Reagents with Carbon-Metal Bonds

1. Organometallic Compounds Reagents with Carbon-Metal Bonds

2. FIRST A REVIEW MAKING CARBON-CARBON BONDS

3. MAKING CARBON-CARBON BONDS A limited number of methods of making carbon-carbon bonds exist in organic chemistry. You have seen several already: SN2 reactions with cyanide and acetylide Section 12.15 .. .. - - : : : : : : + .. .. new C-C bond .. .. - - : : : : + .. .. Section 12.14 new C-C bond

4. MAKING CARBON-CARBON BONDS Diels-Alder Reaction Section 14.11 + Sections 9.13 & 14.12 Carbene and carbenoid reactions +

5. MAKING CARBON-CARBON BONDS This chapter introduces a new class of reagents that are capable of making new carbon-carbon bonds. This will allow us to combine small molecular fragments and build larger molecules from them. All of these new reagents are organometallic compounds.

6. CARBON-METAL BONDS ORGANOMETALLIC COMPOUNDS R-M R-M-X R-M-R R is an organic (carbon) group M is a metal

7. R-X + 2 M R-M + MX example: CH3-Li example: CH3-Mg-Br R-X + M R-M-X R-X + 2 M R-M-R + MX2 example: CH3-Cd-CH3 Organometallic Compounds Alkyl halides (R-X) will react with some metals to produce organometallic compounds: compounds with a carbon-metal bond Monovalent Metals ( M = Na, Li ) Divalent Metals ( M = Mg, Cd)

8. .. _ + . : : : + + .. .. . . FORMATION OF AN ALKYLLITHIUM COMPOUND SAMPLE MECHANISM R-X + 2 Li R-Li + LiX .. These active metals all give up an electron to the alkyl halide, breaking the C-X bond. fishhook (one barb) = movement of one electron

9. -C-X -C-Li -C-MgX X Li MgX C-X THE SCOPE OF THE REACTIONS Most halides can be used directly to make an organometallic lithium or magnesium compound except alkynyl halides. These can be made, but special methods (later) are required. R-X + 2 Li R-Li + LiX R-X + Mg R-Mg-X sp3 alkyl halide or sp2 vinyl halide =C-X =C-Li or =C-MgX sp2 aryl halide or sp X alkynyl halide doesn’t work directly * *discussed later

10. BONDING IN ORGANOMETALLIC COMPOUNDS

11. d- d+ - + : most reactive Carbon-metal bonds are frequemtly classified as to how much “ionic character” they have, by using an index called the percent ionic character. bond percent ionic strongest base C-K 51 C-Na 47 C-Li 43 C-Mg 35 C-Zn 18 C-Cd 15 C-Cu 9 Li and Mg are the metals used most often This index states the importance of the ionic resonance con- tributor relative to the covalent structure. best nucleophile least reactive ORGANOMETALLIC BONDS ( CARBON-METAL ) carbanion Carbon-metal bonds are polar bonds that can be represented by a resonance hybrid of covalent and ionic structures. covalent ionic

12. BASES AND NUCLEOPHILES All of these reagents react as nucleophiles or bases, which are bonded to various degrees to the associated metal. LEWIS BASE - NUCLEOPHILE electron-pair donor + varying degrees of covalent character depending on the metal

13. ORGANOMETALLICS FROM MONOVALENT METALS Na K Li

14. MONOVALENT METALS NaK Li Organosodium and organopotassium reagents are too reactive to make good organometallic reagents. There are problems when trying to form R-Na or R-K : E2 dehydrohalogenation is an important side reaction, especially if the alkyl halide is secondary or tertiary. SN2 coupling takes place to form dimers. Both of these problem reactions are shown on the next slide * * Organolithium reagents ( R-Li ) generally work best.

15. d- d+ E2 SN2 DIFFICULTIES WITH POTASSIUM AND SODIUM ( TOO REACTIVE, R-M IS A STRONG BASE ) + ELIMINATION - Na+ - Na+ COUPLING ( WURTZ REACTION ) In both cases the reagent reacts with the starting material !

16. SOME EXAMPLES OF THE WURTZ REACTION If the alkyl halide is a liquid, no solvent is used. Na d+ Na d-

17. PHENYLSODIUM Phenyl sodium is an exception ! It can be formed without difficulty. + Bromobenzene will not undergo either E2 or SN2 complications because the bromine is attatched to an sp2 carbon in the benzene ring, not to an aliphatic chain. Phenylsodium has strong ionic character and is a very strong base. - + :

18. ORGANOLITHIUM COMPOUNDS

19. 2 Li + R-X R-Li + LiX rate: X = I > Br > Cl (bromine is preferred) Formation of Organolithium Reagents R = 10, 20, some 30, vinyl and aryl (phenyl) solvents : ethers, pentane, benzene EXAMPLES ether + 2 + pentyllithium + + benzene phenyllithium

20. SOLVENTS THAT ARE FREQUENTLY USED .. diethyl ether .. THF tetrahydrofuran .. .. pentane These solvents do not react with the metals themselves or with the organometallic compounds formed. benzene .. .. 1,4-dioxane .. ..

