REDUCTION WITH COMPLEX METAL HYDRIDES NORMAN G. GAYLORD Interchemical Corporation, New York, N. Y.
Tm
successful application of inorganic reagents in the preparation of organic or organometallic compounds has been a widespread practice for many years. During the past decade a new clam of inorganic reagents has found extensive acceptance and application by inorganic and organic chemists alike. These reagents, the complex metal hydrides (I), are exemplified by the highly reactive lithium aluminum hydride and magnesium and sodium aluminum hydrides, and the selectively reactive lithium, sodium and potassium borohydrides, and lithium gallium hydride. LITHIUM ALUMINUM HYDRIDE &AH)
Lithium aluminum hydride is an extremely powerful reducing agent. It is indefinitely stable a t room temperature and is soluble in ether-type solvents. Reductions generally can be carried out at room temperature or in refluxing ether without the use of unusual equipment. Under these mild conditions, such as are used with the Grignard reagent, functional groups which are resistant to other methods of reduction have been reduced with LAH. Due to its violent reaction with water and the liberation of hydrogen with compounds containing active hydrogen, it cannot be used for reductions in aqueous media. However, it reacts readily and often quantitatively with substances soluble in ether-type solvents such as diethyl ether, di-nbutyl ether, dioxane, and tetrahydrofuran. Suhstances which are insoluble in these solvents but are soluble in benzene, petroleum ether, pyridine or N-ethylmorpholine can be reduced by adding the appropriate solution t,o an ether solution of the hydride. Substances which are difficultly soluble in ethereal solvents can be reduced readily by an extraction technique, i.e., the substance to be reduced is placed in the thimble of a Soxhlet extractor above a flask containing a refluxing et,hereal solution of LAH. I n reductions involving LAH the side reactions such as polymerization, condensation, and cleavage, often encountered with other reducing agents, are generally avoided, alt,hough they have been known to occur in isolated instances. The reactions are rapid and almost quantitative in most cases and yield very pure products due to the absence of side reactions. The reartion of a functional group with LAH results in the formation of an intermediate complex which is hydrolyzed to liberate the reduction product. The hydrolysis generally is carried out with water, acid, base, ethanol, ethyl acetate, etc., in order to decompose the complex and consume unreacted hydride.
LAH AS AN ANALYTICAL REAGENT
The quantitative nature of the reaction of LAH with various types of organic compounds and the similarity of the behavior of the reagent to that of the Grignard reagent has led to the development of analytical methods, similar to the Zerewitinoff procedure, for the utilization of LAH in the quantitative determination of active hydrogen and reducible groups in organic compounds. LAH is far superior to the Grignard reagent in the determination of active hydrogen, reactions with the former proceeding more vigorously and rapidly at a lower temperature, and further toward completion with fewer side reactions and steric influences. Compounds exhibiting keto-en01 tautomerism react with LAH as though they were partially enolized since rapidity of the reaction with the keto form prevents complete enolization. In contrast, the Grignard reagent indicates the existence of such compounds mostly in the enol form. The two most widely known ketoen01 tautomers show this behavior. 7-E n d
%
LAH 50-70
Ethyl aoetoaoetate Diethyl malonate
50-60
c' /o
Grignard reaeent 90-100 100
The reaction of LAH with an aromatic nitro compound a t room temperature results in the formation of an azo compound and the immediate appearance of the azo color. This has been developed into a color test applicable to the detection of aromatic nitro, nitroso, azoxy, and hydrazo compounds. REACTIONS OF LITHIUM ALUMINUM HYDRIDE
LAH reacts vigorously with water with the evolution of hydrogen: LiAlH.
+ 4H20
-
4Hz
+ LiOH + AI(OH)$
This reaction is used as a basis for the analysis of LAH as well as for water analysis. LAH reacts with ammonia and hydrogen cyanide to yield hydrogen and complex salts. Reaction with diborane yields a mixture of lithium and aluminum borohydrides. The reaction of hydrazoic acid with LAH in anhydrous ether yields the azide LiAI(N& which is stable at room temperature but explosive on shock. The reaction of LAH with carbon dioxide can follow three courses, each of which represents a definite degree of reduction, to yield methanol, formaldehyde
or formic acid. The product obtained is determined by the ratio of carbon dioxide to LAH:
+ 3LiAIH, ZCO, + LiAlH,
4CO2
4.20,
+ LiAlH4
-
-
H>0
LiAl(OCH& LiAI(0CH.).
