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Degenerate Cope Rearrangement of the 2 6-Bisazoniabicyclo[5.1

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NMM
PS-DVB
n
V
+
co,
+DCCI
I
CH2
bS-DVB
1 , 2 NHC~/CH,COOH
Solid p o l y m e r i c r e a g e n t
Soluble peptide polymer
Fig. 1. Reaction scheme for peptide synthesis by coupling of polymer reagent with soluble peptide polymers.
A = amino acid, Boc = tert-butyloxycarbonyl, DCCI = dicyclohexylcarbodiimide, DCHU =dicyclohexylurea,
N M M = N-methylmorpholine, POE = polyoxyethylene, PS-DVB = 2 % crosslinked polystyrene-divinylbenzene.
The synthesis of some olig~peptides[~]
shows that, surprisingly, no complications arise in the inhomogeneous reactions
of the two polymers. The advantages of the liquid-phase synthesis”] (no reduced solubility of the growing fully-protected
peptide chain, precise control of conversions)and the polymeric
reagents (maintenance of supply of activated, N-protected
building units, regeneration, favorable process engineering in
batch or continuous column processes) are retained. Our repetitive peptide synthesis leads to fundamental simplification
and improvement, since for the first time in peptide coupling,
neither are side-products formed, nor do excess coupling components have to be removed.
General procedure:
A mixture of amino acid polyoxvethvlene ester with free
amino groupa (moleculor mass 6000. loading at least
0.2 mmol g. H-A-0-I’OEI in CH2C12( 5 ml) and N-Boc-amino
acid- 1 -hydroxybenzotriazole ester bound to solid polystyrene
(5 g)(loading about I mmolig) is stirred for 2 h at 20°C;the pH
is maintained at 7-8 with N-methylmorpholine (NMM). The
solution of the peptide-polymer Boc-A2-0-POE is removed
from the polymeric reagent by filtration. After determination
of the coupling yield by titration or dansylation of the liberated
amino groups, recoupling is continued until less than 0.1 %
free amino groups are detectable. After removal of solvent
the Boc group of the dipeptide polymer is cleaved in the
usual way with 1.2 N HCl/glacial acetic acid. The next coupling
to the N-protected tripeptide polyoxyethylene ester can then
be carried out. Considerably shorter coupling times and
smaller excess quantities of reagent are required with the
2
1
“16
18
20
22
2L
polymer-bound 1-hydroxybenzotriazole derivatives than with
the corresponding 2-nitrophenol derivativesl41 (Fig. 2).
Received: July, 1977 [Z 787 IE]
German version: Angew. Chem. 89,681 (1977)
M. Mutter, E. Buyer, Angew. Chem. 86, 101 (1974); Angew. Chem.
Int. Ed. Engl. 13, 88 (1974).
[2] R. Kalir, M. Friedkin, A. Patchornik, Eur. J . Biochem. 42, 151 (1974).
[3] R. Kalir, A. Warshawsky, M. Fridkin, A. Patchornik, Eur. J. Biochem.
59, 55 (1975).
[4] G. Jung, G. Bovermann, W Gohring, G. Heusel in: Peptides: Chemistry,
Structure and Biology. Proc. 4th Amer. Pept. Symp. Ann Arbor Science
Publ. 1975, p. 433.
[I]
Degenerate Cope Rearrangement of the 2,6-Bisazoniabicyclo[5.1.0]octa-2,5diene Dication[**I
By Helmut Quast and Josef Stawitzp]
In memoriam Professor Hans Schmid
None of the non-classical semibullvalenes and diazasemibullvalenes with delocalized, bishomoaromatic ground states
as proposed by Hoffmann[‘l and Dewar[’], has yet been synthesized. In the search for realistic models for one of these compounds, 3,7-diazasemibulIvalene (I )Iz1, we recently investigated the Cope rearrangement of the bisimines (2) resulting
in thediazepines (3)[31.We report here on the Cope rearrangement of 2,6-bisazonia-bicyclo[5.1.0]octa-2,5-diene dications
(7).
