The Work-Up

Although the number and diversity of reachons in the synthehc toolbox constantly changes and increases, the techniques used to isolate reachon products have changed little over the past 200 years. In order to get greener reachons, chemists and engineers need to focus on work-up as well as reaction efficiency. The 

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To separate the oil added an equal volume of fresh cool water (note waited until solution cooled before adding the water). The oil started to drop out perfectly, used DCM to extract all traces of the oil. This woik up is by far the cleanest, easiest and simplest to date... (This dreamer was tried all method of ketone synthesis)... Once the oil was extracted, the extracts were pooled washed with sodium bicarbonate lx, saturated solution of NaCI 1x, and two washes with fresh dHzO... Some time was required for the work up as there was a little emulsion from the use of the base wash and then with the first water wash. The JOC ref suggested using an alumina column to remove the catalyst (could be a better way to go). 

If two equivalents of the reagents are used, disubstitution to ECeC-CH(E)R occurs in most cases, but interestingly the reaction of LiCeCCH(Li)R with an excess of COj gives mainly the allenic dicarboxylic acids. These are probably the result of a rapid isomerization of the primary dilithium salt of the acetylenic diacid during the work-up or during the reaction of the dilithio compound with COj ... 

Note 1. Compare also Exp. 10 for notes, and precautions during the work-up. 

Note 1. The product is very sensitive to oxygen. All operations during the work--up must therefore be carried out under nitrogen. 

Note 2. In view of the sensitivity of cumulenic ethers to oxygen the work up was carried out under nitrogen with water that had been saturated with ni trogen. 

Hate 3. All glassware used for the work-up and distillation must be rinsed with a dilute solution of triethylamine in diethyl ether or acetone in order to be sure that traces of acids on the glass walls have been neutralized. Allenic sulfides with the structure C=C=C(SR)-CH- isomerize under the influence of acids to give conjugated dienes, C=C-C(SR)=C. 

Note 2. The allenic ether is extremely sensitive towards oxygen. All operations during the work-up must be carried out under nitrogen. After termination of the distillation nitrogen should be admitted to the distillation apparatus. Too strong heating during the distillation involves the risk of an explosion. 

Kota 1. If more than 100 mg of the iron salt is used as catalyst for the conversion of lithium, the separation of the layers during the work-up may be difficult, owing to the formation of iron hydroxide gel. 

Note 2. In connection with the extreme water-sensivity of the yneamine, moisture must be excluded during the work-up. 

The performance of this experiment was very similar to the preparation of 3,4--hexadienenitrile (see this Chapter, Exp. 20). The same molar amounts of reagents and the same amounts of solvents were used. The work-up was also similar to that... 

Caution-. Use rubber gloves during the work-up, the allenyne alcohol probably is a skin irritant. 

Note 5. At room temperature the 3,3-sigmatropic rearrangement begins. The anmonia, still present during the work up, will cause ring closure of the allenic dithioester to a 2-ff-thiopyran derivative. 

The reactions described so far can be considered as alkylation, alkenylation, or alkynylation reactions. In principle all polar reactions in syntheses, which produce monofunctional carbon compounds, proceed in the same way a carbanion reacts with an electropositive carbon atom, and the activating groups (e.g. metals, boron, phosphorus) of the carbanion are lost in the work-up procedures. We now turn to reactions, in which the hetero atoms of both the acceptor and donor synthons are kept in a difunctional reaction produa. 

Folyphosphoric acid trimethylsilyl ester (PPSE)[1] can be used in sulfolane, CH,Cl2 or nitromethane. It is similar to polyphosphoric acid but the overall conditions arc milder and the work-up more convenient. PPSE has been used in the cydization of ris-arylhydrazones of cyclohexane-l,2-diones to give indolo[2,3-a]carbazole analogues[2],... 

Use of the trapping agent is recommended as the most efficient method for running acyloin condensations for many reasons. Among them are (a) the work-up is very simple filter and distil (b) the bis-(silyloxy)olefin is usually easier to store than the free acyloin and is readily purified by redistillation (c) unwanted base-catalyzed side reactions during reduction are completely avoided and (d) the bis-(silyloxy)olefin can be easily converted directly into the diketone by treatment with 1 mole of bromine in carbon tetrachloride.Other reactions are described in Riihlmann s review and in Organic Reactions ... 

Since 1-ethoxy-1-butyne is very volatile, extreme care should be taken during the work-up to minimize loss of product due to evaporation. Extractions especially should be accompanied by careful and frequent venting of the separatory funnel to prevent excessive pressure. 

The time necessary for completion of the reaction may vary from 0.5 to 4 hours, depending on the actual activity of the alumina. The progress of conversion should be monitored by infrared analysis of a concentrated sample of the solution. Stirring should be continued for 15 minutes after the nitroso band at 1540 cm. has disappeared. A strong diazo band at about 2100 cm. will then be present. The carbonyl band at 1750 cm. initially due to nitrosocarbamate, will usually not disappear completely during the reaction, because some diethyl carbonate is formed in addition to carbon dioxide and ethanol. Diethyl carbonate is removed during the work-up procedure. 

