Separation and thermal racemization of the enantiomers of spiro[cyclohexadiene-dihydroacridines]

Article abstract of DOI:10.1007/s007060070041

The enantiomers of substituted spiro[cyclohexadiene-dihydroacridines] were separated by enantioselective liquid chromatography with the sorbent/solvent systems triacetylcellulose/ methanol, tris-(3,5-dimethylphenylcarbamoyl)-cellulose/silica gel (Chiralcel OD)ln-heptane/2-propanol, and (+)-poly-(trityl methacrylate)/silica gel/n-heptane/2-propanol. Interconversion barriers of the enantiomers were determined for a series of derivatives by thermal racemization. Electrocyclic ring opening/ring closure in terms of the Woodward-Hoffmann rules is discussed for the enantiomerization mechanism; the interconversion of the enantiomers by enolization is ruled out by deuterium exchange experiments.

Full text of DOI:10.1007/s007060070041

Monatshefte f uÈ r Chemie 131, 1083±1090 (2000)
Separation and Thermal Racemization of the
Enantiomers of Spiro[cyclohexadiene-
dihydroacridines]
1;Ã
2
2
Thomas Zimmermann , Nikola Pustet , and Albrecht Mannschreck
1
Institut f u r Organische Chemie, Universit a t Leipzig, D-04303 Leipzig, Federal Republic of
Germany
2
Institut f u r Organische Chemie, Universit a t Regensburg, D-93040 Regensburg, Federal Republic
of Germany
Summary. The enantiomers of substituted spiro[cyclohexadiene-dihydroacridines] were separated
by enantioselective liquid chromatography with the sorbent/solvent systems triacetylcellulose/
methanol, tris-(3,5-dimethylphenylcarbamoyl)-cellulose/silica gel (Chiralcel ODTM)/n-heptane/2-
propanol, and ꢀ‡†-poly-(trityl methacrylate)/silica gel/n-heptane/2-propanol. Interconversion
barriers of the enantiomers were determined for a series of derivatives by thermal racemization.
Electrocyclic ring opening/ring closure in terms of the Woodward-Hoffmann rules is discussed for
the enantiomerization mechanism; the interconversion of the enantiomers by enolization is ruled out
by deuterium exchange experiments.
Keywords. Spiro[cyclohexadiene-dihydroacridines]; Enantiomers; Enantioselective liquid chroma-
tography; Thermal racemization.
Introduction
Some years ago a novel class of photochromic substances [1], the aroyl-
spiro[cyclohexadiene-azaheterocycles], in which an aroylcyclohexadiene moiety is
spiro-connected with a ®ve- or six-membered nitrogen heterocycle, was discovered
[2] and has been intensely studied since that time [3±7]. This type of spiro
compounds can easily be synthesized by ring transformation of pyrylium salts with
suitable nitrogen heterocycles possessing an integrated enamine structure. Thus,
the reaction of 2,4,6-triarylpyrylium salts 1a±h with the in situ generated
anhydrobase 3 of the 9,10-dimethylacridinium methylsulfate 2 leads to racemic
0
0
0
0
6
-aroyl-3,5-diaryl-10 -methylspiro[cyclohexa-2,4-diene-1,9 -9 ,10 -dihydroacri-
dines] 6a±h [4]. The N-unsubstituted analogues 6i±l are obtained from the
pyrylium salts 1a,f±h and 9-methylacridine 4 via its tautomer 5 [4].
UV-Irradiation of the aroylspiro[cyclohexadiene-dihydroacridines] 6 gives rise
to red coloured merocyanines of the type 7 which can be recyclized to the starting
spiro compounds 6 photochemically with visible light or by heat [6].
à Corresponding author