Diaza-3,4-homotropilidenes (4), which are closely related
to 3,7-diazasemibullvalene (I), should not exist as such but
are expected to tautomerize to their more stable tautomers
(5)[41. Their double protonation should however regenerate
the structure ( 4 ) and produce the dications (7) having the
structural prerequisites for a Cope rearrangement.
t IhlFig. 2. Comparison of the coupling of Boc-L-Ala-O-(polyctyrenehydl.osyhonzotriazole) with H-L-Val-0-POE of mol. masses 6000 (a), 10000 (b). and 20000
(c), and of Boc-L-Ala-O-(polystyrene-2-nitrophenol)
with H-L-Val-0-POE
of mol. mass 6000 (d). A threefold excess of polymeric reagent was used
in each case.
Angew. Chem. lnt. Ed. Engl. 16 (1977) No. 9
[*] Prof. Dr. H. Quast, Dip].-Chem. J. Stawitz
Institut fur Organische Chemie der Universitat
Am Hubland, D-8700 Wurzburg (Germany)
[**I This work was supported by the Fonds der Chemischen Industrie.
The results are taken from the planned dissertation of J. Stawitz.
643
(5b) (92%) is obtained in aqueous, acetate-buffered solution from the dihydrochloride of cis-1,2-cyclopropanediarniner'] and 2,4-pentanedione after 45 h at 7 5 T , followed
by basification and ether extraction; it is formed as pale
yellow crystals (m.p. 161--164°C) which sublime at 100120°C/10-5 torr. The structure of (5b) and its uerchlorate
(6b), 'x=c104, is based on IR, UV,' 'H-NMR (Table 1)
and mass spectra.
as is shown by the intact ABXz spectra of the cyclopropyl
protons. Accordinalv. under these conditions D may add
H R
to (6), but the Cope rearrangement of the dications, which
are present only in minimal amounts, apparently cannot yet
compete with the reverse reaction. Addition of an equal volume
of [D2]-sulfuric acid to the solution of [D3]-(6a) in [D]-triH
fluoroacetic acid results in the immediate-disappearance of
the AB part of the spectrum which only exhibits two equally
intense singlets for I-H, 7-H and 3-H, 5-H and thus proves
formation of [D6]-(7U) as the result of a rapid, degenerate
Cope rearrangement.
The Cope rearrangement of (7b) should be rendered more
difficult by the two methyl groups on the cyclopropane ring"]
of (8b). Indeed the formation of [D6]-(7b) requires more
(5)
(6)
severe conditions, namely the warming of [D3]-(6b) in [ID]The unsubstituted (6a) is less readily accessible than (6b)
trifluoromethanesulfonic acid.
since the formation of a formal dimer with a 14-membered
The 'H-NMR spectra of the dications (7a) and (7b) (Table
competes with the ring closure yielding (6a). Indeed
1)in trifluoromethanesulfonic acid are temperature dependent.
the 14-membered ringr61 alone is formed from cis-1,2-cycloThe AB spectrum of the protons 4-H and 4'-H of (7b) is
propanediamine and malondialdehydedianil p e r c h l ~ r a t e [ ~ , ~ ] already broadened at 30°C,this being especially evident in
which has successfully been used in the synthesis of 2,3the low-field half of the spectrum. At 90°C, only a broad
dihydro-I H-l,4-diazepines having unsubstituted 5-, 6- and 7singlet is observed for one of the two protons while the signal
positions, such as (3). Only in rather dilute solution (5 x
of the other proton at lower field can no longer be recognized.
to 6 x
M) in water/ethanol (1 :I)
did the sodium salt
The reason for this is the difference in the rates of exchange
of malondialdehyde and the dihydrochloride of cis-1,2-cycloof the protons 4-H and 4'-H with trifluoromethanesulfonic
propanediamine afford the cation (6a) free from dimer and
acid which, at the higher temperatures, are comparable with
decomposition products. It was isolated as the tetraphenylbothe 'H-NMR time scale. In contrast, the ABXz spectrum
rate (yield 49 %) which crystallized from dioxane, together
of the cyclopropane protons of ( 7 b ) remains unchanged up
with one mol of dioxane, as light-sensitive,pale yellow crystals
to 90°C. There is even a certain sharpening of the ABXz
with m.p. 226-228°C. Its structure was established by IR,
spectrum.-In the 'H-NMR spectrum of (7a) in trifluoroUV and 'H-NMR spectra (Table 1).
methanesulfonic acid, already at 30°C only the broad signal
- < .
