1. Organometallic Compounds
B.Sc. III
Organic Chemistry

2. Organometallic Compounds
Organometallic compound: a compound that contains a carbon-metal bond
In this chapter, we focus on organometallic compounds of Mg, Li, and Zn
these classes illustrate the usefulness of organometallics in modern synthetic organic chemistry
they illustrate how the use of organometallics can bring about transformations that cannot be accomplished in any other way

3. Organometallic Reagents
The Key Concepts:
Make a carbon negatively charged/polarlized so it is nucleophilic.
Reaction with electrophilic carbons can make carbon-carbon bonds.
This is a Big Deal!

4. Grignard Reagents Discovered by Victor Grignard in 1900
The First Organometallic Reagents…
Grignard Reagents
Discovered by Victor Grignard in 1900
Key factors are ethereal solvent and water-free conditions
Awarded Nobel Prize in 1912
Victor Grignard
Grignard, Victor , 1871–1935, French chemist. He shared the 1912 Nobel Prize in Chemistry for his work in organic synthesis based on his discovery (1900) of the Grignard Reagent. He taught at the Univ. of Nancy (1909–19) and at the Univ. of Lyons (from 1919 until the end of his career).

5. Grignard Reagents Grignard reagent: an organomagnesium compound
prepared by addition of an alkyl, aryl, or alkenyl (vinylic) halide to Mg metal in diethyl ether or THF
ether B r + M g M g B r
1-Bromobutane
Butylmagnesium bromide
(an alkyl Grignard reagent)
ether B r + M g M g B r
Bromobenzene
Phenylmagnesium
bromide
(an aryl Grignard reagent)

6. An Alternative to Grignard Reagents are Alkyl Lithiums
Both are prepared from alkyl, vinyl, and aryl halides under anhydrous conditions

7. Grignard and Organolithium Reagents
Given the difference in electronegativity between carbon and magnesium (lithium), the C-Mg (C-Li) bond is polar covalent, with C- and Mg+ ( Li+ )
Grignard and organolithium reagents behave like carbanions
Carbanion: an anion in which carbon has an unshared pair of electrons and bears a negative charge 23 23 23

8. Grignard and Organolithium Reagents
Carbanion: an anion in which carbon has an unshared pair of electrons and bears a negative charge
Carbanions are strong bases--they are easily quenched by even very weak acids (water, alcohols, amines, amides, carboxylic acids, even terminal alkynes). A limitation to utility! 23 23 23

9. Grignard and Organolithium Reagents
Carbanion: an anion in which carbon has an unshared pair of electrons and bears a negative charge
Carbanions are strong bases--they are easily quenched by even very weak acids (water, alcohols, amines, carboxylic acids, amides, even terminal alkynes). A limitation to utility! 23 23 23

10. Limitations
Can’t make Grignards with acidic or electro-philic functional groups present in the molecule:
R2NH pKa 38-40
Terminal Alkynes pKa 25
ROH pKa 16-18
Carbonyls & Nitros pKa 11-27

11. Grignard and Organolithium Reagents
Carbanion: an anion in which carbon has an unshared pair of electrons and bears a negative charge
Carbanions are also great nucleophiles. This is the reason for their great utility!

12. Key Point: Grignard and Organolithium Reagents
Great nucleophiles that add efficiently to electrophilic carbons, such as epoxides and carbonyl group of aldehydes, ketones and esters. However, their basicity can be a limitation!
Epoxides illustrate how many common organic functional groups contain electrophilic carbons 23 23 23

13. Grignard and Organolithium Reagents
Carbanions (nucleophiles) can react with electrophilic carbon centers in favorable cases. The net result is a carbon-carbon bond--a big deal!
Grignards and organolithium reagents react with many oxygen-containing electrophiles, but not with alkyl halides.
We’ll illustrate this with epoxides.
Recall, acidic protons will “kill” our reagents and/or won’t allow them to be generated in the first place 23 23 23

