented in the program PLATON (Spek, 2009), was
performed. This gave probability values P3(true), P3(twin)
and P3(wrong) of 1.000, 0.000 and 0.000, respectively. The
calculation was based on 14 290 Bijvoet pairs. The determi-
nation of the absolute configuration of (IV) was less challen-
ging, owing to the presence of the heavy S atom, and in this
case the Flack parameter was determined as 0.016 (11).
The crystal packing arrangements for the 4-aminophenyl
analogues (III) and (IV) are very similar to those found in
both the enantiopure 4-hydroxyphenyl and 2,4-dihydroxy-
phenyl analogues, (I) and (II), with the formation of an
extended linear N—HÁ Á ÁO or N—HÁ Á ÁS hydrogen-bonded
chain along the [100] direction (Figs. 3–6, and Tables 1 and 2).
However, in the case of the amino compounds, only one of the
two available N—H bonds of the amino group is utilized in the
hydrogen-bonding arrangement, thereby breaking Etter’s first
rule of hydrogen bonding for organic compounds which states
that all good proton donors and acceptors are used in
O1(S1)/C10/C5/C4/C3 by 0.641 (1) and 0.809 (2) A, respec-
tively, which are directly comparable with the displacements of
˚
À0.649 and À0.647 A found for atom C2 for the 4-hydroxy-
phenyl and 2,4-dihydroxyphenyl analogues, respectively. In
marked contrast, the conformation of the heterocyclic
chroman ring in the racemic forms of (I) and (II) (Beresford et
al., 1999) is best described as a half-chair or H form, with
atoms C2 and C3 displaced from the mean plane defined by
˚
atoms O1/C10/C5/C4 by 0.331 (2) and À0.352 (2) A for (I),
˚
and 0.384 (3) and À0.317 (3) A for (II). A change in the
magnitude of the C2—C3—C4—C11 torsion angle from ca 80ꢀ
in the racemic forms of (I) and (II) to ca 150ꢀ in the pure
enantiomers leads to very short intramolecular contacts
between the syn-related methyl groups, C17 and C18, of 3.287,
˚
3.325 (3), 3.314 (2) and 3.419 (2) A for (I)–(IV), respectively,
which are all less than the sum of the van der Waals radii of
˚
4 A (Chang, 2000). The corresponding C17Á Á ÁC18 distance in
˚
˚
the racemic forms is 4.9066 (15) A for (I) and 4.925 (4) A for
(II).
The absolute configurations of (III) and (IV), respectively R
and S at the chiral centre C4, were determined by anomalous-
dispersion methods (Flack, 1983). The determination of the
absolute configuration of (III) was challenging, given that the
molecule contains only a single N and a single O atom. To
ꢁ
Acta Cryst. (2011). C67, o188–o191
Frampton et al.
C18H20O2, C18H21NO and C18H21NS o189

organic compounds
Experimental
For the preparation of 4-(4-aminophenyl)-2,2,4-trimethylchroman,
(III), 2-phenyl-3-[4-(2,2,4-trimethylchroman-4-yl)phenyl]quinazolin-
4(3H)-one (Gilmore et al., 1977) (4.5 g, 9.5 mmol) was heated
(Scherrer & Beatty, 1972) at 423 K for 22 h in ethylene glycol
(100 ml) with KOH pellets (6.5 g) under pure nitrogen with magnetic
stirring. After ether extraction (3 Â 100 ml), washing with brine and
removal of the solvent, the amine (2.37 g, 93%) was recrystallized
from ethanol or CCl4 to give prisms [m.p. 409–410 K (sealed tube)].
Analysis for C18H21NO requires (found): C 80.86 (80.59), H 7.92
1
(7.62), N 5.24% (5.51%). MS m/z: 267.16204, calc. 267.162306. H
NMR (100 MHz, CDCl3): ꢁ 0.97 (s, 3H), 1.37 (s, 3H), 1.68 (s, 3H), 2.19
(q, 2H, ꢁAB = 0.29 p.p.m., JAB = 14 Hz), 3.8–3.3 (br s, 2H), 7.4–6.4
(aromatic, 8H); FT–IR (ꢂmax, ATR, cmÀ1): 3467, 3369 [ꢂ(N—H)].