CHIOH
Hz0
--. HCHO H10
LiA1(OCH8)4dIICOOH
This method has been applied to the preparation of labeled methanol containing C'3 or C14 as well as formaldehyde-C14, by the use of labeled carbon dioxide. The use of lithium aluminum deuteride permits the preparation of CD30H. Methanol is also prepared by the reaction of LAH with carbon monoxide or phosgene. The reaction of inorganic halides with LAH in ether solution yields complex hydrides, Me(AIH&: MeCI,
+ n LiAIH4
-
+ LiA1H4
1~'iinctionolgroup
-
Primary alcohol Seoondary alcohol Hydroquinone Primary alcohol Primary alcohol Primary alcohol Primary alcohols Did Alcohol Aretal Alcohol Alcohol Alcohol
Imide Carhamate Nitrile Isoeyanide Oxime I~ocyanate Nitrogen oxide C-Nitro80 compound Nitrosamine Nitro, alk,yl Nitro, aryl Hvdroxvlrtmine
Primwy amine Secondary amine Tertiary amine or aldehyde Cyrlir amine C\rrlie smine Amine alcohol Primary amine or aldehyde Secondary amine Amine Secondary amine Amine Amine Hydraeine Primary amine Aeo compound Amine Aso comnound Amine Amine
+ n LiCl
BeH,
+ LiAIHGH,
REDUCTION OF ORGANIC COMPOUNDS BY LITHIUM ALUMINUM HYDRIDE
The greatest interest in the complex metal hydrides in general and in LAH in particular has been in the reduction of organic compounds. Successful reductions have been carried out when other methods have had indifferent or no success. Although in most cases the reactions proceed without complication, in a limited number of compounds the nature of the reduction product is a function of the quantity of LAH utilized and the reaction conditions. In other compounds, groups which are generally resistant to reduction are attacked under drastic conditions. The types of functional groups which are reduced under normal conditions are summarized in Table 1. GENERAL MECHANISMS OF LITHIUM ALUMINUM HYDRIDE REACTIONS
It has been postulated that an ethereal solution of LAH consists of lithium cations and aluminohydride anions (A1H4-). Infrared and Raman spectra of an ethereal solution have indicated a tetrahedral model for the aluminohydride ion in solution. The presence of ions has been proved by measurements of the specific conductance. Trevoy and Brown have observed that most LAH
Produrl
OXYGEN-CONTAININQ GROUPS Aldehyde Ketone Quinone Carbaxylie acid Acid anhydride Acyl halide Ester Lactone Epoxide Orthoester Hydroperoxide Peroxide Osonide
Me(AlH&),
In many cases these complex hydrides are unstable a t ordinary temperature and decompose to form simple hydrides. Salts of the following elements have been used in this reaction: copper, silver, gold, beryllium, magnesium, zinc, cadmium, mercury, boron, aluminum, gallium, indium, thallium, silicon, titanium, zirronium, germanium, tin, phosphorus, arsenic, antimony, and uranium. As in the reduction of inorganic halides with LAH, alkyl or aryl derivatives of such halides are reduced to the corresponding hydrides. I n this connection, organohalo derivatives of silicon, germanium, antimony, tin, arsenic, boron, lead, and magnesium are reduced to the corresponding substituted hydrides. The reaction between LAH and metal alkyls has been utilized in the preparation of hitherto unknown or difficultly accessible hydrides. (CH&Be
TABLE 1 Functional Groups Reduced by Lithium Aluminum Hvdride
+
Diazo compound Quaternary salts Cvclic o-Dihydroamine Akyclic Amine SULFZTR-CONTAINING GROTIPS Dithiol Mercaptan Disulfide Mercaptan Trisnlfide Mercsptan Tetrasulfide hlercaptan Epiaulfide Mereaptan Sulfoxide Sulfide R,llfirl0 Sulfone .....Sulionic anhydride Sulfinie acid or mercaptan Sulionvl halide Mercaptan Sulfonic ester Alkyl Hydrocarbon Phenol Aryl Sulfinlc acid Disulfide mercaptan Sulienyl halide Disulfide Thiaeitm Alcohol Thioamide Amine nitrile Thioevanate Merca~tan
+
+
HALOGEN-CONTAINING GROUPS Alkyl halide Alkane
reductions involve the displacement of a strongly electronegative atom, such as oxygen, nitrogen or halogen, by hydrogen, the reaction probably involving initially an attack by the aluminohydride ion on carbon. A himolecular nucleophilic displacement proceeding by an SW2mechanism in ~vhichhydrogen is transferred as hydride to the center of low electron density, i.e., the carbon atom, has been postulated. The exact nature of the attacking anion is a matter of speculation. Trevoy and Brown have postulated that the reactant is actually a series of complex aluminohydride ions AIHr,R, which act as carriers for the hydride ion, where n progresses from 0 to 4 during the course of the reaction. Paddock has argued that this mechanism ignores the solvent, and has proposed that there is an equilibJOURNAL OF CHEMICAL EDUCATION
