1. Chapter 4 Formation of carbon-carbon bonds: reaction of organometallic compounds
Topics:
Grignard reagents and electrophiles
Other organometallic reagents and electrophiles
Reactions of nucleophiles derived from alk-1-ynes
Review
Worked example

2. 4.1 Grignard reagents and electrophiles
Alkylation
Reactions with carbonyl compounds
4.1.3 Reactions with imine and cyano compounds
4.1.4 Reactions with α,β-unsaturated carbonyl compounds
4.1.5 Alkenyl and alkynyl Grignard reagents

3. 4.1.1 Alkylation

4. For example

5. 4.1.2 Reactions with carbonyl compounds

6. For example

8. For example

9. Synthesis of Alcohol by Grignard Reaction

11. 4.1.4 Reactions with compounds containing C≡N

12. 4.1.4 Reactions with α,β-unsaturated carbonyl compounds

13. 4.2 Other organometallic reagents and electrophiles
4.2.1 Organolithium reagents
more reactive and less bulkyl
4.2.2 Organozinc and organocadmium reagents
less reactive and used only for special purposes
4.2.3 Organocopper (I) reagents
less reactive and more selectivity

14. 4.2.1 Organolithium reagents
Preparation
RBr + 2Li RLi + LiBr
RBr + R’Li RLi + R’Br
(Generally R’ refers to n-BuLi)
Organolithium reagents react similarly with Grignard reagents and more efficiently in certain cases. With α,β-unsaturated carbonyl compounds they show a greater preference for addition at the carbonyl carbon.

16. 4.2.2 Organozinc and organocadmium reagents
Organozinc reagents (Reformatsky reaction)
Note: Reactions with α,β-unsaturated carbonyl compounds give preferentially the 1,2-addition products.

17. Organocadmium reagents
Preparation
2RMgX CdCl R2Cd
Used especially for the conversion of acyl chlorides into ketones
R2Cd + 2R’COCl RCOR’
e.g. [CH3(CH2)3]2Cd ClCH2COCl CH3(CH2)3COCH2Cl (51%)
[(CH3)2CHCH2CH2]2Cd ClCO(CH2)2CO2CH3
(CH3)2CH(CH2)2CO(CH2)2CO2CH3 (73%)

18. 4.2.3 Organocopper (I) reagents
Preparation
RMgX CuX RCu MgX2
RLi CuX RCu LiX
RLi RCu R2CuLi
2R-Li CuX R2CuLi LiX
Ponits of synthetic importance:
Displacement of halogens is particularly facile.
Acyl halides are the only class of carbonyl compound to react with.
When reacting with α,β-unsaturated carbonyl compounds give 1,4-addition products.
Coupling reactions occur when heated.

19. 4.3 Reactions of nucleophiles derived from alk-1-ynes
4.3.1 Sodium, lithium and magnesium derivatives
They can undergo the usuall range of reactions with electrophiles:
Alkylation
Reaction with carbonyl compounds

20. 4.3.2 Alkynylcopper(I) compounds
Preparation
Ponits of synthetic importance:
Displacement of halogens from’unreactive’ positions.
Conversion of acyl halide into ketone
Coupling reactions giving conjugated diynes.

21. 4.4 Review R-R’  R-; R’+ R’-Y (Y = X (halides), OTs (sulfonates))
RCH2CH2OH  R-; +CH2CH2OH
RCO2H  R-; +CO2H
CO2 
R-;

22. Synthetic equivalents
Nucleophilic
Synthons R-
RMgX, RLi, R2Cd, RCu, R2CuLi
Electrophilic R+
RCl, RBr, RI, ROSO2R1
RC+=O
RCOCl, (RCO)2O, RCO2R1,RCN
HC+=O
HCO2R1, | OH
CO2
C+H2OH
HCHO
RC+HOH
RCHO
R2C+OH
R2CO
+CH2CH2OH

23. 4.5 Worked example 1-phenyl-butan-2-ol
Two synthetic routes have therefor emerged:
PhCH2MgBr + CH3CH2CHO and PhCH2CHO + BrMgCH2CH3

24. Pentadecan-4-one

26. 3-Phenyl-butyric acid methyl ester

29. pent-3-yn-1-ol

30. Summary Grignard reagents, RMgX, are strongly nucleopholic, I.e.
they act as synthetic equivalents of the synthon R-.
They are alkylated by halogenoalkanes, they undergo addition to the carbonyl group of aldehydes and ketones, they react with acyl halides, anhydrides and esters giving first ketones and thence tertiary alcohols, with carbon dioxide giving carboxylic acids, and with tertiary amides, orthoesters and nitriles giving , after hydrolysis, carbonyl compounds (aldehydes or ketones).

31. Summary
With α,β-unsaturated carbonyl compounds, nucleophilic addition to the carbonyl group and conjugate addition (at the β-carbon) are both observed, the former usually predominating. Grignard reagents are also strong bases and are protonated even by weak acids such as water, alcohols and alk-1-ynes.

32. Organolithium reagents react similarly but are even stronger nucleophiles and stronger bases. With α,β-unsaturated carbonyl compounds they show a greater preference for addition at the carbonyl carbon.
Organozinc and organocadmium reagents are less reactive nucleophiles than Grignard reagents but are used nowadays only for certain specific purposed.
Organocopper(I) reagents (Rcu or R2CuLi), although also synthetic equivalents of the synthon R-, show a different pattern of reactivity: they readily undergo alkylation, acylation and conjugate addition but do not undergo addition to carbonyl groups.

33. Deprotonation of alk-1-ynes (using a strong base such as sodamide or a Grignard reagent) furnishes useful nucleophiles which undergo the expected reactions, e.g. alkylation and reaction with carbonyl compounds. Alkynyl-copper(I) reagents react smilarly to alkyl- and aryl-copper reagents but they also undergo oxidative coupling to give conjugated diynes.
Some rules for the disconnection of target molecules, tabulated lists of synthetic equivalents for various synthons and one worked example are includeded at the end of the chapter.