CONVERSION OF ALCOHOLS TO HALIDES

1. CONVERSION OF ALCOHOLS TO HALIDES

2. CHAPTER 12 12.1 Nomenclature of Alcohols 12.2 Nomenclature of Ethers learn on your own 12.4 Conversion of Alcohols to Alkyl Halides lecture some review read on your own Tosylates Review Section 10.3 pp 916-917 and 12.3 (end) just before Section 12.4 & lecture 12.7 Synthesis of Ethers review read on your own not much new here 12.8 Epoxides 12.14 Synthesis of Alkynes using Acetylide Ions lecture 12.15 Synthesis of Nitriles using Cyanide Ion

3. ALCOHOLS ARE UNREACTIVE TO SN1 / E1 AND SN2 / E2 ….. EXCEPT IN ACID

4. strong base ALCOHOLS Alcohols are frequently the best starting point for a synthesis. Many alcohols are available from chemical suppliers, and they are relatively inexpensive. Unfortunately, alcohols have a drawback in that they are not reactive in nucleophilic substitution or elimination reactions since hydroxide is a poor leaving group. - + R + OH R OH SN1 - R Nu + OH SN2 Nu: + R OH no reaction in either case poor leaving group

5. R O H O H H Acid conditions must be used to change the leaving group to water, a neutral group. + H+ SN2 R Nu + O H Nu: + R O H + H H SN1 neutral R+ + Alternatively, the hydroxyl group can be converted to a different functional group through chemical reaction. R OH R Cl R OTs or Often the hydroxyl group is converted to a halide, or a tosylate which can then react readily in elimination and substitution reactions.

6. METHODS FOR THE CONVERSION OF ALCOHOLS TO HALIDES OR TOSYLATES

7. METHODS FOR THE CONVERSION OF ALCOHOLS TO ALKYL HALIDES OR TOSYLATES We will examine several methods to convert alcohols to more reactive groups (slides follow). concentrated haloacids RCl 1. ROH + conc HCl ( also HBr and HI ) H2SO4 halide salts + sulfuric acid 2. ROH + NaCl RCl ( also NaBr and NaI ) 3. ROH + PCl3 RCl phosphorous halides ( also PCl5, PBr3, PBr5 ,PI3 ) 4. ROH + SOCl2 RCl thionyl chloride tosylates 5. ROH + TsCl ROTs ROTs + NaX RX

8. CONCENTRATED HCl, HBr, HI

9. CONCENTRATED HYDROCHLORIC ACID HCl - strong acid - completely ionized in water alcohol 1. primary slow 2. alkyl chloride primary substrate acid-assisted SN2 The mechanism depends on the nature of the substrate.

10. CONCENTRATED HYDROCHLORIC ACID tertiary 1. slow 2. rearrangement is possible with some alcohols 3. some E1 will occur tertiary substrate acid-assisted SN1 The mechanism depends on the nature of the substrate.

11. REARRANGEMENTS ARE COMMON WHEN THE MECHANISM IS SN1 (CARBOCATION) conc. HCl ionization rearranges expected some E1 will occur found + alkene

12. ALTERNATE CONDITIONS

13. AN EQUIVALENT METHOD TO USING CONCENTRATED HX IS TO USE NaX + H2SO4 NaX + H2SO4 conc HX H2O H2O = H3O+ + X- H3O+ + X- + Na+ + SO42- spectator ions

14. ALL THREE REACTIONS GIVE ESSENTIALLY THE SAME RESULT 1-butanol (primary alcohol) All examples above are acid-assisted SN2 mechanisms.

15. STEREOCHEMISTRY

16. STEREOSPECIFICITY The reactions of alcohols in strong acid solutions are rarely stereospecific. Other reactions are used when a stereospecific result is required, usually phosphorous halides (PX3) or inversion we will discuss these next thionyl chloride (SOCl2) 1. retention - ether solvent 2. inversion - pyridine solvent

17. PHOSPHOROUS HALIDES

18. PHOSPHOROUS HALIDES PCl5 and PBr5 , the pentachloride and pentabromide, also work in a similar fashion : : phosphorous trichloride phosphorous tribromide Synthesis: P + X2 PX3 The iodides are less frequently used, since they are unstable, but PI3 is a known reagent.

19. SN2 displacement at phosphorous the phosphorous group is a better leaving group than OH .. - : : .. + SN2 displacement at carbon the remaining two chlorines can also react (inversion if a stereocenter)

20. CONVERSION OF AN ALCOHOL TO A HALIDE WITH PCl3 SN2 inversion of configuration ether Benzene or ethers or can be used as a solvent. If the alcohol is a liquid, frequently no solvent at all is used ( a “neat” reaction = w/o solvent ). This SN2 reaction works best with primary and most secondary alkyl halides. Tertiary halides are a bad choice.