If the reaction mixture does not solidify during the heating, it is well to work it up at once while it can still be poured from the flask. Otherwise the work-up can be postponed to the next day. If the reaction mixture is too difficult to remove from the flask, the acid-ice slurry can be added all at once to the reaction flask immersed in ice. The vigorous surface decomposition is thus partly quenched. However, the cake is seldom difficult to remove unless polyhalogenation has occurred. 

Methyl-d-Anhalonidine, C13H19O3N. From a selected fraction of bases in the mother liquors from the working up of mescal buttons Spath and Bruck (1939) isolated this base as the crystalline d-tartrate. It is an oil, b.p. 140°/0-05 mm. (bath temp.), + 20-7° (MeOH),... 

Reduction of linearly conjugated 4,6-dien-3-ones with lithium-ammonia yields either 5-en-3-ones or 4-en-3-ones depending upon the work-up procedure. Protonation of the dienyl carbanion intermediate (58) occurs at C-7 to give ultimately the enolate ion (59) kinetic protonation of (59) occurs largely at C-4 to give the 5-en-3-one (60). ... 

The reactions are generally run at room temperature or below. With steroids the product is usually isolated by addition of the reaction mixture to water followed by filtration or extraction. The inorganic product of the reaction, chromium III, is soluble in neutral or aqueous acid solutions and can be removed by washing. When steroidal amines are oxidized, the work-up is usually modified such that the steroid may be extracted from the insoluble basic chromium III salts. °... 

The use of dimethyl sulfoxide-acetic anhydride as a reagent for the oxidation of unhindered steroidal alcohols does not appear to be as promising due to extensive formation of by-products. However, the reagent is sufficiently reactive to oxidize the hindered 11 j -hydroxyl group to the 11-ketone in moderate yield. The use of sulfur trioxide-pyridine complex in dimethyl sulfoxide has also been reported. The results parallel those using DCC-DMSO but reaction times are much shorter and the work-up is more facile since the separation of dicyclohexylurea is not necessary. Allylic alcohols can be oxidized by this procedure without significant side reactions. 

Another reagent system that has been recently employed in the Paal synthesis of thiophenes is the combination of bis(trialkyltin)- or bis(triaryltin) sulfides with boron trichloride. Known as the Steliou reagent,it has been utilized in the transformation of 1,4-diketone 11 to thiophene 12. Higher yields are obtained in shorter reaction times in contrast to the use of Lawesson s reagent. Additionally, others have noted the relative ease of the work-up procedure using the Steliou conditions, and the fact that the tributyltinchloride byproduct of the reaction is reusable. Similarly, the combination of the bis(trimethylsilyl)sulfide has been used in conjunction with trimethylsilyltriflate for the preparation of thiophenes in an analogous manner. ... 

A wide variety oi reaetion temperatures and times have been employed in carrying out these reactions in an extreme case tem-teratures of up to ca. 350° were employed. Under these conditions it is quite possible that the actual products isolated were formed as the result of seeondary reactions occurring after the primary products had been formed. Standard procedures for the working up of reaction mixtures obtained in Grignard reactions arc usually followed. 

A variation of the general method for the synthesis of 2-amino-selenazoles is to avoid the use of the free a-halogenocarbonyl compound and in its place react the corresponding ketone and iodine with selenourea.This procedure is also taken from thiazole chemistry. By contrast with thiourea, the reaction with selenourea needs a longer reaction time and the work up of the reaction mixture is somewhat more difficult. Usually an excess of the ketone is used. In the preparation of 2-amino-4-( n-nitrophenyl)selenazole, a very high yield, calculated on the amount of iodine used, was obtained. To explain this peculiar result, the oxidative action of the nitro group was invoked. This liberates free iodine from some of the hydrogen iodide eliminated in the condensation reaction, and the free iodine then re-enters into the reaction. 

Treatment of (11 aS)-3-isopropyl-11 a-methyl-4-phenyl-1,6,11,11 a-tetrahy-dro[l,4]oxazino[4,3-6]isoquinolin-l-one (243) with 6N HCl in a pressure tube, then the reaction of the work-up residue with propylene oxide gave (3S)-3-methyl-l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (244) (99S704). 

Cyclopropyltriphenylphosphonium Bromide (5). The lactone salt is pyrolyzed by placing it in a round-bottom flask fitted with an adaptor attached to a vacuum source (aspirator is sufficient). The flask is heated (oil bath) to 180-190° for 48 hours. The residue is a virtual quantitative yield of the tan product, which may be crystallized from ethyl acetate giving cream crystals, mp 189-190°. An alternate setup is convenient if a drying pistol (Abderhalden) is available. The compound is placed in the pistol, which is then evacuated. Decalin (bp approx. 187°) is refluxed over the pistol to provide the heating source. The work-up is the same. 

Much larger benefits can be expected if there is a ready market for more product, if the work-up train has spare capacity, and if the reaction rate can... 

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