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Conformational analysis of 12,12,21,21-tetradeuterio-1,4-dioxa-[4.3.3](1,3,5)Cyclophane
Tetrahedron Letters,Vol.29,No.48,pp Printed in Great Britain
CONFORMATIONAL
ANALYSIS
6275-6278,1988
0040-4039/88 $3.00 Pergamon Press plc
+
.oo
OF 12,12,21,21-TETRADEUTERIO-1,4-DIOXA-
[4.3.3](1,3,5)CYCLOPHANE'
Katsuya
SAKO,
Department
Takafumi
HIRAKAWA,
Takahiko
INAZU:
of Chemistry, Hakozaki
t
Department
Faculty
6-10-1,
of Chemistry,
boat)
All possible
of the title
three
compound
Faculty
[3_3)Metacyclophane
conformers
in the syn geometry
chains
in the crystalline
detected
prepared
of 'H NMR spectrum,
of 1 and its related processes
phenomenon however,
in terms Semmelhack
the benzene conversion
ring
systems
have been
of benzene
ring
of 1 in solution,
report.
We designed
estimate
the energy
barrier
7
processes
type).5
attention
process.4
temperisom-
and two
of the benzene
We have
that the dynamic
because
interpreted
In the recent
process
there
of the benzene
the report,
was not due to
of
H NMR
the synthesis method
rings
spectrum
points
bridges
is prohibited.
much
easier.
we applied
to under
Introduc-
of the trimethylene
and conformational
of deuteriums,
uncertain 2 in order
of trimethylene
at C-2 and C-II positions 1
are still
[4.3.3)cyclophane
for the inversion
the interpretation
As an introduction
inversion
tribridged
inversion
like to report
It
but due to the chair-boat type interbridges. 3 We therefore reexamined the confor-
behavior
will make
223K(-50'C)
process,
in their
tion of four deuteriums
below
in which 1 shows strong 3,4 This conformational much
inversion
et al. concluded
inversion
where
and boat-
in 1976 by US.~
attracted
(chair-boat
mational
we would
have
proposed:
bridges
of the trimethylene
the conditions
chair-boat,
with a chair-chair arrangement of the trimethylene state. 3,4 The preferred geometry of 1 in solution
phenomenon
and trimethylene
33,
and Engineering,
by 'H NMR spectrum
at low temperatures.
inversion
University
812, Japan
(chair-chair,
is also a syn on the basis
rings
SHINMYOZU:
1, Saga 840, Japan
ature-dependent erism
Kyushu
of Science
(1) was originally
exists
Teruo
HORIMOTO+
Fukuoka
Honjo-cho
were
FUJIMOTO,
of Science,
Higashi-ku,
Saga University,
Summary;
Naoki
and Hideaki
bridges
In this paper,
analysis
of 2-d4.
the reductive
M';qo~&;qM~*:;$%$$:@
L;X=H A-d4;X=D
a)HSCH2CH2SH,BFjOEt2/AcOH d)TsOCH2CH20Ts,NaH/DMF
0 I-d4 b)n-Bu3SnD,AIBN/xylene
Scheme 6275
1
0 Z-d4 c)BBr3/CH2C12
6276
desulfurization of 1,3-dithiolanes with n-Bu3SnH developed by Gutierrez et a1..6
Scheme 1 shows the synthetic route to 2-d4.
into dithioacetal 3 in an 80% yield.8
Ketone z7 was converted
Hydrogenolysis of the dithioacetal 2
with n-Bu3SnDg in the presence of AIBN in refluxing xylene did produce 2,2,11,11-d4[3.31metacyclophane derivative z-d4 in a 77% yield. Demethylation of the methoxy groups in z-d4 with BBr3 in CH2C12 at room temperature, followed by the coupling reaction of the resulting phenol with ethylene glycol ditosylate in DMF in the presence of NaH afforded desired tribridged [4.3.31cyclophane z-d4 in a 29% yield." Fig. 1 shows the 'H NMR spectrum of g-d4 at 283K(lO"C) in CD2C12: 2.68 (br s,8H,Hc and Hd), 4.49(s,4H,-OCH2CH20-1, 6.22(s,4H,Ha), 6.63 ppm(s,2H,Hb). The benzylic protons (Hc and Hd) exhibit strong temperature-dependent phenomenon (Fig. 2); its broad singlet at 283K(lO'C) broadens as the temperature is lowered, and then it begins to resolve at 262K(-II'C) into two broad signals and finally each splits into four doublets.