14. Grignard reagents react productively with:
formaldehyde to give primary alcohols
aldehydes to give secondary alcohols
ketones to give tertiary alcohols
esters to give tertiary alcohols
CO2 to give acids
epoxides to give primary alcohols
The one we are choosing for the sake of initial illustration

15. Epoxides: The Example We Want to Stress
New C-C bond d+ d-
Considered
Retrosyn-
thetically:
These is an extremely valuable reaction…

16. Detailed Mechanism Highlighting Retention of Stereochemistry
A Related Example
Detailed Mechanism Highlighting Retention of Stereochemistry
New C-C bond
Key Points to Note:
Attack at least hindered carbon
Mechanism is SN2-like in initial step
Single enantiomeric product
Chiral center not affected by reaction
Relief of ring strain helps drive reaction
H3O+ breaks up initial salt

17. Two More Examples of Additions to Epoxides
New C-C bond
New C-C bond
Note: Stereochemistry at epoxide retained in product

18. Gilman Reagents
Lithium diorganocopper reagents, known more commonly as Gilman reagents
prepared by treating an alkyl, aryl, or alkenyl lithium compound with Cu(I) iodide

19. Gilman Reagents Coupling with organohalogen compounds Example
form new carbon-carbon bonds by coupling with alkyl and alkenyl chlorides, bromides, and iodides. (Note that this doesn’t work with Grignard or organolithium reagents. THEY ARE TOO BASIC AND DO E2 ELIMINATIONS.)
Example
New C-C bond

20. Gilman Reagents
coupling with a vinylic halide is stereospecific; the configuration of the carbon-carbon double bond is retained
New C-C bond

21. Gilman Reagents
A variation on the preparation of a Gilman reagent is to use a Grignard reagent with a catalytic amount of a copper(I) salt

22. Gilman Reagents Reaction with epoxides
regioselective ring opening (attack at least hindered carbon)
New C-C bond

23. Interim Summary of Introduction to Organometallic Reagents…
Organolithium reagents and Grignard reagents are very basic but also great nucleophiles. They react with epoxides at the less hindered site to give a two-carbon chain extended alcohol. They do not couple with alkyl-, aryl-, or vinyl halides.
Gilman reagents react with epoxides as do organolithium reagents and Grignard reagents. However, they also add to alkyl-, aryl-, and vinyl halides to make new C-C bonds.

24. Back to Grignard Reagents…
Addition of a Grignard reagent to formaldehyde followed by H3O+ gives a 1° alcohol
This sequence (mechanism) is general and important! 24 24 24

25. Grignard Reactions These are valuable and important reactions…
Please add to your card stock!

26. Grignard reagents react with esters
OCH3 •• R'
diethyl ether d+ R C
OCH3 •• d– R
MgX C + O O ••
• •
MgX
• • •• –
but species formed is unstable and dissociates under the reaction conditions to form a ketone 23

27. Grignard reagents react with esters
OCH3 •• R'
diethyl ether d+ R C
OCH3 •• d– R
MgX C + O O ••
• •
MgX
• • •• –
–CH3OMgX
this ketone then goes on to react with a second mole of the Grignard reagent to give a tertiary alcohol C O R R'
• • •• 23

28. Example O + 2 CH3MgBr (CH3)2CHCOCH3 1. diethyl ether 2. H3O+
Two of the groups attached to the tertiary carbon come from the Grignard reagent OH
(CH3)2CHCCH3
CH3
(73%) 26

29. Practice

30. Practice

31. O + H2C CHLi CH 1. diethyl ether 2. H3O+ CHCH CH2 (76%) OH
The Same Chemistry is seen With Organolithium Reagents O +
H2C
CHLi CH
1. diethyl ether
2. H3O+
CHCH
CH2
(76%) OH

32. Practice

33. Other Organometallic Reagents
We can also make R-Zn, R-Sb, R-As, R-Be, R-Ca, R-Hg, R-Sn, … reagents. We choose other metals for different degrees of reactivity and for greater selectivity.
Organozinc reagents are used in synthesis owing to their greater selectivity (see J. Vyvyan)

