SYNTHESIS OF ACID CHLORIDES

1. SYNTHESIS OF ACID CHLORIDES

2. benzene R-OH + SOCl2 R-Cl + SO2 + HCl D benzene + SOCl2 + SO2 + HCl D ACID CHLORIDE SYNTHESIS THIONYL CHLORIDE RECALL THIONYL CHLORIDE: Chapter 12, Section 12.4, pp. 12-24 to 12-27. alcohol alkyl chloride The -OH group of an acid reacts the same way. acid acid chloride RLi + CO2 Recall how to make an acid?

3. REDUCTIONS OF ACID CHLORIDES

4. LiAlH4 with Acid Chlorides ACID CHLORIDES REACT TWICE two hydrides react Acid Chloride LiAlH4 + LiCl + AlCl3 cleaves

5. The tetrahedral intermediate collapses easily, because the bond to Al is not strong. COLLAPSE OF THE INTERMEDIATE bond is highly polar - not strong AlH3 .. - FIRST ADDITION O : : Cl- is lost R C H Cl SECOND ADDITION reacts again

6. reaction doesn’t stop here LiAlH4 Reduction of an Acid Chloride + - .. .. : : tetrahedral intermediate collapses + - leaving group + Li+ Cl- workup aldehyde TWO HYDRIDES REACT

7. REDUCTIONS OF ESTERS ….. ESTERS ALSO REACT TWICE

8. LiAlH4 with Esters ESTERS REACT TWICE two hydrides react Ester LiAlH4 + two alcohols cleaves

9. reaction doesn’t stop here LiAlH4 Reduction of an Ester + - .. : : tetrahedral intermediate collapses + - .. : : - leaving group + R’O workup aldehyde + TWO HYDRIDES REACT two alcohols R’-OH workup

10. ROSENMUND REDUCTION Converts Acid Chlorides to Aldehydes

11. This reaction allows you to stop the reduction at the aldehyde stage and not continue to the alcohol (which would be the result with LiAlH4). stops here Acid Chloride Aldehyde one stage of reduction X Alcohol second step does not occur This is an older method. Yields are not always adequate, but it is sometimes a useful method.

12. . . . H H H . H Rosenmund Reduction Ordinary catalysts would continue and reduce the aldehyde. SOCl2 Rosenmund catalyst

13. DIBAL-H A Newer Method …...

14. DIISOBUTYL ALUMINUM HYDRIDE ( DIBAL-H ) SYNTHESIS two moles ( iBuOH ) DIBAL-H isobutyl alcohol less active than LiAlH4 gas Remember: - .. H:- + H-O-R H-H + :O-R .. strong base takes the place of hydride

15. Reduction of Esters to Aldehydes DIBALH is soluble in hydrocarbon solvents because of the isobutyl groups; ethers must be used for LAH. At 20o C, LiAlH4 will reduce the aldehyde, DIBAL-H stops at the aldehyde at the lower temperature. toluene - 70o C esters some carboxylic acids may be reduced RCOOH NOTE Sometimes LiAlH4 will also stop at the aldehyde if the temperature is below -60o C. DIBAL-H is more consistent.

16. DIBAL-H ALSO REDUCES ACID CHLORIDES TO ALDEHYDES DIBAL-H -70o ether This method gives better yields than the Rosenmund reduction. stable at -70o Apparently the tetrahedral intermediate does not collapse at -70o 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

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

18. 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.

19. ORGANOMETALLIC COMPOUNDS WITH ESTERS AND ACID CHLORIDES

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

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

22. COLLAPSE OF THE INTERMEDIATE bond is highly polar - not strong DECOMPOSES & REACTS AGAIN .. - The tetrahedral intermediate collapses easily, because the bond to Li+ is not strong. : : The leaving group RO- is expelled. 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

23. ORGANOCADMIUM REAGENTS

24. Ketone Synthesis Organocadmium Reagents organocadmium compound R2Cd Less active than RLi or RMgX reacts once

25. STOPS HERE ORGANOCADMIUM REAGENTS DO NOT REACT TWICE WITH ESTERS .. Cd-R reacts once : workup H3O+ - :O-CH3 .. ketone + HO-CH3 Acid chlorides also react this way.

26. STABLE TETRAHEDRAL COMPLEX The bond has more covalent character than a bond to Li or Mg - it is stronger. - 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 complex is stable and does not break down and react again.

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

28. LITHIUM DIALKYL CUPRATES

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

30. SUMMARY

31. 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

32. BIOLOGICAL REDUCING REAGENTS

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

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

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