They can be assigned to four AB quartets on the basis of relative intensity of signals and geminal coupling constants (Fig. 5), as described later.
The aromatic protons broaden
as the temperature is lowered (Fig. 3).
Finally, the Ha is resolved into four peaks (6.16, 6.20, 6.29, and 6.32 ppm), while the Hb signal becomes three peaks (6.61, 6.71, and 6.83 ppm), as shown in Fig. 4. Semmelhack et al. HO suggested an order of thermodynamic TMS
stability of chair-chair>chair-boat>boat-boat based on molecular mechanics calculation in J_.3 On the basis of the result, 'H NMR spectrum of Ha protons can be assigned as follows; the most
PP"'intense signal (6.32 ppm) and the least intense
k. 7
6
5
4 3 Fig.1
2
10
one (6.16 ppm) are ascribed to chair-chair &
Hc,Hd
and boat-boat 2c,
respectively, while the two peaks with equal medium intensities
--r---r---r---r-w2383K
2
326ZK 2
3248K 2
:33K
2
d23K
2
3
183K Fig.2
2
(6.20 and 6.29 ppm) are assigned to chair-boat conformer 2b, since it has two kinds of nonequivalent Ha protons.
Similarly Hb
protons can be assigned as follows: 6.61 (chair-chair a), '283K6
'238K6 Fig.3
7 233K'
7
223K6
' 183K6
(chair-boat a),
6.71 and
6.83 ppm (boat-boat
2c). The population of the three isomers is estimated to be 2a:2b:2c=47:44:9 based on the 'H NMR integral of these three peaks.
6277
203K f
Ha
chair-chair c-C c-b;chair-boat 6.61
c-c;
b-b;
boat-boat c-b
r-
Hb c-b c-b 6.29 6.20
27OMHz
, PPm 6
I
7
Fig.5
Fig.4
Free energy difference between & and & is smaller than the estimated values in 1. 3 Based on these results, the benzylic protons of z-d4 are assigned as follows: chair-chair
2.46
(d,J=l3.8Hz) and 2.95 (d,J=l3.7Hz); chair-e
2.35
(d,J=14.7Hz) and 3.02 (d), chair-boat 2.47 (d,J=l3.8Hz) and 2.95 (d,J=13.7Hz); boat-boat 2.32 (d,J=l4.6Hz) and 3.03 ppm(d). The chemical shifts and coupling constants of 2a are, in fact, in good agreement with those of the syn(chairchair) conformer of l-d, [2.50 (d,J=13.7Hz) and 2.97 ppm (d,J=13.7Hz)l. The ethylenedioxy protons appear at 4.49 ppm as a singlet at 283K(lO"C), which split into seemingly two singlets with unequal intensities corresponding to the chair-chair and chair-boat conformers at 218K(-55°C).
Probably the peak
due to the ethylenedioxy protons of the boat-boat conformer may overlap with This result indicates that the internal
those of the other conformers.
rotation of the ethylenedioxy bridge still exists at temperatures where the rotation of two trimethylene bridges are already frozen. 'H NMR data of three conformers of 2-d, are summarized in Fig. 6. 6.71
From the above results, we can 3.03
3.02
D ~l~:~~~~~~*.~l~~~~~
chair-chair 2a
:;1:4.6) .B-,_f
chair-boat 2b
boat-boat 2c
in the follow-
ing order: Fig.6 chair-chair>chair-boat>boat-boat, while the tendency is reversed in Ha protons.