rium in solution: AM-
= H- + AIHs
The function of the ether is to coordinate with the aluminum hydride and drive the equilibrium to the right. This implies that the active entity is the Hion rather than the A M - ion. The ether, analogous to Grignard reactions, acts as a donor solvent. The reactions of LAH with various functional groups are in many ways analogous to the reaction of the Grignard reagent. Differences in the nature and extent of the reactions are due to the greater reactivity of the hydride and the influence of steric factors. The hydride and the Grignard reagent both respond to the Gilman-Schulze color test. This test, involving reaction with Michler's ketone, is characteristic for compounds having carbon-metal bonds. The test has been used for determining the stoichiometry of LAH reductions. SPECIFIC REDUCTIONS BY LAH The great number of functional groups reduced by LAH, as shown in Table 1, represent a broad arena of reactivity. However, certain reactions are worthy of individual mention. LAH reductions are generally carried out by one of two methods: (a) "direct" or normal addition, and (b) "inverse" addition. The direct addition method involves the addition of a solution of the compound to be reduced to a solution of LAH. The inverse addition method involves the addition of the LAH solution t o the organic compound. I n the first method an excess of LAH is present during the reaction while in the second method, generally carried out with a calculated amount of LAH and a t low temperatures, the compound to be reduced is in excess. The inverse procedure permits a reaction to be carried to an intermediate point with resultant partial reduction. Thus, since the reduction of nitriles passes through an imine intermediate, a primary amine or an aldehyde can be obtained by the appropriate technique:
1
1 LAH
I
While the normal reductiou of lactones yields glycols, the inverse addition of one-quarter mole of LAH a t 30°C. yields hydroxyaldehydes (3): R2C(CHs).CHxOH
Similarly, the partial reduction of lactams yields aminoaldehydes while normal reduction yields cyclic amines:
I
direct
I
inverse
The reduction of halides with LAH generally proceeds with difficulty. Aromatic halides either are not reduced or are reduced only under drastic conditions. Alkyl halides are reduced mith LAH at elevated temperatures. Therefore a compound coutaining a halogen atom and a reducible functional group can be treated with LAH to yield a product which still retains the halogen. The LAH reduction of sulfonic esters usually proceeds by one of two reaction paths to yield either hydrocarbons or phenols: R0SO1R' ArOS02R'
LAH LAH
4
+ HOSOnR' ArOH + HOSOR' RH
The LAH reduction of alkyl tosylates generally yields hydrocarbons while aryl sulfonic esters are reduced to phenols. The LAH reduction of sugar tosylates yields alcohols. Ethers are generally resistant to attack by LAH. The nonreduction of acetals and ketals mith LAH has been utilized for the protection of carbouyl groups during LAH reductions. The OCO group in other structures as well as in acetals and ketals is resistant to attack with LAH. Similarly, the OCS group, as in hemithioketals, is resistant to attack. However, the NCO group and the NCS group are generally rleaved by LAH between the carbou-oxygen and carbonsulfur bonds, respectively. An isolated double bond is generally resistant to attack by LAH. Thus crotonaldehyde is reduced to crotyl alcohol:
I
I
The presence of the double bond in a structural grouping containing an aromatic ring a t one end and a polar functional group a t the other, i.e., ArC=C-C=O or ArC=C-N, generally results in saturation of the carbon-carbon double bond under normal reaction conditions. However, inverse addition with the calculated amount of LAH at low temperatures results in retention of the double bond. Thus, cinnamaldehyde is converted to hydrocinnamyl alcohol by direct addition a t room temperature while inverse addition below 10°C. yields cinnamyl alcohol:
direct
EsC-(CHA
OH
I o-Lo
inverse
VOLUME
34,
NO. 8, AUGUST.
1957
\\
inverse O-IOT.