21. REACTIONS OF ORGANOLITHIUM COMPOUNDS

22. d- d+ - + : - + + REACTIONS OF ORGANOLITHIUM COMPOUNDS strong base good nucleophile significant (-) charge at the carbon 57% covalent 43% ionic ether or R-Li are strong bases and react with acids, even weak acids like water and alcohols. CH3:- + H+ strong base acid Li+

23. Any -O-H, -S-H, or -N-H bonds are sufficiently acidic to react. - - + + - .. - + + .. - .. - + + .. The reaction with H2O also means that you must rigorously exclude water ( and water vapor = air ) from your reactions.

24. REMOVING A HALOGEN The reaction with water is a way of reducing ( or dehalogenating ) an alkyl halide ( converting C-X to C-H ) . ether Removal of Br H2O Li + -

25. + - .. - + + .. MAKING DEUTERIUM COMPOUNDS ether Li+ Li+ ether Replacing Br with D D2O Li phenyllithium The reaction of an alkyllithium compound with water is generally not useful unless you wish to remove the halogen on the starting compound, or you use D2O, which is a way of placing a deuterium atom in your compound.

26. THESE COMPOUNDS CAN BE USED WHEN YOU NEED A VERY STRONG BASE When usual bases, such as NaOH or NaOR are not strong enough, R-Li or Ph-Na can be used. NaOH + reacts slowly + or NaOEt Ph-Na smooth reaction + + + or - CH3CH2CH2CH2-Li .. C:- is a stronger base than O:- since oxygen is more electronegative and better accommodates the charge. These are also stronger bases than NH2- (same reason).

27. YOU MUST EXCLUDE AIR FROM THESE REACTIONS water vapor (see previous slides), oxygen, and carbon dioxide react

28. WATER Water or traces of moisture (water vapor) destroy the reagent ! R-Li + H2O R-H + LiOH - - strong base + + Your glassware must be scrupulously dry, and you must not expose the reagent to humid air.

29. OXYGEN Oxygen reacts with alkyllithium compounds to form hydroperoxides. - + + butyllithium H2O a hydroperoxide This reaction usually proceeds in low yield, meaning it is not a good synthetic method ….. however, it can be a annoying problem when trying to prepare alkyllithium compounds.

30. CARBON DIOXIDE Carbon dioxide reacts to make the lithium salts of carboxylic acids. R-Li + CO2 R-COO- Li+ This reaction can be used as an effective synthetic method ….. discussed in the following slides

31. SYNTHESIS OF CARBOXYLIC ACIDS

32. SYNTHESIS OF CARBOXYLIC ACIDS Carbon dioxide reacts to form the lithium salt of a carboxylic acid. This is a good method of making a carboxylic acid. - + + crushed dry ice lithium benzoate phenyllithium add H3O+ For synthesis, solid carbon dioxide (dry ice) is used.

33. REACTIVITY OF THE CARBONYL GROUP electrophiles attack here H+ or E+ nucleophilic at oxygen .. .. - d- : : : d+ + electrophilic at carbon Nu: nucleophiles attack here NUCLEOPHILIC ADDITION

34. REACTIONS WITH THE CARBONYL (C=O) GROUP .. Since oxygen is more electronegative than carbon, the carbonyl group is electron-deficient at carbon, that is, it is an electrophile. d- : d+ .. - Li+ : : - + new C-C bond The organometallic compound (R-Li) behaves as a nucleophile with an unshared pair on the carbon. NUCLEOPHILIC ADDITION TO CARBONYL

35. SYNTHESIS OF A CARBOXYLIC ACID .. : Li dry-ice d+ ether : .. d- .. : H3O+ workup step .. - + : Li .. H3O+ CO2 Li R-Br R-Li R-COO- Li+ R-COOH usually dil. HCl

36. SYNTHESIS OF ALCOHOLS Read the following section only from Chap 16 : (16.7)

37. + formaldehyde primary alcohol SYNTHESIS OF ALCOHOLS Reaction of RLi with aldeydes and ketones yields alcohols. + other aldehydes secondary alcohol + ketones tertiary alcohol The type of alcohol depends on whether you use formaldehyde, another aldehyde, or a ketone.

38. THERE ARE ALWAYS THREE DIFFERENT WAYS TO SYNTHESIZE AN ALCOHOL Start with two groups in the carbonyl compound and add the third.

39. SYNTHESIS PROBLEM TARGET : Method three, using the other phenyl, is identical. METHOD ONE METHOD TWO

40. USING NaBH4 TO SYNTHESIZE ALCOHOLS

41. donates hydride ions to suitable donors - SODIUM BOROHYDRIDE IS A HYDRIDE DONOR _ + : B H B H Review also Section 12.13

42. A CARBONYL GROUP IS A SUITABLE ACCEPTOR OF H:- FROM NaBH4 .. .. - d- nucleophilic addition : : : d+ - .. - : : The carbon of C=O is electron deficient. +

43. + formaldehyde methanol USING NaBH4 TO SYNTHESIZE ALCOHOLS H - H C H O H H: O 2 H C H C H 3 3 - H: H C H O H O + H other aldehydes primary alcohol C H C H 3 3 - H C O H + O H: C H C H 3 3 ketones secondary alcohol

44. SYNTHESIS PROBLEM TARGET : METHOD ONE METHOD TWO _ + What is the third method?

45. SYNTHESIS PROBLEM MULTISTEP

46. SYNTHESIS PROBLEM from

47. C H O 3 Br C C O H H C H H C 3 3 C O H Li + C O H H C H C H 3 3 CO 2 C Li C Cl H H SYNTHESIS PROBLEM from