2. The chemical shift difference between the axial and equatorial
protons of benzylic protons (Hc and Hd) is 0.48-0.49 ppm for a chair form but 0.67-0.71 ppm for a boat form.
The geminal coupling constants of the benzylic
protons are 13.7-13.8 Hz for a chair form but 14.6-14.7 Hz. for a boat form. These features may be a diagnostic tool for the assignment of the conformation of trimethylene bridges in (3.3lmetacyclophanes. The energy barrier for the inversion of trimethylene bridges in z-d4 is estimated to be 12.1-12.3 kcal/mol with Tc=262K(-110C),11 which is comparable to that for the inversion of trimethylene bridges in l-d4 (11_6kcal/mol). We concludes therefore that temperature-dependent phenomenon of j_ at low
6278 temperatures can be ascribed to the inversion of the trimethylene bridges as was already pointed out by Semmelhack et a1..3
At higher temperatures,
benzylic protons of z-d4 appear as an AB quartet [2.61 (J=13.9Hz), 2.65 ppm (J=13.9Hz))(Fiq. 7), while those protons of z-d4 and l-d4 appear as singlets. 333K
The result suggests that benzylic protons (Hc
and Hd) of 2 are magnetically nonequivalent, even if the
DMSO
rapid inversion of the trimethylene bridges is occurring. 4ooMHz DMSO-d
Consequently, benzene ring inversion process, which makes 6
Hc and Hd equivalent, is suggested along with the inversion process of the trimethylene bridges in 5-d4 and '-d4.
PPm ,1;[ 2.8
Semmelhack et al. proposed only inversion process
of the trimethylene chains. 3 2.6
-ix
Our study, however, suggests
that the inversion process of benzene rings also exists.
Fig.7 Currently we are preparing optical active (3.3lmetacyclophane derivatives in order to seek unambiguous evidence for the benzene ring inversion process. Acknowledqment
We would like to thank gratefully the support of this work
by the Grant-in-Aid for Scientific Research (No. 62540388) from the Ministry of Education, Science and Culture, Japan. REFERENCES AND NOTES 1
Presented at the 19th Symposium on Structural Organic Chemistry, Sendai, Oct. 1987; Abstr. No. P-38.
2 3
T. Shinmyozu, T.Inazu, and T. Yoshino, Chem. Lett., 1405 (1976). M. F. Semmelhack, J. J. Harrison, D. C. Young, A. Gutigrrez, S. Rafii, and J. Clardy, J. Am. Chem. Sot., 107, 7508 (1985).
4
In the early stage of the present work, we independently undertook an X-ray structure determination of 1 and variable temperature 'H NMR study (60MHz) of 1-d4: T. Hirakawa, K. Kurosawa, M. Tanaka, T. Shinmyozu, Y. Miyahara, T. Inazu, T. Yoshino, presented at the 14th Symposium on Structural Organic Chemistry, Kyoto, Oct. 1982; Abstr. No. B2-28.
The result will be reported
elsewhere. 5
For a review, see; R. H. Mitchell, in "Cyclophane I", P. M. Keehn and S. M. Rosenfeld, Ed., Academic Press (1983), p. 239.
6
C. G. Gutierrez, R. A. Stringham, T. Nitasaka, K. G. Glasscock,
7
J. Org. Chem., 45, 3393 (1980). Prepared by the coupling reaction of 3,5-bis(bromomethyl)anisole and its TosMIC adduct followed by acid hydrolysis of the coupling product.
8
D. Krois and H. Lehner, J. Chem. Sot. Perkin I 447 (1982).
9
G. J. M. Van der Kerk, J. G. Noltes, and J. G. A. Luijten, J. Appl. Chem., 1, 366 (1957); G. M. Whitesides and J. S. Fillippo, Jr., J. Am. Chem. Sot., 92, 6611 (1970).
