Organomagnesium (Grignard) and organolithium reagents

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Maud Pitts
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1 rganomagnesium (Grignard) and organolithium reagents

2 Different polarization of non-metallic and organometallic reagents H CH 3 - I H - CH 3 + I H 3 H 3 C H 3 C H 3 + H 3 C H 3 C H 2 H 3 C H3C H I - CH 3 CH 3 - M CH 3 - CH 3 + M + I CH 3 CH 3 - M CH 3 CH 3 CH 3 + M CH 3

3 rganometallic reagents (R-M) are not fully ionic Metal K a Li Mg % Ionic Character reactivity of organometallic reagents

4 Ethers are the only solvents for organomagnesium (Grignard) reagents R - X + Mg RMgX Et X 2 Mg R Et 2 Et 2 X = I, Br, Cl R = alkyl, aryl, alkenyl Et 2 R Mg X X Mg R Et 2

5 Generation of Grignard reagents by metallation (hydrogen metal exchange) RH + R 1 MgX RMgX + R 1 H R-C C-H + C 2 H 5 MgBr R-C C-MgBr + C 2 H 6 + C 2 H 5 MgBr + C 2 H 6 H H H MgBr

6 Reactivity: magnesium atom is transferred to a more electronegative atom, as in metallation RH + R 1 MgX R-MgX + R 1 H R 2 H + R 1 MgX R 2 -MgX + R 1 H R 2 C + R 1 MgX R 2 R 1 C--MgX + n-bumgbr then H + n-c 6 H 13 H

7 S 2 -type (coupling) reactions EtMgBr + Br + MgBr MgCl + Et Et S + MgCl(S 2 Et MgCl + n-bu--s 2 - Me C 5 H 11 -n + MgCl(Ts) Me Br Me 1) Mg Me Me Me Me 2) (Me) 2 S 2 Me + MgBr(S 2 Me)

8 Transition metal ion (e.g. CuBr) mediated 1,4- addition to unsaturated carbonyl compounds + EtMgBr (from pure Mg) then H + Et H EtMgBr 1) Et EtMgBr 2) H + 1,4-addition H + + Et H 1,2-addition Et MgBr 1) Me-I Et 2) H + intermediate enolate

9 rganolithium reagents Methyllithium CH 3 -Li (MeLi) a strong base and a strong nucleophile n-butyllithium n-c 4 H 9 -Li (n-buli) a strong base and a strong nucleophile t-butyllithium Me 3 C-Li (t-buli) a strong base and a strong nucleophile basicity increases in the following order: MeLi < n-buli < t-buli

10 Basicity vs. nucleophilicity Phenyllithium C 6 H 5 -Li (PhLi) a strong base and a strong nucleophile A basic reagent has a strong affinity for proton (e.g. removal of proton from a C-H moiety A nucleophilic reagent has a strong affinity for carbon in the molecule (e.g. S 2 reaction at the carbon atom) Lithium diisopropylamide ipr 2 -Li (LDA) a strong base and a relatively weak nucleophile LDA: lithium diisopropylamide Li

11 Alkyllithium and aryllithium reagents are strongly basic and strongly nucleophilic, while lithium amide reagents are strongly basic and relatively non-nuleophilic R-Li (any temperature) addition Li R H LDA - 78 o C lithiation MeI Li Me LDA: lithium diisopropylamide Li

12 Generation of organolithium reagents RCl + 2Li RLi + LiCl the reaction of alkyl halides with lithium metal RLi + R 1 X R 1 Li + RX lithium halogen exchange in the reaction of an alkyllithium reagent and an alkyl halide, X = I or Br RLi + R 1 H RH + R 1 Li lithium hydrogen exchange in the reaction of an organolithium reagent with a relatively acidic hydrocarbon portion of a molecule (lithiation)

