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Oxidation and Elimination Reactions of the DiazomethaneЦ2 2-Bi-(1 4-naphthoquinone) Adduct.

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Oxidation and Elimination Reactions of the
Diazomethane-2,2-Bi-( 1,4-naphthoquinone)
By A . Zeeck [*I
Both half-molecules of 2,2’-bi-(1,4-naphthoquinone) react
with diazomethane in a cycloaddition yielding the adduct
( I ) 111. This compound can be stabilized in three ways, each
of which involve attack o n the bonds from C-9a and C-9’a
and aromatization:
mined by these methods. Since (5) contains the structural
units of o-aroylbenzoic acids, ring-chain tautomerism also
occurs. Reaction with diazomethane yields the normal dimethyl ester, whereas acetylation or reduction result in ring
closure in both halves of the molecule to yield 1,l’-diacetyl4,4’-bis(3-acetoxyphthalid-3-yl)-5,5’-bipyrazoleor 4,4’-bis(phthalid-3-y1)-5,5’-bipyrazole,respectively.
The parent of (5), namely, 3,3‘- or 5,5’-bipyrazole (7) (m.p.
259 “C) is obtained on decarboxylation of the dicarboxylic
acid (6); it is formed, with benzoic acid, in an alkali melt at
160 OC.
1. Warming the adduct in anhydrous toluene gives 3,3’-dimethyl-2,2’-bi-(l,4-naphthoquinone)(2) (thermal elimination
of nitrogen).
Lecture at Gottingen on December 15th, 1966
[VB 56 IE]
German version: Angew. Chem. 79,477 (1967)
2. In the presence of electrophilic agents disproportionating
fragmentation occurs, yielding benzLflindazole-4,9-quinone
(3) and its hydroquinone (4). The latter is rapidly oxidized
by air to the former. (3) and (4) can be identified in admixture by means of acetic anhydride/pyridine (with exclusion
of air) when the N-acetyl derivative of ( 3 ) , and the leucotriacetate derivative of (4) are obtained. In a side reaction,
( I ) loses half of its nitrogen before the two molecular fragements have separated; a nitrogenous quinone of molecular
weight 352 but unknown structure results.
Organisch-Chemisches Institut der Universitat
Windausweg 2
34 Gottingen (Germany)
[I] Oxidative degradation of diazomethane adducts of type (f]
can be used for determination of the structure of biquinones. H . Brockmann, K.van der Merwe, and A . Zeeck, Chem. Ber. 97,
2555 (1964); H . Brockmann, A. Zeeck, K. van der Merwe, and
W. MuNer, Liebigs Ann. Chem. 698, 209 (1966).
3. Oxidation in 2 to 4 N alkali hydroxide solution leads to (a)
decoupling of the C-9a/C-9’a bond, yielding two molecules
of (3), or (b) fission of the C-9/C-9a and the C-9’1C-9a
bonds, yielding 4,4’-bis(2-carboxybenzoyl)-5,5’-bipyrazole
(5). Use of hydrogen peroxide as oxidizing agent gives
mainly (3) [I], and use of potassium hexacyanoferrate(n1)
gives (energetically more favorable) mainly ( 5 ) . Both reactions are expected to occur by way of an dianion of ( I ) and a
Commercial Processes for Antibiotic Fermentation
[*I Dr. A. Zeeck
By R. KreutzfeldtI*l
Industrial fermentation has recently achieved increased importance, principally by production of antibiotics. Some 1000
antibiotics have been discovered in the last 25 years, of which
about 50 have acquired economic significance, notably the
penicillins, tetracyclins, and streptomycins. About 3000 tons
of antibiotics were prepared in USA in 1964 (ca. 50 % of the
world production), at a value of ca. $400 million. The world
production of penicillins can be estimated as about 1500 tons
a year.
In spite of many years’ experience, penicillin production
remains one of the most difficult and most sensitive. Fleming
achieved yields of 2-10 units/ml in his first fermentations:
today 10000 units/ml are considered normal. The fermentations are carried out in a technically similar way for all
antibiotics, and the technique for penicillin fermentation
alone will be described more closely here.
The penicillin-forming mold is preserved as a permanent
culture in the anhydrous state at about -5 “ C in order t o
exclude any metabolism. From this permanent culture subcultures are made on the laboratory scale, and further cultures are grown in prefermenters. The amount of inoculum
for the main fermenter is chosen to be between 2 and 20%
of the amount to be harvested; larger amounts of inoculum
shorten the fermentation time.
radical anion, which either splits into two parts or, when
attacked by hydroxide ions a t C-9 or C-9’, initiates another
reaction path (oxidative-hydrolytic scission of two C-C
The structures of (5) and some of its derivatives can be
proved by IR, NM R , and mass spectrometry. The position
of the hydrogen atom in the pyrazole rings cannot be deter-
The fermenters are fitted with a n aeration system, a stirrer,
and a cooling system that keeps the temperature constant
within t 0.5”C. Provision of oxygen and formation of
penicillin are closely related. Fermenters in commercial use
today may have a capacity of 400 m3.Antibiotic fermentations
must be carried out without admission of foreign infections :
Only sterilization by steam (at least 120°C for at least 20
min) comes into consideration for large-scale production.
Fermentation conditions: 7 Days a t 25 ;? 0.5OC; 0.3 m3 of
air per min per 1 m3 of liquor. The following are required
for production of 100 kg (4.3 % yield) of penicillin-Na: 1200
kg of carbohydrate, 60 kg of animal and vegetable fats, 770
kg of corn steep liquor, 220 kg of inorganic substances (as
buffer, and as source of sulfur and phosphorus), and 100 kg
of phenylacetic acid for formation of penicillin G.
The material balance of penicillin production from these
quantities (input 2350 kg of raw materials) is: 100 kg of
penicillin-Na (4 wt-x), 825 kg of mould mycelium (35 %),
660 kg of residual substances in the culture solution (28 %),
765 kg of COz (33 %).
Angew. Chem. internat. Edit. 1 Vol. 6 (1967)
1 No. 5
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elimination, adduct, oxidation, reaction, naphthoquinone, diazomethane
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