Although the carbon-carbon double bond generally is not attacked by LAH, Ziegler reported that alphaolefins, including ethylene, can be reduced to the corresponding paraffin hydrocarbons by LAH, aluminum hydride and aluminum trialkyls. At high temperatures the aluminum trialkyls catalytically convert ethylene and other olefins into higher paraffins and olefins by polymerization (8). Polyethylene with a higher melting point and density than that obtained by conventional high pressure techniques has been prepared by the low pressure polymerization of ethylene using aluminum alkyls complexed with a metal halide such as titanium tetrachloride. The polymerizations proceed very readily at low pressures (from normal to 30 atm.) and a t low temperatures (from room temperature up t o 60°C.). A synthetic polyisoprene having a nearly all cis 1,4 structure very similar to that of Hevea natural rubber has beeu prepared using the aluminum triethyl-cocatalyst system. Aluminum trietbyl forms a complex with sodium fluoride which is capable of conducting an electric current and permits the preparation of tetraethyl lead, according to the equation: ALUMINUM HYDRIDE
An ethereal solution of aluminum hydride is unstable and the hydride polymerizes spontaneously to a high molecular weight, ether-insoluble, polymerization product, postulated as follows: 3LiAIH,
+ AlCl
--
z Al(AIHA
+
A1(AlH4)~ 3LiCI 4(AIHsL
Monomeric aluminum hydride can be stabilized by the addition of trimethylamine as well as by treatment with an ethereal solution of an aluminum halide. The reaction of aluminum hydride in a 1:1 ratio with aluminum chloride in ether solution yields an ethersoluble addition compound formulated as AIH,.AlCl, or A1HICI.A1HC12,which is isolated as.a colorless distillable liquid. The ethereal solution behaves chemically like a mixture of aluminum chloride and monomeric aluminum hydride and permits the carrying out of more selective reductions than with LAH. Aluminum hydride has been used in the preparation of formic acid from carbon dioxide. Reaction with aluminum iodide and bromide yields the respective mono- and dihaloaluminum hydrides rather than the addition compound obtained with the chloride. Or-
ganic functional groups which have beeu reduced by an ethereal solution of the monomeric hydride include carbonyl, ester, amide and nitrile groups. Various patents involving the reduction of carbonyl and ester groups by LAH have indicated the equivalence of aluminum hydride for these reductions. The stable, ether-soluble addition product with aluminum chloride has been utilized for the reduction of the functional groups summarized in Table 2. While LAN converts aliphatic nitro groups to arniues and aromatic nitro groups to azo compounds, with amines as byproducts, reduction with the addition compound yields amines in both cases, with azo compounds as byproducts from the aromatic nitro derivatives. Alkyl halides, reduced with difficulty with LAH, and aromatic ketones, readily reduced with LAH, are not reduced by the aluminum hydride-aluminum chloride addition compound. TABLE 2 Functional Groups Reduced by the Aluminum HydrideAluminum Chloride Addition Compound Product
Functional group
Aldehyde Ketone, aliphatic Quinone Carboxylic acid Acid chloride Ester Brnide Nitrile Nitro, aliphatic Nitro, aromatic Halide, benzyl
Primary alcohol 8eoondary alcohol Hvdroauinane PFimari alcohol Primary alcohol Primary alcohol Amin, Primary amine Primary amine Primary amine Hydrocarbon
MAGNESIUM ALUMINUM HYDRIDE
The behavior of magnesium aluminum hydride in ether solution is analogous to that of the other aluminohydrides in reducing polar double and triple bonds, e.g., carbonyl and nitrile groups, while nonpolar groups are not attacked. The functional groups which have been subjected to treatment with the magnesium compound are tabulated in Table 3. The carbon-carbon double bond in ciunamic acid and the triple bond in propargyl aldehyde are not reduced by magnesium alun~inun~ hydride, representing a point of difference from the behavior of LAH. TABLE 3 Functional Group. Reduced by Magnesium Aluminum Hvdrlde Functional orom
Product
Aldehyde Ketork Quinone Carboxvlio acid Ester Amide Nitrile
Primary rtlcohol Secondary alcohol Hydroquinone Primarv alcohol ~rimarGslcohol Amine Primary amine
SODIUM ALUMINUM HYDRIDE
Due to the insolubility of sodium aluminum hydride in ether, reductions are generally carried out in tetrahydrofuran solution. The functional groups shown in Table 4 indicate that reductions are similar for the sodium and lithium complex hydrides. In fact, the sodium compound is no milder a reagent JOURNAL OF CHEMICAL EDUCATION
than LAH. Normal reduction of cinnamaldehyde results in saturation of the double bond and, as with LAH, the unsaturated cinnamyl alcohol can be obtained only by the inverse addition of sodium aluminum hydride to the unsaturated aldehyde. Similarly, inverse addition is necessary to reduce benzonitrile t o benzaldehyde rather than the amine (4). TABLE 4 Functional G r o u ~ sReduced bv Sodium Aluminum Hydride
