SYNTHESIS OF SYNTHESIS OF ACID CHLORIDES

ACID CHLORIDE SYNTHESIS R-OH + SOCl 2 R-Cl + SO 2 + HCl  benzene THIONYL CHLORIDE + SOCl 2 + SO 2 + HCl  benzene The -OH group of an acid reacts the same way. Chapter 12, Section 12.4, pp to RLi + CO 2 RECALL THIONYL CHLORIDE: Recall how to make an acid? alcoholalkyl chloride acid chloride

REDUCTIONS OF REDUCTIONS OF ACID CHLORIDES

Acid Chloride LiAlH 4 + LiCl + AlCl 3 LiAlH 4 with Acid Chlorides two hydrides react ACID CHLORIDES REACT TWICE cleaves

CR O H Cl AlH 3.. :: - bond is highly polar - not strong The tetrahedral intermediate collapses easily, because the bond to Al is not strong. COLLAPSE OF THE INTERMEDIATE reacts again Cl - is lost FIRST ADDITION SECOND ADDITION

.. :: workup reaction doesn’t stop here aldehyde TWO HYDRIDES REACT tetrahedral intermediate collapses LiAlH 4 Reduction of an Acid Chloride + Li + Cl - leaving group -

REDUCTIONS OF ESTERS ….. ESTERS ALSO REACT TWICE

Ester LiAlH 4 + two alcohols cleaves LiAlH 4 with Esters two hydrides react ESTERS REACT TWICE

LiAlH 4 Reduction of an Ester TWO HYDRIDES REACT :: +R’O - :: workup reaction doesn’t stop here R’-OH two alcohols aldehyde leaving group workup + tetrahedral intermediate collapses

ROSENMUND REDUCTION Converts Acid Chlorides to Aldehydes

Acid Chloride Aldehyde Alcohol X one stage of reduction This reaction allows you to stop the reduction at the aldehyde stage and not continue to the alcohol (which would be the result with LiAlH 4 ). stops here This is an older method. Yields are not always adequate, but it is sometimes a useful method. second step does not occur

Rosenmund Reduction Rosenmund catalyst Ordinary catalysts would continue and reduce the aldehyde. SOCl 2. H H H H...

DIBAL-H A Newer Method …...

DIISOBUTYL ALUMINUM HYDRIDE ( DIBAL-H ) ( iBuOH ) isobutyl alcohol DIBAL-H less active than LiAlH 4 Remember: H: - + H-O-R H-H + :O-R.. - strong base two moles takes the place of hydride gas SYNTHESIS

Reduction of Esters to Aldehydes At 20 o C, LiAlH 4 will reduce the aldehyde, DIBAL-H stops at the aldehyde at the lower temperature. esters Sometimes LiAlH 4 will also stop at the aldehyde if the temperature is below -60 o C. DIBAL-H is more consistent o C toluene DIBALH is soluble in hydrocarbon solvents because of the isobutyl groups; ethers must be used for LAH. RCOOH some carboxylic acids may be reduced NOTE

DIBAL-H ALSO REDUCES ACID CHLORIDES TO ALDEHYDES DIBAL-H This method gives better yields than the Rosenmund reduction. Apparently the tetrahedral intermediate does not collapse at -70 o C (expel the leaving group). This doesn’t happen until you warm the solution and add aqueous acid which destroys the DIBAL-H. + - does not react again -70 o ether stable at -70 o

CR O Cl H Al H Li + - H3O+H3O+ CR O Cl H H CR O H HYDROLYSIS OF THE INTERMEDIATE :.. Aqueous acid breaks the complex apart. + LiCl

DIBALH ALSO REDUCES ALDEHYDES AND KETONES The main feature of DIBALH is that it reacts only ONCE to form a stable tetrahedral complex. Since the complex doesn’t fall apart until workup, a second reduction is avoided. Aldehydes and ketones only need one hydride to be fully reduced …... therefore, DIBAL-H reduces aldehydes and ketones. With esters, acid chlorides and acids, more than one hydride is required. Since DIBAL-H reacts only once, they are not fully reduced, stopping at the aldehyde.

ORGANOMETALLIC COMPOUNDS ORGANOMETALLIC COMPOUNDS WITH ESTERS AND ACID CHLORIDES WITH ESTERS AND ACID CHLORIDES

R’Li ether R’Li ether + Acid Chloride Ester RLi with Esters and Acid Chlorides two alcohols cleaves ( also RMgX ) REACT TWICE two RLi react

RMgX with Esters and Acid Chlorides Reacts Twice ! ketone :: ::.. doesn’t stop here + R’O - - R’-OH ( also R-Li ) Tetrahedral complex not stable - weak O-Mg bond. DECOMPOSES

.. :: - bond is highly polar - not strong The tetrahedral intermediate collapses easily, because the bond to Li + is not strong. The leaving group RO - is expelled. COLLAPSE OF THE INTERMEDIATE DECOMPOSES & REACTS AGAIN The complexes formed from Grignard reagents react in the same way. The bond to Mg is not strong. breaks down and yields a ketone which reacts again

ORGANOCADMIUM REAGENTS

Ketone Synthesis Ketone Synthesis Organocadmium Reagents Less active than RLi or RMgX organocadmium compound R 2 Cd reacts once

:.. reacts once :O-CH STOPS HERE ORGANOCADMIUM REAGENTS ORGANOCADMIUM REAGENTS DO NOT REACT TWICE WITH ESTERS ketone H3O+H3O+ Cd-R workup HO-CH 3 + Acid chlorides also react this way.

Apparently the tetrahedral intermediate does not collapse (expel the leaving group) during the reaction. It only breaks down on hydrolysis, and then the leaving group is expelled. - The bond has more covalent character than a bond to Li or Mg - it is stronger. STABLE TETRAHEDRAL COMPLEX The complex is stable and does not break down and react again.

CR O OR R Cd H3O+H3O+ CR O OR R H CR O R HYDROLYSIS OF THE INTERMEDIATE :.. Aqueous acid breaks the complex apart. + LiCl R Ketone is isolated.

LITHIUM DIALKYL CUPRATES

Ketone Synthesis Lithium Dialkylcuprates Ketone Synthesis Lithium Dialkylcuprates Less active than RLi or RMgX ketone

SUMMARY

MANTRA Aldehydes react with one mole of reducing agent to give a Primary Alcohol Ketones react with one mole of reducing agent to give a Secondary Alcohol Acid Chlorides react with two moles of reducing agent to give a Primary Alcohol Esters react with two moles of reducing agent to give a Primary Alcohol + a second alcohol

BIOLOGICAL BIOLOGICAL REDUCING REAGENTS

Nicotinamide Adenine Dinucleotide NADH adenine ribose nicotinamide diphosphate.. : : COENZYME biological works with an enzyme

Reduction of Acetaldehyde in Fermentation in Fermentation.. This “coenzyme” can also oxidize depending on the associated enzyme. REVERSIBLE hydride transfer RED OX ethanol acetaldehyde

Reduction of Pyruvic Acid in Muscle Tissue in Muscle Tissue.. lactic acid formed when muscles contract pyruvic acid