+
Table 1 . Chemical shifts and coupling constants (Hz) in the 90 MHz 'H-NMR spectra of 2,6-diazabicyclo[5.1.0]octa-2,4-diene ( 5 ) and of the cations (6) and ( 7 )
derived therefrom. The data of the ABXl spectra of the cyclopropane protons were optimized using the LAOCOON 111 program.
Cpd.
(5a)
(6a)
(7a)
(5b)
(66)
(76)
[a]
[b]
[c]
[d]
[el
Solvent
Cyclopropane protons
1-H,
Js.8,
7-H
8-H
8'-H
(endo)
(exo)
CDCl3 [a]
CF3COzH [b]
CF3S03H [c]
0.51
1.89
1.87
2.20
2.50
3.04
3.44
4.22
-4.78
-6.23
-7.75
6.35
6.07
6.47
8.57
7.65
9.10
R=H
6.84(d, J=7.6)
7.36(t,3=8.0)
8.76 [d] (d, J =5.6)
CDCI3 [a]
CFiCOZH [b]
CF3SO3H [c]
0.39
0.99
1.71
1.63
1.94
2.12
2.93 [el
3.39
3.98
-4.57
-6.07
-7.83
5.92
6.00
5.85
8.08
7.67
8.66
R=CHa
1.98 (s)
2.31 (s)
2.90 (s)
1.18
Js.1
Jsr.i
=Js.7
=.l8,.7
3-R,
5-R
Other protons
4-H
4.61 (t)
5.23(t)
4.86 [d]
4.62 (s)
5.14(t,5=1.88)
4.26 (AB, J = 15.2)
4'-H
NH
-
-
8.34 [d]
-
5.26
8.29
4.95 [d]
Internal standard TMS=O.
Internal standard [2,2,3,3-D4]-3-trimethylsilylpropionicacid = 0.
External standard TMS (50 percent in CCI,).
Broadened.
7-H still coupled with 6-H.
2,3-Dihydro-lH-l,4-diazepiniumcations, e.g. (3).H+,
already show rapid H/D exchange at their I-, 4- and 6-posit i o n ~ [in~ [D]-trifluoroacetic
J
acid. Ifthe two methylene groups
in (7) were to become equivalent due to a Cope rearrangement,
then in deuterated strong acids the [L)6]-bisazonia-3,4-homotropilidene dications [D6]-( 7a) and [D6]-(7b) should be
formed from (6a) and (6b), respectively.
In [D]-trifluoroacetic acid however, only the trideuterated
cations [D3]-(6) are observed in the 'H-NMR spectra,
644
of one of the two protons 4-H and 4'-H can be recognized.
Their rate of exchange with trifluoromethanesulfonic acid
approximately corresponds to that of (76) at 90°C. Contrary
to the changes observed with (7b), in the case of ( 7 a ) an
increase in temperature causes a broadening of all signals
due to the rapid, degenerate Cope rearrangement; the fine
structure of the ABXz spectrum also disappears. Above 100°C
slow decomposition begins. The 'H-NMR spectra of (7a)
and [D6]-(7a) can be used to estimate a coalescence temperaAngew. Chem. Int. Ed. Engl. 16 (1977) No. 9
ture of 110flO"C for the signals of I-H, 7-H and 3-H, 5-H
and thus an activation barrier of A Gf = 73 2 kJ/mol
(Av =409 Hz) for the degenerate Cope rearrangement
(assuming that all of ( 7 a ) is present as the dication).
The activation barrier is thus clearly larger than that of 3,4homotropilidener8] but very similar to that of disubstituted
3,4-h0rnotropilidenes~~~.
Received: June 14, 1977 [Z 759 IE]
German version: Angew. Chem. 89, 668 (1977)
CAS Registry numbers:
(5a), 63466-72-8; ( 5 b ) , 63466-73-9; (6a),63466-74-0; [D,]-(6a),63466-77-3;
(66). 63466-78-4; [Da]-(6b), 63466-80-8; ( J u ) , 63466-82-0; [Ds]-(7~),
63466-84-2; ( 7 b ) , 63466-86-4; [D& 7 b), 63466-88-6; cis-1 ,2-cyclopropanediamine dihydrochloride, 63466-89-7; 2,4-pentanedione, 123-54-6; Na salt of
malondialdehyde, 24382-01-5
[ t ] R. Hofmann, H! D. Srohrer, J. Am. Chem. SOC.93, 6941 (1971).