Functional group Aldehyde Ketone Csrboxylic acid Acid chloride Ester Amide Nitrile Nitro, alkyl Nitro, aromatic Halide, alkyl
Pmduel
Primary alcohol Secondarv alcohol Primary &lcohol Primary alcohol Primry alcohol Amine I'rimarv amine or aldehyde Smine ' .4so compound Alkane
SODIUM BOROHYDRIDE
In contrast to the extremely powerful reducing action of the aluminohydrides, especially LAH, the borohydrides have a lower degree of reactivity which in many instances permits selective reductions. Sodium borohydride is a crystalline, salt-like compound with a structure probably consisting of tetrahedral borohydride ions and sodium ions, NafBH4-. Because of its salt-like character the borohydride is insoluble in diethyl ether and soluble in water. Reductions with the borohydride may be carried out in water, methanol, dioxane, tetrahydrofuran, and the dimethyl ethers of diethylene glycol and triethylene glycol. Aqueous systems can be utilized since the borohydride is very soluble in cold water with very little decomposition. Therefore, ether-insoluble compounds such as the sugars can be reduced in aqueous solution where LAH is unsuitable. In cases where hydrolytic side reactions may occur, as in the reduction of acid chlorides, dioxane or other nonhydrolytic solvents are used. In some cases, as in the reduction of sugars, the formation of horon-containing complexes makes the work-up and isolation of reduction products difficult. This may be overcome by acetylation of reduction products and/or passage through ion exchange columns. Although only a very small amount of hydrogen is liberated by the hydrolysis of sodium borohydride a t ordinary temperatures, rapid hydrolysis occurs at higher temperatures to liberate 2.37 liters of hydrogen (gas at S.T.P.) per gram of borohydride: NaBH,
+ 2Hs0
-
4H2
+ N~BOI
The addition of acid to the stable cold aqueous solution liberates the theoretical amonlit of hydrogen. This may be used as the basis for the analysis of the borohydride by hydrolysis with dilute hydrochloric acid. Dissolving the borohydride in a slightly basic solution prevents the initial generation of hydrogen and permits the use of the reagent as a reducing agent in aqueous solution. Where the generation of hydrogen is desired, a rapid and controlled reaction is obtained by the use of pellets containing sodium borohydride and various
VOLUME 34, NO. 8, AUGUST, 1957
accelerators. Acidic compounds such as boric oxide, oxalic acid, aluminum chloride and phosphorus pentoxide, and metal salts such as cobaltous, nickelous, ferrous and cuprous chlorides are effective catalytic accelerators. The reaction of various inorganic halides with sodium borohydride yields the corresponding metal borohydrides by metathetical reactions:
The borohydrides are in many cases unstable at ordinary temperatures and are, therefore, prepared a t low temperatures. Although this reaction is more generally utilized with lithium borohydride, as discussed in a later section, sodium borohydride has been utilized in the synthesis of beryllium, aluminum, lithium, potassium and calcium borohydrides. Sodium borohydride reacts quantitatively with boron trifluoride etherate to liberate diborane:
In aqueous solution, sodium borohydride is a powerful reducing agent. I t reacts with certain metal ions in four different ways (1, 5, 6): (a) reduction to the next lower stable, hut soluble, valence state, e.g., cerium(IV), chromium(VI), thallium(III), mercury(11), vanadium(V) and iron(II1); (b) reduction to the free metal with precipitation, e.g., silver, bismuth, arsenic, antimony, lead and selenium; (c) precipitation of a metal boride, e.g., nickel(II), cobalt(II), manganese(II), iron(I1) and copper(I1); (d) formation of a volatile hydride, e.g., tin, arsenic and bismuth. In the analysis of iron, sodium borohydride has been used t o replace stannous chloride in the Jones reductor. By this method iron may be determined in the presence of chromium, manganese and nickel, without the tedious separation required by the usual procedure. The boride precipitates have been prepared and isolated for use as hydrogenation catalysts. They are also effective catalysts for the generation of hydrogen from an aqueous solution of sodium borohydride. The catalytic action is highest in the case of the cobalt product, somewhat less for nickel, and least for iron, manganese and copper. REDUCTION OF ORGANIC COMPOUNDS BY SODIUM BOROHYDRIDE
