· (MW 147.39)
(electrophile which can react with a variety of nucleophiles,1 insert into metal-C, -N, and -O bonds,2 undergo ene and Diels-Alder reactions,3 add to ketenes,4 and function as a hydride acceptor5)
Alternate Name: 2,2,2-trichloroacetaldehyde.
Physical Data: anhydrous: bp 98 °C; mp -57.5 °C; d 1.512 g cm-3; refractive index 1.4557 (20 °C); hydrate [Cl3CCH(OH)2]: mp 57 °C; bp 96 °C; d 1.908 g cm-3.
Solubility: anhydrous: sol CH2Cl2, CHCl3, CCl4, C6H6, Et2O, THF, EtOAc, n-C6H14; sol and reacts with H2O and alcohols; hydrate: sol H2O, EtOH, Et2O, C6H6.
Form Supplied in: anhydrous: colorless oily liquid, fairly widely available; hydrate: colourless crystals, widely available.
Analysis of Reagent Purity: various iodometric and colorimetric methods are available, but analysis by GLC offers the best discrimination.1
Purification: fresh commercial ~99% material is suitable for most purposes; chloral hydrate and polychloral are removed by distillation from P2O5.
Handling, Storage, and Precautions: toxic by inhalation, ingestion, and skin absorption. Irritating to the eyes, nose, throat, and skin; liquid and vapors are especially damaging to the eyes. Handle in an efficient fume hood and wear safety glasses, rubber or plastic gloves, and a laboratory coat. Bottles should be tightly sealed and refrigerated. Limited shelf life; hence may require redistillation from P2O5 before use. The hydrate, which is a powerful soporific, is much more stable but the same handling precautions apply. For small accidental spillages, (<~5 mL), flood with water and wash down the drain. Treat larger spillages with about 2-3 volumes of water and then adsorb onto proprietary spillage granules for disposal. Small quantities of unwanted reagent may be destroyed by hydrolysis to chloroform and sodium formate: add the chloral (x mol) slowly to a cooled (0 °C) and stirred solution of
sodium hydroxide (1.5x mol) in water (100x mL). After 2 h,
extract the chloroform layer with water and add to the departmental waste chlorinated solvent; the aqueous residues may be washed down the fume hood drain with plenty of water.
Chloral is an important source of dichloroacetic acid and its derivatives,1 and the relative ease with which the Cl3C-, Cl3CCH(OH)- and Cl2C= groups, derived from chloral by reaction, can be transformed into other types of functionality1,3a makes chloral a versatile synthetic reagent.
Formation of Hemiacetals and Acetals.
Anhydrous chloral reacts vigorously with a wide variety of alcohols to form hemiacetals.1,6 Acetals are formed with acid catalysts and azeotropic distillation of water. Similarly, diols, hydroxy acids, and hydroxy ketones react to give cyclic acetals.1,7 Chloral hydrate is usually used in combination with concentrated H2SO4.1 Useful erythro-threo equilibration of lithium ketolates has been achieved through the formation of the chloral hemiacetal (eq 1).8 Chloral adds Sodium Methoxide to form first the sodium salt of the hemiacetal which decomposes into dichlorocarbene, methyl formate and sodium chloride.9a Potassium t-Butoxide, however, is usually preferred for generating :CCl2 from chloral.9b
The hemiacetals formed from 2-alken-1-ols and chloral are cyclized in the presence of Mercury(II) Trifluoroacetate to the acetals. Demercuration and reductive cleavage gives cis-diols (eq 2).10 The HgII-assisted addition of chloral to 1-penten-3-ol, followed by the electrophilic displacement of the mercury atom with iodine, gave a mixture of the stereoisomers of (1), which were used in a synthesis of the insect pheromone exo-brevicomin (2) (eq 3).11 The transposition of the double bond and the hydroxyl group in 5-alkyl-4-hydroxycyclopentenones (in connection with a prostaglandin synthesis) has been achieved through a similar cyclic acetal formation (eq 4).12
As an Alkylating and Acylating Agent for Amines and Amides.