For the preparation of 4-(4-aminophenyl)-2,2,4-trimethylthia-
chroman, (IV), 2-phenyl-3-[4-(2,2,4-trimethylthiachroman-4-yl)phenyl]-
quinazolin-4(3H)-one (6.7 g, 13.7 mmol) was heated at 423 K for 22 h
in ethylene glycol (120 ml) with KOH pellets (13 g) under pure
nitrogen with magnetic stirring. After ether extraction (3 Â 250 ml),
washing with brine and removal of the solvent, the amine (3.6 g,
92.5%) was recrystallized from ethanol after decolorizing with
powdered animal charcoal to give colourless needles [m.p. 410–411 K
(sealed tube)]. Analysis for C18H21NS requires (found): C 76.30 (76.14),
H 7.47 (7.46), N 4.94 (4.65), S 11.31% (11.67%). MS m/z: 283, calc.
1
283. H NMR (100 MHz, CDCl3): ꢁ 1.1 (s, 3H), 1.39 (s, 3H), 1.73 (s,
Figure 5
The packing of (III), viewed down the a axis. Only amine H atoms are
shown.
3H), 2.27 (q, 2H, ꢁAB = 0.32 p.p.m., JAB = 14Hz), 3.51 (br s, 2H), 7.3–
6.6 (aromatic, 8H); FT–IR (ꢂmax, ATR, cmÀ1): 3442, 3353 [ꢂ(N—H)].
‘Guest-free’ racemic 4-(4-hydroxyphenyl)-2,2,4-trimethylchroman,
(I), was prepared as follows. Racemic (I) was prepared and desol-
vated as described by Baker et al. (1956). Clear colourless prisms of
the guest-free form of (I) suitable for X-ray analysis were obtained by
sublimation of desolvated material in vacuo (at ca 10À3 mm Hg). 1H
NMR (400 MHz, CDCl3): ꢁ 0.93 (s, 3H), 1.36 (s, 3H), 1.69 (s, 3H), 2.07
(d, 1H, JAB = 14 Hz), 2.36 (d, 1H, JAB = 14 Hz), 4.61 (br s, 1H), 6.68–
6.73 (m, 2H), 6.86–6.90 (m, 1H), 6.91–6.96 (m, 1H), 7.04–7.09 (m, 2H),
7.15–7.23 (m, 2H); FT–IR (ꢂmax, ATR, cmÀ1): 3285 (br) [ꢂ(O—H)].
Compound (III)
Crystal data
3
˚
C18H21NO
Mr = 267.36
V = 1413.71 (2) A
Z = 4
Orthorhombic, P212121
˚
Cu Kꢀ radiation
ꢃ = 0.60 mmÀ1
T = 100 K
0.50 Â 0.45 Â 0.20 mm
a = 10.23394 (11) A
˚
b = 10.25106 (10) A
˚
c = 13.47563 (13) A
Data collection
Agilent SuperNova dual source
diffractometer with an Atlas
detector
Absorption correction: multi-scan
(CrysAlis PRO; Agilent
Technologies, 2010)
Tmin = 0.697, Tmax = 1.000
25124 measured reflections
2876 independent reflections
2864 reflections with I > 2ꢄ(I)
Rint = 0.024
Figure 6
The packing of (IV), viewed down the a axis. Only amine H atoms are
shown.
Refinement
R[F2 > 2ꢄ(F2)] = 0.026
wR(F2) = 0.072
S = 1.00
2876 reflections
193 parameters
H atoms treated by a mixture of
independent and constrained
refinement
Áꢅmax = 0.21 e A
À3
˚
À3
˚
Áꢅmin = À0.14 e A
Absolute structure: Flack (1983),
with 1221 Friedel pairs; Hooft
et al. (2008)
hydrogen bonding (Etter, 1990). Further work is currently in
progress on racemic and quasi-racemic analogues of Dianin’s
compound.