As with LAH, the principal interest in sodium borohydride is in its usefulness as a reducing agent for organic compounds. Sterically hindered compounds containing certain functional groups are easily reduced with the horohydride. Side reactions are generally avoided and reduction products are obtained in good yields. A considerably smaller number of functional groups is reduced with sodium borohydride than with the aluminohydride. This lower reactivity is advantageous in permitting the selective reduction of groups such as the carbonyl or acid chloride groups in the presence of functional groups which would be reduced with the aluminohydride but which are not attacked by the horohydride. The reduction behavior of sodium borohydride under normal reaction conditions is summarized in Table 5. While esters are normally
not reduced, the borohydride has been utilized in the reduction of various uronates and steroid esters. TABLE 5 Reductions with Sodium Borohvdride FUNCTIONAL GROUPSREDUCED Aldehyde
Primary alcohol Secondarv alcohol Acid chloride Primary hleohol Dialeohol Lactone Alcohol Hydroperoxide o-Dihydro derivative Quaternary ammonium salt Meredan Sulfoxide FUNCTIONAL GROUPSNORMALLY NOTREDUCED' Carboxylie acid; anhydride; ester; amine; imide; aoetal; nitrile; nitro, aromatic; halide; double bond. Knt,one
Sodium borohydride has been utilized as an analytical reagent in the determination of organic functional groups in aqueous solution. Various aldoses and ketoses are analyzed by this method. I t has recently been reported that the addition of certain metal halides to a solution of sodium borohydride in tetrahydrofuran or the dimethyl ethers of diethylene and triethylene glycol results in the facile reduction of organic functional groups not normally reduced by the borohydride alone (7). Among the halides ntilized in this connection are aluminum chloride, lithium bromide and chloride, and calcium iodide and chloride. It is possible that the true reducing agents in these cases are aluminum, lithium and calrium horohydrides, respectively: AICh
+ 3NaBH'
-
AI(BHds
+ 3NaCI
However, sodium chloride is insoluble in the solvents used and the failure to observe a precipitate in the preparat.ion of the reagent indicates that this simple explanation is not adequate. Functional groups which have been reduced with sodium borohydride in the presence of various metal halides are summarized in Table 6. POTASSIUM BOROHYDRIDE
Potassium borohydride is a white cryst,alline material which is nonhygroscopic and stable in moist and dry air. The borohydride is soluble in cold water
without decomposition. Aqueous solutions are stabilized up to 100°C. by the addition of a small amount of base. Heating the aqueous solution to this temperature results in the liberation of hydrogen. Potassium borohydride can be used in the synthesis of other borohydrides by reaction with various inorganic halides, e.g., aluminum borohydride by reaction with aluminum chloride or bromide. The reaction with boron trifluoride in ether is suitable for the preparation of diborane. Reductions of organic compounds can be carried out in aqueous or alcoholic solution. The behavior of potassium borohydride under normal reaction conditions is summarized in Table 7. TABLE 7 Reductions with Potassium Borohyd~ide Functional g ~ o u p
Product
FUNCTIONAL GROUPSREDUCED Aldehyde Ketone Acid chloride Quaternary ammonium salt
Primary alcohol Secondary alcohol Primary alcohol o-Dihydro ar tetrahydro derivative ~ U N C T I O N A LGROUPS NORMALLY NOT REDUCED Csrboxylio acid; ester; amide; imide; aeetal; nitro, aromatic; hzlidn.
Although esters are generally resistant to reduction with potassium borohydride, reduction can be successfully carried out with an equimolar mixture of potassium borohydride and lit,hium chloride in tetrahydrofuran. LITHIUM BOROHYDRIDE
Lithium borohydride is a crystalline salt-like compound containing tetrahedral borohydride ions. I t is quite hygroscopic and may occasionally ignite on contact with water. A coating of white oxide will form on all surfaces within a few minutes after initial exposure to air. Contact with cellulosic material, e.g., paper, cloth, etc., is reported to result in spontaneous combustion within two minutes. Although powdered lithium borohydride may ignite when moistened, it can be dissolved in ice water with only slow decomposition. Hydrolysis is accelerated
TABLE 6 Reductions with Sodium Borohydride end Metal Halides Functional gmap
6
372
Produet
Aldehyde*
Primary slcohol
Ketones
Secondary alcohol
Epoxide Cerboxylio acid Ester
Alcohol Primary alcohol Primary alcohol
Lsctone Anhydride Acid chloridea
Glycol Primary alcohol Primary alcohol
Nitrile Halide, henzyl Disulfide 1-Olefin
Primary amine Hydrocarbon Mercctptan Organohorme
Soluent' DEDEG THF DEDEG THF DEIIEG DEDEG DEDEG THF 1)ioxane DEDEG DEDEG DEDEG THF DEDEG DEDEG DEDEG DEDEG
Halide LiBr, AlCL LiBr LiRr, AICb LiBr AlCl, LiBr, AICb LiBr, AICb LiBr, L E I , C ~ ' S
GILL
AlCL AICls LiBr, AICb LiBr, CaIn AlCL AICls AlCL AICL
Reducible with sodium borohydride in absence of metal halid~s. Solvent: DEDEG = dimethyl ether of diethylene glycol; T H F = tetrahydrofuran.