T. Zimmermann et al.: Enantiomers of Spiro[cyclohexadiene-dihydroacridines]
1085
In the case of racemic aroylspiro[cyclohexadiene-indolines] [7] as well as
spiro[indoline-chromenes] and spiro[indoline-benzoxazines] [8], the separation of
the enantiomers can be achieved by liquid chromatography on non-racemic
stationary phases. The thermal racemization of the enantiomers obtained allows the
6
determination of the free enthalpy of activation ÁG for the enantiomerization
reaction as a valuable parameter for the interpretation of the enantiomerization
mechanism. Our continuous interest in the elucidation of such reactions prompted
us to extend these studies to the spiro compounds 6 in order to get ®rst insights into
the nature of their thermally induced reactions. In this paper we report on the
results of such investigations.
Results and Discussions
According to their N-substitution pattern, spiro[cyclohexadiene-dihydroacridines]
can be divided into the methyl derivatives 6a±h and the NH-compounds 6i±l,
6
representing tertiary and secondary amines, respectively. In both series we
prepared examples with electron donating (Me, MeO) or accepting (Cl, Br)
substituents in para-position of the phenyl rings in the aroyldiarylcyclohexadiene
moiety.
Attempts to separate the enantiomers (R)-6 and (S)-6 of the spiro[cyclohexa-
diene-dihydroacridines] by liquid chromatography were started using triacetyl-
cellulose as the sorbent and methanol as the eluent. With the exception of 6f, no
separation could be achieved (cf. Table 1). Much better results were obtained with
the sorbent tris-(3,5-dimethylphenylcarbamoyl)-cellulose on silica gel (Chiralcel
TM
OD , eluent: n-heptane/2-propanol), allowing the separation of 6a±c and 6f±j.
Table 1. Chromatographic parameters for the separation of enantiomers of spiro[cyclohexadiene-
ꢁ
0
0
dihydroacridines] 6 by liquid chromatography on different sorbents at 15-25 C; k , k : retention
1
2
ꢀ
0
factors of enantiomers [9]; Z: Sign of rotation at 260 nm or 275 nm of the ®rst eluted enantiomer; k :
mean retention factor [9]
Triacetylcellulosea Tris-(3,5-dimethylphenylcarbamoyl)-
ꢀ‡†-Poly-(trityl methacrylate)
b
cellulose on silica gel
TM b
on silica gel
(Chiralcel OD
)
0
0
ꢀ0
0
0
ꢀ0
0
0
k
2
ꢀ0
k
k ꢀZ†
k
k
k ꢀZ†
k
k
k ꢀZ†
1
2
1
2
1
6
6
6
6
6
6
6
6
6
6
6
6
a
b
c
d
e
f
0.9
0.8
1.1
0.9
1.0
0.6 (‡)
0.5 (‡)
1.0 (‡)
0.7
0.6
1.1
1.2 (� )
1.1 (� )
1.9 (� )
1.1 (� )
1.1 (� )
2.6
2.7
3.6
3.7
4.3
0.6
0.6
1.0 (� ) 1.4
0.6 (‡)
0.5 (‡)
0.6 (‡)
1.4 (� )
1.3 (‡)
1.0
0.9
0.9
1.8
1.6
1.4
g
h
i
0.6
1.0
0.7
0.5
0.8
0.8
1.2
1.2
4.0 (‡)
1.7 (‡)
1.8 (‡)
1.9 (‡)
16.3
2.6
4.6
4.8
j
k
l
1.2
1.3
a
Eluent: methanol; b eluent: n-heptane/2-propanol ꢀv : v ˆ 9 : 1†