10 2-d4: colorless needles from ethanol, mp 170.5-172'C. 11 AG$ (kcal/mol)=2.303x1.987Tc(10.319-loqlOkc+loqloTc) where kc=(a/fi)[(vA-vB)2+6J2)1~2; I. C. Cadler and P. J. Garratt, J. Chem. Sot. B., 660 (1967). (Received in Japan 8 September 1988)
CONFORMATIONAL
ANALYSIS
6275-6278,1988
0040-4039/88 $3.00 Pergamon Press plc
+
.oo
OF 12,12,21,21-TETRADEUTERIO-1,4-DIOXA-
[4.3.3](1,3,5)CYCLOPHANE'
Katsuya
SAKO,
Department
Takafumi
HIRAKAWA,
Takahiko
INAZU:
of Chemistry, Hakozaki
t
Department
Faculty
6-10-1,
of Chemistry,
boat)
All possible
of the title
three
compound
Faculty
[3_3)Metacyclophane
conformers
in the syn geometry
chains
in the crystalline
detected
prepared
of 'H NMR spectrum,
of 1 and its related processes
phenomenon however,
in terms Semmelhack
the benzene conversion
ring
systems
have been
of benzene
ring
of 1 in solution,
report.
We designed
estimate
the energy
barrier
7
processes
type).5
attention
process.4
temperisom-
and two
of the benzene
We have
that the dynamic
because
interpreted
In the recent
process
there
of the benzene
the report,
was not due to
of
H NMR
the synthesis method
rings
spectrum
points
bridges
is prohibited.
much
easier.
we applied
to under
Introduc-
of the trimethylene
and conformational
of deuteriums,
uncertain 2 in order
of trimethylene
at C-2 and C-II positions 1
are still
[4.3.3)cyclophane
for the inversion
the interpretation
As an introduction
inversion
tribridged
inversion
like to report
It
but due to the chair-boat type interbridges. 3 We therefore reexamined the confor-
behavior
will make
223K(-50'C)
process,
in their
tion of four deuteriums
below
in which 1 shows strong 3,4 This conformational much
inversion
et al. concluded
inversion
where
and boat-
in 1976 by US.~
attracted
(chair-boat
mational
we would
have
proposed:
bridges
of the trimethylene
the conditions
chair-boat,
with a chair-chair arrangement of the trimethylene state. 3,4 The preferred geometry of 1 in solution
phenomenon
and trimethylene
33,
and Engineering,
by 'H NMR spectrum
at low temperatures.
inversion
University
812, Japan
(chair-chair,
is also a syn on the basis
rings
SHINMYOZU:
1, Saga 840, Japan
ature-dependent erism
Kyushu
of Science
(1) was originally
exists
Teruo
HORIMOTO+
Fukuoka
Honjo-cho
were
FUJIMOTO,
of Science,
Higashi-ku,
Saga University,
Summary;
Naoki
and Hideaki
bridges
In this paper,
analysis
of 2-d4.
the reductive
M';qo~&;qM~*:;$%$$:@
L;X=H A-d4;X=D
a)HSCH2CH2SH,BFjOEt2/AcOH d)TsOCH2CH20Ts,NaH/DMF
0 I-d4 b)n-Bu3SnD,AIBN/xylene
Scheme 6275
1
0 Z-d4 c)BBr3/CH2C12
6276
desulfurization of 1,3-dithiolanes with n-Bu3SnH developed by Gutierrez et a1..6
Scheme 1 shows the synthetic route to 2-d4.
into dithioacetal 3 in an 80% yield.8
Ketone z7 was converted
Hydrogenolysis of the dithioacetal 2
with n-Bu3SnDg in the presence of AIBN in refluxing xylene did produce 2,2,11,11-d4[3.31metacyclophane derivative z-d4 in a 77% yield. Demethylation of the methoxy groups in z-d4 with BBr3 in CH2C12 at room temperature, followed by the coupling reaction of the resulting phenol with ethylene glycol ditosylate in DMF in the presence of NaH afforded desired tribridged [4.3.31cyclophane z-d4 in a 29% yield." Fig. 1 shows the 'H NMR spectrum of g-d4 at 283K(lO"C) in CD2C12: 2.68 (br s,8H,Hc and Hd), 4.49(s,4H,-OCH2CH20-1, 6.22(s,4H,Ha), 6.63 ppm(s,2H,Hb). The benzylic protons (Hc and Hd) exhibit strong temperature-dependent phenomenon (Fig. 2); its broad singlet at 283K(lO'C) broadens as the temperature is lowered, and then it begins to resolve at 262K(-II'C) into two broad signals and finally each splits into four doublets.