34. • The first organozinc ever prepared = diethylzinc (Et2Zn), by Edward Frankland in 1849, was also the first ever compound with a metal to carbon sigma bond.
• Many organozinc compounds are pyrophoric and therefore difficult to handle.
• Organozinc compounds in general are sensitive to oxidation, dissolve in a wide variety of solvents where protic solvents cause decomposition.
• In many reactions they are prepared in situ. All reactions require inert atmosphere: N2 or Ar
• The three main classes of organozincs are: organozinc halides R-Zn-X with, diorganozincs R-Zn-R, and lithium zincates or magnesium zincates M+R3Zn- with M = lithium or magnesium Organozinc

35. Preparations
• Primary and secondary alkylzinc iodides (RZnI) are best prepared by direct insertion of zinc metal (zinc dust activated by 1,2-dibromoethane or chlorotrimethylsilane) into alkyl iodides or by treating alkyl iodides with Rieke zinc. The zinc insertion can tolorate a lot of functional groups, allowing preparation of polyfunctional organozinc reagents.

36. Unfunctionalized dialkylzincs (R2Zn) are obtained by transmetalation of zinc halides, such as ZnCl2, with organolithium or Grignard reagents.
• Iodide-zinc exchange reactions catalyzed by CuI provide a practical way for preparing functionalized dialkylzincs.
• Diorganozincs are always monomeric, the organozinc halides
form aggregates through halogen bridges

37. Dialkylzinc (R2Zn)
• Alkyl group exchange between diethylzinc and diiodomethane produces the iodomethyl zinc carbenoid species, tentatively assigned as EtZnCH2I (Furukawa’s reagent).
oxidative addition of Zn metal to diiodomethane affords an iodomethylzinc iodide, tentatively assigned as ICH2ZnI (Simmons-Smith reagent), which is used for cyclopropanation of alkenes.

38. Reaction of Organozinc compounds
The Reformatsky Reaction
• involves condensation of ester-derived zinc enolates with aldehydes or ketones to give corresponding β-hydroxy esters.
• zinc enolates are generated by addition of an α-haloester in THF, DME, Et2O, benzene, or toluene to an activated zinc, such as a Zn-Cu couple or zinc obtained by reduction of zinc halides with potassium (Rieke zinc).

39. Reactions of functionally substituted RZnI
• application of functionally substituted organozincs allows for construction of C-C bonds while circumventing tedious protection-deprotection strategies.

40. Reactions of functionally substituted RZnI
Note that tosyl cyanide reacts with alkenyl or arylzinc reagents
to provide α,β-unsaturated alkenyl or aromatic nitriles, respectively

41. Reaction of Organozinc compounds
Cyclopropanation
• Cyclopropane rings are encountered in many natural products
possessing interesting biological activities.
• Cyclopropane moiety represents a useful synthon for further
synthetic transformations.
• In 1958, Simmons and Smith reported that treatment of a zinccopper
couple with diiodomethane in ether produces a reagent that adds to alkenes to form cyclopropanes.

42. The cyclopropanation reaction of simple alkenes appears to proceed via stereospecific syn-addition of a Zn-carbenoid (carbene-like species) to the double bond without the involvement of a free carbene.

43. stereospecific syn-addition of Zn-carbenoid to the double bond

44. Cyclopropanation modifications of Simmons-Smith :
• Furukawa’s reagent, (iodomethyl)zinc derived from diethylzinc and diiodomethane, or its modification using chloroiodomethane instead of diiodomethane, allows more flexibility in the choice of solvent.
• The reagent is homogeneous and the cyclopropanation of olefins can be carried out in noncomplexing solvents, such as dichloromethane or 1,2-dichloroethane, which greatly increase the reactivity of the zinc carbenoids.

45. Directed Simmons-Smith Cyclopropanation
• A particularly interesting aspect of the Simmons-Smith
reaction is the stereoelectronic control exhibited by proximal
OH, OR groups, which favor cyclopropanation to occur from
the same face of the double bond as the oxy substituents.
• order of decreasing directive effects : OH > OR > C=O