[2] M. J. S. Dewar, D. H . Lo, J. Am. Chem. SOC. 93, 7201 (1971); M.
J. S. Dewar, Z . Ndhlousk4, B. D. Ndhlouskj, Chem. Commun. 1971,
1377.
[3] H. Quast, J. Stawitz, Tetrahedron Lett. 1977, 2709.
[4] D. Lloyd, H. P . Cleghorn, D. R . Marshall, Adv. HeterocycL Chem. 17,
1 (1974).
[S] Cf. H. Quost, J. Stawitz, Tetrahedron Lett. 1976,3803.
[6] H. Quast, J. Stawitz, K . Peters, H.G . uon Schnering, unpublished.
[7] M. C. Flowers, H . M . Frey, Proc. Roy. SOC.(London) A257, 122 (1960);
W D. Good, J. Chem. Thermodyn. 3, 539 (1971).
[8] H. Giinther, J.-B. Pawliczek, J . Ulmen, W Grimme, Chem. Ber. 108,
3141 (1975); R. Bicker, H. Kessler, W Ott, ibid. 108, 3151 (1975).
[9] H. Kessler, H! Ort, J. Am. Chem. SOC.98, 5014 (1976).
Formation of Chlorophenols by Microbial Transformation of Chlorobenzened']
By Karlheinz Ballschmiter, Charlotte Unglert, and Peter Heinzmann 1'1
Only chloropyrocatechols have hitherto been described as
products of the microbial degradation of chlorobenzenes[21.
We have now investigated the microbial transformation of
Table 1. Microbial transformation of chlorobenzenes (1) into chlorophenols
(4) (experimental conditions see text).
Chlorobenzenes
(1)
( l a ) 1-
( l b ) 1,2-
( l c ) 1,3-
( I d ) 1,4-
Chlorophenols
(4)
____
(4a)
(4b)
(4c)
(4d)
(4e)
(4f)
(4d)
(4e)
i
(4f)
22,33,42,62,42s2.62,423-
[a1
Chlorobenzenes
(1 )
2
( 1 e) 1,2,3-
Ratio
1
Cbl
6
1
PI
3
1
Chlorophenols
(4)
i
(lf)
1,2,4-
(1 g )
(1 h )
(1 i)
(1j )
( 1 k)
1,3,51,2,3,41,2,3,51,2,4,51,2,3,4,5-
(49)
(4h)
(40
(4j)
(4k)
(4k)
(41)
(4m)
(4 n )
2,3,42,3,63,4,5-
Received: June 6, 1977 [Z 783 IE]
German version: Angew. Chem. 89, 680 (1977)
Ratio
[a1
7
1
[b]
~ 4 ~ 5 2,4,62,4,62,3,4,52,3,4,62,3,5,6[CI
[a] Ratio after 24 h; [b] detected after 100h; [c] not detectable
[*] Prof. Dr. K. Ballschmiter ['I, Ch. Unglert, Dr. P. Heizmann [**I
Abteilung fur Analytische Chemie der Universitat
Oberer Eselsberg, D-7900 Ulm (Germany)
['I Author to whom correspondence should be addressed.
r * ] New address: C.O.F. Hoffmann-La Roche AG, F/BP Phakin, CH-4005
Basel (Switzerland).
Angew. Chem. lnr. Ed. Engl. 16 (1977) No. 9
the monochloro- to pentachlorobenzenes ( I ) (Table 1) into
chlorophenols ( 4 ) .