1086
T. Zimmermann et al.
Fig. 1. Chromatograms of the spiro[cyclohexadiene-dihydroacridines] 6f (left, 5 mg in n-heptane/
2
-propanol ꢀv : v ˆ 9 : 1† on tris-(3,5-dimethylphenylcarbamoyl)-cellulose/silica gel (Chiralcel
TM
OD )) and 6j (right, 10 mg in n-heptane/2-propanol ꢀv : v ˆ 9 : 1† on (‡)-poly-(trityl methacry-
late)/silica gel; A and ÁA: absorbance and differential absorbance at 275 nm using the Jasco CD-
1595 detector, V: volume of eluate (V ˆ 0 upon injection)
The remaining spiro compounds 6d,e and 6k,l were successfully separated on
‡†-poly-(trityl methacrylate) on silica gel (eluent: n-heptane/2-propanol). This
system also worked well in the cases of 6a±c and 6i,j but was unable to separate
f±h. Furthermore, these investigations showed that obviously no connection exists
ꢀ
6
between the substitution of the nitrogen atom in 6, i.e. the presence of a secondary
or a tertiary amine structure, and the result of the separation on different sorbents.
Representative examples of the chromatograms of both types of compounds are
shown in Fig. 1.
For the thermal racemizations, the spiro[cyclohexadiene-dihydroacridines] 6a,
f,g ꢀR ˆ Me† and 6i±k ꢀR ˆ H† were chosen. The half-life times t and the
0
:5
6ˆ
values of the free enthalpy of enantiomerization ÁG obtained are summarized in
Table 2.
Table 2. Results of thermal racemization of spiro[cyclohexadiene-dihydroacridines] 6 in 1-propanol
as monitored by polarimetry at 436 nm; t0:5: half-life time, ÁG : free enthalpy of activation for ring
opening
6
ꢁ
6
� 1
T Æ 0:5= C
t0:5=min
ÁG Æ 0:2=kJ Á mol
6
6
6
6
6
6
a
69.6
69.0
69.6
69.6
69.0
69.6
453.8
150.8
626.8
33.7
114.5
111.2
115.4
107.1
108.5
104.7
f
g
i
j
58.5
k
14.5

Enantiomers of Spiro[cyclohexadiene-dihydroacridines]
1087
In the case of the N-methyl substituted derivatives 6a,f,g the interconversion
of the enantiomers occurs with a free enthalpy of activation ÁG comparable to
6
that obtained for spiro[cyclohexadiene-indolines], in which the dihydroacridine
system is replaced by an indoline moiety [7], as well as for structurally related
spiro[indoline-chromenes] [8]. The exchange of the methyl substituent at the
nitrogen atom by hydrogen in 6i±k is accompanied by a decrease of the activation
barrier. Obviously, the more basic tertiary amines 6a,f,g can be better stabilized
by hydrogen bonding with the OH-group of 1-propanol used as solvent than
6
the secondary amines 6i±k, thus leading to smaller ÁG values upon going
from 6a,f,g to 6i±k. In both series of compounds, the activation parameters
are not signi®cantly in¯uenced by the nature of the substituents at the phenyl
rings.
At ®rst glance one may assume that the interconversion of the enantiomers
R†-6 and ꢀS†-6 occurs via enols of type 8. The acidic enol hydrogen of 8 should
ꢀ
be exchangeable by deuterium in the presence of deuterium donors. When the
spiro[cyclohexadiene-dihydroacridines] 6a and 6i were re¯uxed in ethanol-OD and
1
triethylamine or triethylamine/acetic acid-d , respectively, it could be shown by H
4
NMR spectroscopy (cf. Experimental) that no deuterium incorporation at C-6 had
occurred, thus ruling out the enolization path.
An alternative mechanism for the thermal interconversion of the enantiomers
(R)-6=(S)-6, which has already been discussed for the explanation of the thermal
racemization of the structurally related spiro[cyclohexadiene-indolines] [7],
consists of an electrocyclic ring opening to the merocyanines 7, followed by an
electrocyclic ring closure to the starting spiro compounds 6. According to the
Woodward-Hoffmann rules for electrocyclic processes [10], a disrotatory ring
opening of ꢀR†-6 with a clockwise rotation of the orbitals at C-6 and an anti-
clockwise rotation of those at C-1 (cf. Scheme 2) should give the merocyanine
7
A, the double bonds of which show the con®gurations ꢀE† and ꢀZ†. The disrotatory
ring opening in the opposite direction would give rise to the merocyanine 7B where
the double bonds are in ꢀE†-con®gurations. Both merocyanines 7A and 7B can
also be formed from the enantiomer ꢀS†-6 by disrotatory ring openings with the
opposite directions of rotation at C-1 and C-6. The reactions ꢀR†-6 ! 7A and
ꢀ
S†-6 ! 7A should have the same activation energy since during the cleavage of
the C1-C6 single bond the same substituents approach each other or move away
from each other. For the reactions ꢀR†-6 ! 7B and ꢀS†-6 ! 7B, one may again
assume the same activation energy which, however, differs from that for the
ring opening (forming 7A), since the moving groups are not the same in both
cases.
From the data obtained by our experiments it cannot be decided which of these
ring opening reactions is favoured and hence which of the merocyanines, 7A or 7B,
is formed a an intermediate. On the other hand, the charge delocalization in
merocyanines usually leads to low barriers of ꢀE†=ꢀZ† isomerization [11], i.e. an
interconversion of the merocyanines 7A=7B cannot be excluded.
For the disrotatory ring closures of 7A and 7B, analogous considerations can be
made (cf. Scheme 2). However, we assume that ring opening, not ring closure, is
6
the rate determining step, corresponding to the experimental ÁG values in
Table 2.