JOURNAL OF CHEMICAL EDUCATION
by the presence of acid or cobaltous ion. One gram of horohydride liberates more than four liters of hydrogen (gas at S.T.P.) by this reaction. Actually, when lithium borohydride is dissolved in water, only a portion of the available hydrogen is liberated and the solution becomes strongly basic. The reaction between lithium borohydride and carbon dioxide is similar to that of LAH and yields formic acid and methanol: JH,O 3LiBHd
+ 4C02
-
HCOOH I,iB(OCHs)n
+ 2LiBOz
The reaction of inorganic halides with lithium horohydride yields the corresponding borohydrides. Cuprous, beryllium, zinc, cadmium, aluminum and titanium (111) borohydrides have been prepared by this method : MeCI,
+ n LiBH,
-
Me(BH,),
+ n LiCl
Silver borohydride, which decomposes at -30°C., is prepared by the reaction of lithium borohydride with silver perchlorate a t -80°C. Diborane may be prepared by the reaction of lithium horohydride and boron trifluoride etherate. REDUCTION OF ORGANIC COMPOUNDS BY LITHIUM BOROHYDRIDE
Lithium borohydride is a more powerful reducing agent than sodium borohydride, but is milder than LAH. The reagent is soluble in diethyl ether although most of the reported reductions have been carried out in tetrahydrofuran. The difference between reducible and nonreducible groups is not always clearly defined; usually reducibility is a function of compound stmcture and/or reaction conditions. Whereas carbonyl derivatives are generally reduced rapidly at room temperature, esters react slowly and require refluxing conditions. Thus, selective reduct,ion of a keto-ester to a hydroxy-ester can he accomplished a t low temperatures. On the other hand, carboxylic acid and aromatic nitro groups, generally resistant to attack, are partially reduced on prolonged refluxing. The reduction behavior of lithium borohydride under normal reaction conditions is summarized in Table 8. A mixture of lithium hydride and lithium boroTABLE 8 Reduction. with Lithium Bomhvdride F~NCTIONAL GROUPS REDUCED Aldehyde Primary aloohol Ketone Secondarv aleahal Ester Primary &oh01 Acid chloride Primary alcohol OF INTERMEDIATE REDUCIBILITY FUNCTIONAL GROUPS Acid, aliphatic Primary alcohol Nitro, aromatic Amine and azo derivatives FUNCTIONAL GROUPSNORMALLY NOTREDUCED Acid, aromatic; amide; scetd; nitrile; halide. VOLUME 34, NO. 8, AUGUST, 1957
hydride has been used in the hydrogenolysis of halides and tosylates without reducing nitro, amide, nitrile, irnine, and acetal groups. Reduction with the borohydride in tetrahydrofuran has been used to determine the structural units of the insulin molecule. OTHER BOROHYDRIDES
Calcium borohydride reportedly has a higher reducing activity than the borohydrides of sodium, potassium, and lithium. In addition to the facile reduction of aldehydes and ketones to the corresponding alcohols, aliphatic and aromatic carboxylic esters are reduced in good yield to the primary alcohols. ltedurtions can be carried out in tetrahydrofuran as well as in alcoholic solution. At low temperatures 50% aqueous ethanol can be used for the reduction of reactive esters. The anhydride group in azlartones is susceptible to reduction. The solutions formed by the metathesis of sodium borohydride and calcium chloride or iodide are suitable for the reduction without isolation and purification of the calcium borohydride (8). Calcium horohydride offers the advantage of allowing the use of hydroxylic solvents without danger of explosion and ignition and, while suitable for the reduction of esters, one of the most important functions of LAH, permits greater selectivity than the latter. Aluminum borohydride is an extremely hazardous covalent liquid, igniting spontaneously on exposure to moist air and reacting explosively with water. A though the borohydride is required for the preparation of the borohydrides of heavy metals, e.g., uranium, thorium, hafnium, zirconium, and titanium, its hazardous nature precludes any widespread application. It has been reported that both orthoesters and acetals are reduced to ethers, and halogen is removed from polyhalomethanes by aluminum borohydride. SODIUM TRIMETHOXYBOROHYDRIDE