Formylation (with simultaneous production of chloroform) of strongly basic primary and secondary amines and the esters of amino acids occurs in good yield on treatment with chloral.1 Aromatic amines usually require the presence of Et3N, otherwise hemiaminals or aminals may form.1,13 Amides are formylated by chloral under alkaline conditions.14 The hemiaminals formed from moderately nucleophilic amines may be dehydrated to afford chloral imines, or suffer elimination of chloroform to give the formyl derivative.15 If the H-atom on the center adjacent to the N-atom of the chloral imine is acidic, then 1,4-elimination of HCl may be observed.16 This chemistry has been used to convert the 7a-amino-1-oxacephem (3) into
its 7b-epimer (57.5% overall) by the reduction (KBH4, 0 °C) and hydrolysis (HCl, MeCN) of the intermediate (4) (eq 5).17 Chloral catalyses the N-nitrosation of various secondary amines in the pH range 6.4-11.0 since the first-formed iminium ion is readily attacked by nitrite anion; the presumed adduct [R2N-CH(CCl3)-ONO] collapses to R2NNO and chloral.18
Aromatic amines condense with chloral hydrate and hydroxylamine to afford N-(hydroxy-iminoacetyl) derivatives which are readily cyclized in the presence of concentrated H2SO4 to provide a good route to isatin and its analogs (eq 6).19 Acid hydrazides when refluxed with chloral in the presence of an alcohol are converted (70-80%) directly into the corresponding ester (eq 7).20 The hydrazide to amide conversion can be made similarly.
Aldol and Related Reactions.1
With aldehydes the best method for the directed cross-aldol condensation involves reaction of chloral with the TMS enolate of the aldehyde in the presence of Titanium(IV) Chloride (eq 8).21 The TMS enolates of ketones react similarly to give the 1,1,1-trichloroethan-2-ols in excellent yields.22 With simple methyl ketones, the condensation occurs at the methyl group.23 Mesityl oxide affords (5) under buffered conditions (AcOH-NaOAc) (eq 9), whereas in the absence of the NaOAc the tetrahydro-1,4-pyranone (6) is formed.23b
The rather more stable enolate anions derived from b-diketones, a-cyanoacetates, a-nitroacetates, etc., are C-alkylated by chloral.24-26 The 1,1,1-trichloro-2-hydroxyethyl derivative thus formed may be dehydrated under suitable conditions.24d When the condensation is performed with solid Potassium Carbonate in THF solution, b-diketones are deacylated. Thus acetylacetone is transformed into Cl3CCH=CHCOMe (74%)25 and 2-acetylcyclopentanone is converted into (8) through a Favorskii rearrangement of the intermediate deacetylated product (7) (eq 10).26 A 1,1,1-trichloro-2-hydroxyethyl derivative is also formed when chloral is allowed to react with various other anions (e.g. those derived from sulfones,27
amides,28 or 2-methylquinoline29). In this last case, chloral has been used as a convenient masked equivalent of glyoxylic acid (eq 11).29
Electrophilic Aromatic Substitution.
Much research on chloral has been devoted to its use in electrophilic aromatic substitution reactions (promoted by acids or Lewis acids), not least because of the former importance of DDT.1 Alkylation produces aryltrichloromethylcarbinols which may be transformed into aldehydes, a-hydroxy acids, and a-alkoxy acids.30 The aryltrichloromethylcarbinols are oxidatively cleaved by alkaline Hydrogen Peroxide to afford carboxylic acids after acidification; yields are 85-98%.31 Mild conditions (i.e. Zinc Chloride) are necessary for furans, or a photochemical procedure can be employed.32 The alkylation of dichloroaluminum phenolates with chloral is ortho selective. The products (9) are transformed by basic Alumina (decalin, reflux) into isoxindigos (10) (eq 12).33
Asymmetric o-selective hydroxyalkyl
ation of phenols occurs when chiral alkoxyaluminum chlorides are used as catalysts; the % ee's, however, are only poor to moderate.34 Acrylate esters undergo formal electrophilic substitution at the a-position when treated with chloral in the presence of 1,4-Diazabicyclo[2.2.2]octane as catalyst.35
Additions to Alkenes, Dienes, and Ketenes.