They can be assigned to four AB quartets on the basis of relative intensity of signals and geminal coupling constants (Fig. 5), as described later.
The aromatic protons broaden
as the temperature is lowered (Fig. 3).
Finally, the Ha is resolved into four peaks (6.16, 6.20, 6.29, and 6.32 ppm), while the Hb signal becomes three peaks (6.61, 6.71, and 6.83 ppm), as shown in Fig. 4. Semmelhack et al. HO suggested an order of thermodynamic TMS
stability of chair-chair>chair-boat>boat-boat based on molecular mechanics calculation in J_.3 On the basis of the result, 'H NMR spectrum of Ha protons can be assigned as follows; the most
PP"'intense signal (6.32 ppm) and the least intense
k. 7
6
5
4 3 Fig.1
2
10
one (6.16 ppm) are ascribed to chair-chair &
Hc,Hd
and boat-boat 2c,
respectively, while the two peaks with equal medium intensities
--r---r---r---r-w2383K
2
326ZK 2
3248K 2
:33K
2
d23K
2
3
183K Fig.2
2
(6.20 and 6.29 ppm) are assigned to chair-boat conformer 2b, since it has two kinds of nonequivalent Ha protons.
Similarly Hb
protons can be assigned as follows: 6.61 (chair-chair a), '283K6
'238K6 Fig.3
7 233K'
7
223K6
' 183K6
(chair-boat a),
6.71 and
6.83 ppm (boat-boat
2c). The population of the three isomers is estimated to be 2a:2b:2c=47:44:9 based on the 'H NMR integral of these three peaks.
6277
203K f
Ha
chair-chair c-C c-b;chair-boat 6.61
c-c;
b-b;
boat-boat c-b
r-
Hb c-b c-b 6.29 6.20
27OMHz
, PPm 6
I
7
Fig.5
Fig.4
Free energy difference between & and & is smaller than the estimated values in 1. 3 Based on these results, the benzylic protons of z-d4 are assigned as follows: chair-chair
2.46
(d,J=l3.8Hz) and 2.95 (d,J=l3.7Hz); chair-e
2.35
(d,J=14.7Hz) and 3.02 (d), chair-boat 2.47 (d,J=l3.8Hz) and 2.95 (d,J=13.7Hz); boat-boat 2.32 (d,J=l4.6Hz) and 3.03 ppm(d). The chemical shifts and coupling constants of 2a are, in fact, in good agreement with those of the syn(chairchair) conformer of l-d, [2.50 (d,J=13.7Hz) and 2.97 ppm (d,J=13.7Hz)l. The ethylenedioxy protons appear at 4.49 ppm as a singlet at 283K(lO"C), which split into seemingly two singlets with unequal intensities corresponding to the chair-chair and chair-boat conformers at 218K(-55°C).
Probably the peak
due to the ethylenedioxy protons of the boat-boat conformer may overlap with This result indicates that the internal
those of the other conformers.
rotation of the ethylenedioxy bridge still exists at temperatures where the rotation of two trimethylene bridges are already frozen. 'H NMR data of three conformers of 2-d, are summarized in Fig. 6. 6.71
From the above results, we can 3.03
3.02
D ~l~:~~~~~~*.~l~~~~~
chair-chair 2a
:;1:4.6) .B-,_f
chair-boat 2b
boat-boat 2c
in the follow-
ing order: Fig.6 chair-chair>chair-boat>boat-boat, while the tendency is reversed in Ha protons.
2. The chemical shift difference between the axial and equatorial
protons of benzylic protons (Hc and Hd) is 0.48-0.49 ppm for a chair form but 0.67-0.71 ppm for a boat form.