We used mixed cultures of soil bacteria-preferably gram
negative, polar flagellated rods-precultured on benzene. In
the mineral salt solution (pH=6.8) the bacteria had access
to further benzene as a source of C. 200mg of benzene and
50mg of one of the chlorobenzenes (I a ) to ( I k ) were allowed
to diffuse from a hard paraffin layer (2 g) into 200ml nutrient
medium, whereupon the concentration of the chlorobenzene
in solution finally amounted to
to lO-'M (ca. 20 to
200ppb). After 24, 100, 240, and 500 hours' incubation at
28°C the cells and nutrient medium were worked up for
c h l o r ~ p h e n o l sThe
~ ~ ~chlorophenols
.
were extractively esterified with acetic anhydride in 0.1 M K 2 C 0 3solution and identified by comparison of the retention indices of the esters with
those of authentic compounds (glass capillary gas chromatography with 63Ni electron-capture detector; Carlo Erba,
Model 2300)[41. Combined GC-MS using glass capillaries
enabled additional confirmation of structure.
The degradation of benzene to phenol and its further hydroxylation to diphenols was investigated in the same experimental
setup. The reaction products phenol, pyrocatechol, resorcinol
and hydroquinone were identified by comparison of the retention indices of their pentafluorobenzyl ethersr5]with those of
the authentic substances. Usually it is assumed that dioxygenases are responsible for the microbial degradation of
benzene[1' .
Microbial degradation of the chlorobenzenes (I) can be
assumed to proceed via attack by a monooxygenase, since
the observed distribution of isomers can only be rationalized
in terms of an intermediary chlorinated cyclohexadiene epoxide ( 2 ) . With epoxides as intermediates, a migration of the
chloro substituents is
After a while diphenols can be detected in the joint degradation of chlorobenzenes and benzene (vide supra). Their mode
of formation is still unclear.
The hydroxylation shows structural specificity. In four
experiments with different cultures only 2-chlorophenol was
formed from chloroben7ene. All chlorophenols up to 3.4-dichloro- and 3,4,5-trichlorophenol are formed by attack at
the ortho position to the chlorine of a -CCl=CH
group.
In assessing the occurrence of phenol and chlorophenols
as pollutants not only their direct release into the environment
must be taken into consideration but also their formation
by microbial transformation of benzene and chlorobenzenes.
CAS Registry numbers:
(I a), 108-90-7; ( 1 b ) , 95-50-1; (1 c), 541-73-1; (1 d ) , 106-46-7;( 1 e ) , 81-61-6;
(If), 120-82-1 ; (1 g ) . 108-70-3; (I h), 634-66-2; ( 1 i), 634-90-2; ( l j ) ? 95-94-3;
(1 k ) , 608-93-5; ( 4 a ) , 95-57-8; ( 4 b ) , 576-24-9; ( 4 c ) , 95-77-2; ( 4 d ) , 87-65-0;
( 4 e ) , l 2 0 - 8 3 - 2 ; ( 4 f ) , 5 8 3 - 7 8 - 8 ; ( 4 9 ) ,15950-66-0; (4h),933-75-5; ( 4 i ) , 609-198; (4j),95-95-4; ( 4 k ) , 88-06-2; (41),4901-51-3; ( 4 m ) , 58-90-2; (4n),935-95-5
[l] Microbiological Degradation of Aromatics, Part 4. This work was supported by the Bundesministerium fur Forschung und Techno1ogie.-Part
3: K. Ballschmirer, Ch. Unglert, H . J . Neu, Chemosphere 6, 51 (1977).
[2] D. T Gibson, J . R . Koch, C . L. Schuld, R. E. Kaliio, Biochemistry 7,
3795 (1968); K . Haider, G. Jagnow, R . Kohnen, S . U . Lim, Arch. Microbiol.
96, 183 (L974); C. M. 7(r, ibid. 108, 259 (1976).
[3] H. J. Neu, K. Ballschmiter, Chemosphere, 6,419 (1977).
[4] M. Zell, H . J . Neu, K . Ballschmiter, Z. Anal. Chem., in press.
[5] K . Ballschmiter, U . Niedrrschulte, H . Thamm, H . J . Neu, Chemosphere
5, 367 (1976).
[6] K. Kiesiich; Microbial Transformations of Non-Steroid Cyclic Compounds. Thieme, Stuttgart 1976; H . J. Knackmus, Chemiker-Ztg. 5 , 213
(1975), and references cited therein.
171 J. W Duly, D. M . Yerina, B. Witkop, Experientia 28, 1129 (1972).
645
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