21. THIONYL CHLORIDE

22. THIONYL CHLORIDE .. .. - : : : .. .. .. .. + .. : : : .. : .. .. .. .. :Nu nucleophiles attack sulfur Electron-deficient at sulfur due to the S-O dipole and the inductive effects of the two chlorines.

23. PYRIDINE SOLUTION INVERSION

24. ALCOHOLS REACT WITH THIONYL CHLORIDE TO MAKE CHLOROSULFITE ESTERS + pyridine MECHANISM IN PYRIDINE SOLUTION lots of free chloride ions

25. : : O : : O .. .. S .. .. : : C l C l .. S .. : C l .. : .. O .. .. C H : O H C H 3 C - H .. :C l : C H 3 .. (S) .. .. O S O .. .. H C H 3 C - .. : C l : .. : C l : .. (R) IN PYRIDINE, THE HIGH CONCENTRATION OF CHLORIDE ION LEADS TO AN SN2 MECHANISM .. .. lots of free chloride ions “fragmentation” SN2 inversion PYRIDINE = SN2 MECHANISM INVERSION

26. ETHER SOLUTION RETENTION

27. ALCOHOLS REACT WITH THONYL CHLORIDE TO MAKE CHLOROSULFITE ESTERS + MECHANISM IN ETHER SOLUTION gas escapes solution chloride ion is lost

28. IN ETHER, THE CONCENTRATION OF CHLORIDE ION IS LOW, DECOMPOSITION (SNi) OCCURS BEFORE SN2 ETHER = RETENTION thermal decomposition (S) “SNi” solvent shell .. no dissociation both ions are trapped in solvent cavity

29. SNi SN2 (R) (S) SUMMARY chlorosulfite ester (R) (R) + pyridine ether THE SOLVENT IS THE THING inversion retention (g) + In pyridine - the chlorosulfite ester is attacked by Cl-, SN2 with inversion. In ether - the chlorosulfite ester undergoes thermal decomposition, SNi with retention.

30. TOSYLATES

31. CONVERSION TO A TOSYLATE WITH TsCl AND PYRIDINE Poor leaving group TsCl .. + .. * : - Cl .. R-OTs pyridine * - + Cl Good leaving group for both SN1 and SN2 If the alcohol is chiral, the conversion to a tosylate retains configuration.

32. EXAMPLE OF THE USE OF A TOSYLATE (R) (R) TsCl CH3-CH-OH CH3-CH-OTs pyridine Ph Ph RETENTION NaCN acetone SN2 INVERSION (S) CH3-CH-CN Ph

33. EXPLANTION OF STEREOCHEMISTRY Same configuration as the starting alcohol. .. : pyridine NaCN acetone The first reaction step does not involve the carbon stereocenter - the atom oxygen reacts. This step is an SN2 reaction with inversion of configuration.

34. CAUTION A COMMON STUDENT ERROR Do not mix up or confuse : pyr. ROH + TsCl ROTs Ts-Cl / pyridine makes a tosylate and pyr. ROH + SOCl2 RCl / pyridine SOCl2 makes an inverted alcohol These are two different reagents.

35. BROSYLATES

36. BROSYLATES WORK LIKE TOSYLATES p -bromobenzenesulfonyl chloride + “Brosyl Chloride” pyridine BsCl a p -bromobenzensulfonate “Brosylate” R-OBs a good leaving group

37. NATURE’S WAY ……... ADENOSINE TRIPHOSPHATE ATP

38. ADENOSINE TRIPHOSPHATE (ATP) adenine ribose adenosine = adenine + ribose triphosphate “tail” Nature’s way of modifying alcohols.

39. .. .. .. :O-R :O-R :O-R H H H R-O-H + ATP R-O-P or R-O-P-P or R-O-P-P-P triphosphate monophosphate All 3 are more reactive than alcohols. diphosphate

40. PHOSPHATES (MONO, DI, AND TRI) ARE GOOD LEAVING GROUPS FOR BOTH SN1 AND SN2 REACTIONS Nu: SN2 SN1 (ionization) .. .. .. .. : : : : : : : .. .. .. .. .. .. .. + .. : : : : .. .. .. .. .. .. .. : : : : : : : .. .. .. .. resonance stabilized ion

41. SUMMARY

42. METHODS FOR SYNTHESIS OF HALIDES Mechanism depends on substrate but generally not stereospecific. Rearrangements can occur with primary or secondary substrates. conc. HX or NaX + H2SO4 Tertiary work well. Inversion of configuration (SN2) Best for primary and secondary substrates. PX3, PX5 neat or ether or benzene Best for primary or secondary substrate, some tertiary OK. SOCl2, ether Retention of configuration (SNi) SOCl2 pyridine Inversion of configuration Best for primary or secondary substrate. (SN2)

43. PROBLEMS

44. PROBLEM 1 Give a method to accomplish this conversion.

45. PROBLEM 2 Give a method to accomplish this conversion.