The geminal coupling constants of the benzylic
protons are 13.7-13.8 Hz for a chair form but 14.6-14.7 Hz. for a boat form. These features may be a diagnostic tool for the assignment of the conformation of trimethylene bridges in (3.3lmetacyclophanes. The energy barrier for the inversion of trimethylene bridges in z-d4 is estimated to be 12.1-12.3 kcal/mol with Tc=262K(-110C),11 which is comparable to that for the inversion of trimethylene bridges in l-d4 (11_6kcal/mol). We concludes therefore that temperature-dependent phenomenon of j_ at low
6278 temperatures can be ascribed to the inversion of the trimethylene bridges as was already pointed out by Semmelhack et a1..3
At higher temperatures,
benzylic protons of z-d4 appear as an AB quartet [2.61 (J=13.9Hz), 2.65 ppm (J=13.9Hz))(Fiq. 7), while those protons of z-d4 and l-d4 appear as singlets. 333K
The result suggests that benzylic protons (Hc
and Hd) of 2 are magnetically nonequivalent, even if the
DMSO
rapid inversion of the trimethylene bridges is occurring. 4ooMHz DMSO-d
Consequently, benzene ring inversion process, which makes 6
Hc and Hd equivalent, is suggested along with the inversion process of the trimethylene bridges in 5-d4 and '-d4.
PPm ,1;[ 2.8
Semmelhack et al. proposed only inversion process
of the trimethylene chains. 3 2.6
-ix
Our study, however, suggests
that the inversion process of benzene rings also exists.
Fig.7 Currently we are preparing optical active (3.3lmetacyclophane derivatives in order to seek unambiguous evidence for the benzene ring inversion process. Acknowledqment
We would like to thank gratefully the support of this work
by the Grant-in-Aid for Scientific Research (No. 62540388) from the Ministry of Education, Science and Culture, Japan. REFERENCES AND NOTES 1
Presented at the 19th Symposium on Structural Organic Chemistry, Sendai, Oct. 1987; Abstr. No. P-38.
2 3
T. Shinmyozu, T.Inazu, and T. Yoshino, Chem. Lett., 1405 (1976). M. F. Semmelhack, J. J. Harrison, D. C. Young, A. Gutigrrez, S. Rafii, and J. Clardy, J. Am. Chem. Sot., 107, 7508 (1985).
4
In the early stage of the present work, we independently undertook an X-ray structure determination of 1 and variable temperature 'H NMR study (60MHz) of 1-d4: T. Hirakawa, K. Kurosawa, M. Tanaka, T. Shinmyozu, Y. Miyahara, T. Inazu, T. Yoshino, presented at the 14th Symposium on Structural Organic Chemistry, Kyoto, Oct. 1982; Abstr. No. B2-28.
The result will be reported
elsewhere. 5
For a review, see; R. H. Mitchell, in "Cyclophane I", P. M. Keehn and S. M. Rosenfeld, Ed., Academic Press (1983), p. 239.
6
C. G. Gutierrez, R. A. Stringham, T. Nitasaka, K. G. Glasscock,
7
J. Org. Chem., 45, 3393 (1980). Prepared by the coupling reaction of 3,5-bis(bromomethyl)anisole and its TosMIC adduct followed by acid hydrolysis of the coupling product.
8
D. Krois and H. Lehner, J. Chem. Sot. Perkin I 447 (1982).
9
G. J. M. Van der Kerk, J. G. Noltes, and J. G. A. Luijten, J. Appl. Chem., 1, 366 (1957); G. M. Whitesides and J. S. Fillippo, Jr., J. Am. Chem. Sot., 92, 6611 (1970).
10 2-d4: colorless needles from ethanol, mp 170.5-172'C. 11 AG$ (kcal/mol)=2.303x1.987Tc(10.319-loqlOkc+loqloTc) where kc=(a/fi)[(vA-vB)2+6J2)1~2; I. C. Cadler and P. J. Garratt, J. Chem. Sot. B., 660 (1967). (Received in Japan 8 September 1988)