13 Lithium halogen exchange S Br n-buli (1.0 equiv) Et 2, -70 o C S Li + n-buli Br n-buli (1.0 equiv) Et 2, -70 o C Li + n-buli

14 Lithiation and complex induced proximity effect (CIPE) n-buli D 2 S S Li S D Li n-buli S complex-induced proximity effect S

15 Lithiation and CIPE (contd.) 1) LDA 2) Me 3 SiCl SiMe 3 Me 3 Si Me Me complex-induced proximity effect SiMe 3 Me

16 CIPE (contd.) H LDA Li MeCH Me Cl Cl Cl complex-induced proximity effect

17 CIPE and transmetallation t-buccbu-t n-buli H t-bu (BC group) BC Li Low yield, many byproducts (n-bu) 3 SnCl High yield, high purity Li n-buli Sn(n-Bu) 3 BC BC

18 Synthesis of ketones RLi R-Li =C= R - Li + R Li R Li H 3 + R R + 2 LiH

19 Reaction with unsaturated carbonyl compounds Ph Ph 1) PhMgBr 2) H + Ph Ph 1,4-addition Ph 1) PhLi 2) H + H Ph Ph Ph 1,2-addition

20 Addition reaction to the formal C= bond of heteroaromatic compounds Cl C Cl then H 2 S H H Cl Cl C (DDQ) H S Li Cl C n-buli Br S S Cl Cl H C

21 Addition to heteroaromatic compounds (contd.) Cl The addition reaction of organometallic reagents

22 rganocopper (RCu) and lithium organocuprates (R 2 CuLi) MeLi + CuI MeCu + LiI colorless yellow MeLi + MeCu Me 2 CuLi colorless

23 1,4-addition reaction of R 2 CuLi (not reactive enough for a 1,2-addition) R R Cu - R R Cu - -RCu R H + R -

24 R 2 CuLi: reactions with acid chlorides and epoxides Cl Me 1) (Me 2 C=CH) 2 CuLi 2) H + Me Me Me 1) Et 2 CuLi H 2) H + Et

25 R 2 CuLi: coupling reactions C 10 H 21 Br Bu 2 CuLi C 14 H 30 1-bromodecane tetradecane Br Bu 2 CuLi

26 Drying of diethyl ether (ether or Et 2 ) and tetrahydrofuran (THF) for organolithium reactions EtEt diethyl ether terahydrofuran Ph Ph a a (metal) Ph Ph H 2 2 Brown mixture benzophenone (colorless) sodium benzophenone ketyl radical (intensively violet)

27 The use of THF THF must be used below 0 o C. The following reaction occurs if the temperature is above o C: n-bu-li Li Li enolate ethylene

28 Titration of organolithium reagents CH CH RLi CH C _ Li + diphenylacetic acid colorless RLi Li C C _ Li + yellow

29 Synthesis of 2-chloro-4-(2-thienyl)pyrimidine Cl 1 then H 2 S H 2 H Cl Cl Cl DDQ C C S S Li n-bu-li S Cl Cl H H C C Cl 3

30 Synthesis of 3-butylcyclohexanone H 2 n-bu-li CuI Bu 2 CuLi Bu 4 Bu

31 Graduate Studies in Chemistry MS and PhD Programs offered in: Competitive stipends and fellowships; waived tuition; and assisted health insurance (PhD s supported: 82) Analytical Biological / Biochemical Biophysical / Computational rganic / Medicinal For more information: chegsc@langate.gsu.edu Ranked top 10 of 178 by ational Research Council in Student support and utcomes and Faculty Diversity Masters program ranked number 9 in the United States (number one in the Southeast) by the American Chemical Society for MS degrees conferred in

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12.5 Organometallic Compounds

12.5 Organometallic Compounds 12.5 rganometallic Compounds Compounds that contain carbon-metal bond are called organometallic compounds. C M C δ δ + M C M Primarily ionic Primarily covalent (M = Na + or K + )(M = Mg or Li) (M = Pb,