Flack parameter: À0.07 (18)
ꢁ
o190 Frampton et al. C18H20O2, C18H21NO and C18H21NS
Acta Cryst. (2011). C67, o188–o191

organic compounds
˚
methyl C—C bond), with C—H = 0.95–0.99 A and with Uiso(H) =
1.5Ueq(C) for methyl groups and 1.2Ueq(C) otherwise.
Table 1
Hydrogen-bond geometry (A, ) for (III).
ꢀ
˚
For all compounds, data collection: CrysAlis PRO (Agilent Tech-
nologies, 2010); cell refinement: CrysAlis PRO; data reduction:
CrysAlis PRO; program(s) used to solve structure: SHELXTL
(Sheldrick, 2008); program(s) used to refine structure: SHELXTL;
molecular graphics: SHELXTL and Mercury (Version 2.4; Macrae et
al., 2008); software used to prepare material for publication:
SHELXTL and Mercury.
D—HÁ Á ÁA
N1—H1AÁ Á ÁO1i
Symmetry code: (i) x À 1; y; z.
D—H
HÁ Á ÁA
DÁ Á ÁA
D—HÁ Á ÁA
0.956 (19)
2.323 (19)
3.2295 (14)
157.9 (15)
Table 2
Hydrogen-bond geometry (A, ) for (IV).
ꢀ
˚
The authors thank the EPSRC for financial support (to
DRW).
D—HÁ Á ÁA
N1—H1AÁ Á ÁS1i
D—H
HÁ Á ÁA
DÁ Á ÁA
D—HÁ Á ÁA
0.88 (2)
2.82 (2)
3.6562 (14)
158.3 (16)
Symmetry code: (i) x À 1; y; z.
Supplementary data for this paper are available from the IUCr electronic
archives (Reference: BM3104). Services for accessing these data are
described at the back of the journal.
Compound (IV)
References
Crystal data
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3
˚
C18H21NS
Mr = 283.42
V = 1480.68 (13) A
Z = 4
Cu Kꢀ radiation
ꢃ = 1.83 mmÀ1
T = 100 K
Orthorhombic, P212121
˚
a = 10.6043 (6) A
˚
b = 10.4104 (5) A
˚
c = 13.4126 (6) A
0.50 Â 0.45 Â 0.20 mm
Data collection
Agilent SuperNova dual source
diffractometer with an Atlas
detector
Absorption correction: multi-scan
(CrysAlis PRO; Agilent
Technologies, 2010)
6825 measured reflections
3015 independent reflections
2976 reflections with I > 2ꢄ(I)
Rint = 0.019
Gilmore, C. J., Hardy, A. D. U., MacNicol, D. D. & Wilson, D. R. (1977).
J. Chem. Soc. Perkin Trans. 2, pp. 1427–1434.
Tmin = 0.654, Tmax = 1.000
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Perkin Trans. 2, pp. 1072–1077.
Refinement
R[F2 > 2ꢄ(F2)] = 0.027
wR(F2) = 0.070
S = 1.00
3015 reflections
193 parameters
H atoms treated by a mixture of
independent and constrained
refinement
Áꢅmax = 0.23 e A
À3
˚
À3
˚
Hooft, R. W. W., Straver, L. H. & Spek, A. L. (2008). J. Appl. Cryst. 41, 96–
103.
Áꢅmin = À0.26 e A
Absolute structure: Flack (1983),
with 1281 Friedel pairs
Flack parameter: 0.016 (11)
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The nonstandard unit cell for (IV), with a > b < c, was necessary to
preserve the isostructural element of the four structures under
comparison. H atoms bonded to N atoms were located in a difference
map and refined freely. Other H atoms were positioned geometrically
and refined using a riding model (including free rotation about the
ꢁ
Acta Cryst. (2011). C67, o188–o191
Frampton et al.
C18H20O2, C18H21NO and C18H21NS o191