1088
T. Zimmermann et al.
Experimental
The synthesis of the spiro[cyclohexadiene-dihydroacridines] 6a±l has been described in a previous
paper [4]. Ethanol-OD ꢀ99:30 Æ 0:10% D† and acetic acid-d4 ꢀ99:10 Æ 0:10% D† were purchased
1
from Deuchem, Leipzig, Germany. The H NMR spectra were recorded on a Varian Gemini 200
spectrometer at 199.975 MHz in CDCl3 at room temperature.
Deuterium exchange experiments
The spiro[cyclohexadiene-dihydroacridines] 6a (258 mg, 0.5 mmol) and 6i (251 mg, 0.5 mmol),
3
3
respectively, were re¯uxed with 51 mg (0.5 mmol) of triethylamine, 5 cm of ethanol-OD, and 5 cm
of toluene for 2 h. In a third and fourth experiment, 32 mg (0.5 mmol) of acetic acid-d4 were added,
the reaction mixtures were evaporated to dryness in vacuo, and the resulting residues were dissolved

Enantiomers of Spiro[cyclohexadiene-dihydroacridines]
1089
1
in CDCl3. H NMR analyses showed that no deuterium exchange of the proton at C-6 [4] had
occurred within error limits.
Chromatography
HPLC was performed on triacetylcellulose (Merck, 10 mm; column 250 Â 8 mm; eluent methanol,
3
� 1
¯
ow rate 1 cm Á min , pressure 75 bar; room temperature), on tris-(3,5-dimethylphenylcarbamoyl)-
TM
cellulose/silica gel (Chiralcel OD ) (Daicel, 20 mm; column 250 Â 4:6 mm; eluent n-heptane/2-
3
� 1
propanol, 9 : 1 ꢀv=v†, ¯ow rate 0:5 cm Á min , pressure 3 bar; room temperature), and on ꢀ‡†-poly-
(
trityl methacrylate)/silica gel (Daicel, 5 mm; column 250 Â 4 mm; eluent n-heptane/2-propanol,
3
� 1
ꢁ
9
: 1 ꢀv=v†, ¯ow rate 1 cm Á min , pressure 120 bar; 15 C).
For photometric detection the UV spectrometers ERC 7210 and ERC 7215 (Erma Optical Works,
Ltd.), and for polarimetric detection the polarimeter Perkin-Elmer 241 were used. Detailed de-
scriptions of the injection and detector systems along with the chromatographic equipment have been
given previously [8,12]. The chromatograms shown in Fig. 1 were obtained using the Jasco CD-1595
detector [13,14].
Thermal racemizations and data processing
Racemization of 6a,f,g and 6i±k was monitored in 1-propanol by an off-line procedure, i.e. the
enantiomers were enriched at a semipreparative scale by repeated chromatography as described
above and then dissolved in 1-propanol. The polarimetric cell which contained the solution of the
enriched enantiomer was thermostated to the given temperature, and the decrease of the angle of
rotation was monitored. The thermal stability was checked by chromatography after thermal
racemization; in all cases the chromatograms obtained were identical with those of the starting
compounds, thus indicating that no decomposition had occurred. The interconversion of the
enantiomers was treated as a reversible ®rst-order reaction as previously described [8]. A computer
6
program [15] was used for the calculation of ÁG for the ring opening [8] (Table 2) from the
polarimetric racemization data.
Acknowledgements
Financial support by the Fonds der Chemischen Industrie is gratefully appreciated. We are grateful to
Mr. R. W u rdinger, Jasco Deutschland GmbH, Groû Umstadt. for kindly giving access to the CD-
1595 detector.
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[
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Received April 3, 2000. Accepted April 12, 2000