Anhydrous chloral affords formal ene adducts on reaction with suitable alkenes. Although chloral is a relatively reactive enophile, the thermal addition is really only successful with the more reactive (i.e. Type 1)36 enes. The addition is strongly catalyzed by Lewis acids (e.g. AlCl3, SnCl4, TiCl4, FeCl3, etc.), such that a solvent (e.g. CH2Cl2, CCl4) is necessary to moderate the room temperature reactions, and the useful reactivity range spans Type 1-Type 4 enes.3a,b The Lewis acid improves the yield and also has a profound effect upon the diastereoselectivity of the addition (eqs 13 and 14). Although the reactions with Type 1 enes appear to be concerted, the formation of significant byproducts with the less nucleophilic
Type 2-4 enes points to an electrophilic addition pathway (eq 15).3b,37,38 Chiral alkoxyaluminum Lewis acid catalysts promote the asymmetric ene addition of chloral to 2-methylpropene with enantioselectivities of about 70-80% ee.39 Aluminum Chloride-promoted electrophilic additions of chloral to alkenes are also well documented.1 For example, addition to 1,5-cyclooctadiene and to norbornadiene affords, respectively, the oxatricyclic compounds (11; 47%) and (12; 36%).40 The cyclohexene-chloral ene adduct is rearranged by AlCl3 into the oxabicyclo[3.2.1]octane (13)3c and not into an oxabicyclo[2.2.2]octane as thought previously.41
Thermal addition of chloral to isoprene yields the expected Diels-Alder adduct predominantly, whereas in the AlCl3 catalyzed addition the ene adduct predominates.3a,d Thermal addition to 1,3-cyclohexadiene affords the oxabicyclo[2.2.2]octane only with pure reagents, otherwise rearrangement occurs to the oxabicyclo[3.2.1]octane (14).3c Chloral undergoes an exothermic formal [4 + 2] cycloaddition to the strained double bonds of t-butyl 2,3,4-tri-t-butylcyclobutadienecarboxylate,42 successfully traps a-oxo-o-quinomethanes to give isocoumarins,3e but otherwise is not an especially versatile and reactive dienophile. It is, however, one of the few carbonyl acceptors for the carbon-carbon double bond of
ketenes.1,4a-d Addition to ketene in the presence of quinidine as a chiral catalyst is highly enantioselective (98% ee) and affords (R)-3-trichloromethyl-2-oxetanone (15; 89% yield).4c Ketene acetals readily add chloral to give 2,2-dialkoxy-4-trichloromethyloxetanes under Lewis acid catalysis (ZnCl2 or EtAlCl2).43
As a Hydride Acceptor.
Chloral on dehydrated chromatographic alumina transforms structurally diverse secondary alcohols (CCl4 solution, 25 °C, 24 h) into ketones in good yields and some diols into the corresponding keto alcohols.5a,44 The readily available b-hydroxy sulfides and selenides are chemoselectively oxidized to b-keto sulfides and selenides.45 The method generally seems to be tolerant of a number of potentially sensitive functional groups, and product isolation simply involves filtration and evaporation. Aldehydes and ketones are also prepared in an Oppenauer oxidation of halomagnesium alkoxides using chloral as the hydride acceptor.5b
Insertion into Metal-C, -N, and -O Bonds.
Although chloral adds simple organometallic compounds (e.g. HC&tbond;C-K+, ArMgX) to form, after hydrolysis, the substituted trichloroethanol,1,2a-e it can be reduced by alkyl Grignard reagents (i.e. hydride transfer) or react at the Cl3C- group with methyl- or phenyllithium.1 The product distribution is often sensitive to reaction conditions and the order of addition of reagents. In the presence of a Lewis acid catalyst (GaCl3, InCl3 or AlCl3) activated RSiMe3 compounds (i.e. R = allyl, aryl, vinyl, ethynyl, or propargyl) add to chloral to give, after hydrolysis, the corresponding a-trichloromethylated carbinols [RCH(OH)CCl3].46 Crotyltributylstannane reacts with chloral at room temperature
without the need for Lewis acid catalysis; the stereoselective substitution reaction occurs with an allylic shift (eq 16).2f,47 Chloral also inserts readily into the metal-O bond of alkoxysilanes, -germanes, and -plumbanes,2g,48 into the Si-N bond of trimethylsilyldimethylamine,49 into the metal-C bond of silyl- and germylketene dimethyl acetals,50 and into the Hg-C and Hg-Si bonds.51
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G. Bryon Gill
University of Nottingham, UK
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