Sodium trimethoxyborohydride is a white solid whirh is stable in dry air and is only slowly attacked by air of average humidity. After the initial vigorous reaction on solution in cold water, additional hydrogen is generated only slowly. Water can therefore be used as a solvent for the reaction between aqueous solutions of various metal ions and sodium trimethoxyborohydride. Silver nitrate, arsenious oxide, bismuth nitrate, and antimony trichloride are reduced to the free metal. Mercuric chloride is reduced to a mixture of mercurous chloride and free mercury. Lead nitrate and zinc nitrate are converted to the insoluble hydroxides. Nickel, cobalt, and ferrous salts yield precipitates which are probably horides. Copper sulfate solutions give dark brown precipitates which do not contain boron and do not evolve hydrogen. Bromine in carbon tetrachloride is immediately decolorized while ferricyanide ion is reduced to ferrocyanide ion. Potassium permanganate, ceric sulfate, and hydrogen peroxide solutions are also reduced by the trimethoxyborohydride. The trimethoxyborohydride reacts with dihorane to yield sodium borohydride. Reaction with carbon dioxide leads to the formation of sodium formate and methyl borate. Boron trifluoride is rapidly absorbed a t room temperature to liberate methyl borate while
the use of boron trifluoride etherate results in the rapid evolution of diborane. As a reducing agent for organic compounds, the trimethoxyborohydride is intermediate in behavior between sodium borohydride and the more powerful lithium borohydride. Aldehydes and ketones are generally reduced to the corresponding alcohols while cyclic quaternary ammonium salts are reduced t,o o-dihydro derivatives. LITHIUM GALLIUM HYDRIDE
The solubilities and reaction characteristics of lithium gallium hydride bear a close analogy to those of the alurninohydrides. Lithium gallium hydride reacts with inorganic halides to yield complex gallium hydrides: MeCI,
+ n LiGaH,
-
Me(GaH4).
+ n LiCl
Thallium gallium hydride is prepared in this manner from thallic chloride. Silver gallium hydride is prepared from silver perchlorate rather than the halide. The reaction of lithium gallium hydride and gallium chloride in ether solution at O°C. yields soluble gallium hydride which precipitates in a few days as the polymeric gallium hydride. Lithium gallium hydride in ether solution is a milder reducing agent than LAH. The reduction behavior, only briefly investigated t o date, is summarized in Table 9.
TABLE 9 Reductions with Lithium Gallium Hydride Product
Funelional orouv
FUNCTIONAL CROUPSREDVCED Aldehyde, aliphatic Primary alcohol Ketone, aliphatic Secondary alcohol Hydroquinone Qu@I, Acid, ahphstic Primary alcohol Amide Amine Nitrile, aliphatic Ptimsry amine NOT REDUCED FUNCTIONAL GROUPSNORMALLY Aldehyde, aromatic: ketone, aromatic; ester; nitrile, aromatic LITERATURE CITED (1) GAYLORD, N. G., "Reduction with Complex Metal Hydrides," Interscience Publishers, Inc., New York, 1956. (2) ARTH,G. A., J. Am. Chem. Soe., 75, 2413 (1953). K., Angm. Chm., 64, 323 (1952). (3) ZIEGLER, (4) FINHOLT,A. E., E. C. JACOBSON, A. E. OQARD,AND P. J. Am. Chem. Sac., 77, 4163 (1955). THOMPSON, INC.,Technical Bulletin 502-F, "Sodium (5) METALHYDRIDES, Borohydride," 1955.
(6) SCHAEFFER, C. W., Papel. 57, Division of Physical and Inorganic Chemistry, 127th Meeting American Chemical Society, Cincinnati, April, 1955. (7) BROWN,H. C., AND B. C. SUBBARAO,J. Am. Cham. Soc., 78. 2582 (1956).
(8) KOLLONITSCH, J., 0 . FUCHS,A N D V. GABOR,Nature, 173, 125 (1954); 175,346 (1955).
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