ChemActivity 19: Carbon Nucleophiles

Model 1: Grignard and Lithium Reagents

A carbon group attached to MgX (where X is a halogen) is called a Grignard (pronounced grin-yard)
reagent. A carbon group attached to lithium is called an organolithium reagent.

1. Considering the difference in electronegativity between carbon and magnesium, put a + and a  -
as appropriate on the R and the Mg in the first reaction.
2. Considering the difference in electronegativity between carbon and lithium, put a + and a - as
appropriate on the R and the Li in the reactants in the second reaction.
3. The bond between carbon and magnesium (or carbon and lithium) can be drawn as ionic instead of
covalent. If drawn with an ionic bond, which atom, the carbon or the magnesium, will be the
negatively charged ion?

4. Draw the Grignard reagent with an ionic bond. Make sure that one atom has a lone pair and
negative charge and the other atom has a positive charge.

5. Draw the lithium reagent with an ionic bond.

6. Will the carbon in these reagents act as an electrophile or a nucleophile?

7. Will the carbon in these reagents act as an acid or a base?

8. Use CH3CH2Br as the starting material in the above reactions instead of RBr. Draw the structures of
resulting Grignard and lithium reagents in both their ionic and covalent forms.
Model 2: Cuprate Reagents
Lithium dialkylcuprate reagents, which can be written as LiR2Cu or , act as carbon
nucleophiles similarly to Grignard and lithium reagents. However, cuprate reagents are not quite as
strong. They can be written as carbons covalently bonded to copper or as a carbanion. It is the
carbanion that is the carbon nucleophile. These reagents will undergo SN2 reactions.

How to make lithium dialkylcuprate reagents from alkyl halides:

1. Use CH3CH2Br as the starting material in the above reactions instead of RBr. Draw the structure of
resulting lithium dialkylcuprate in both forms.

2. Synthesis of 1 mole of the following target molecule can be accomplished using 3 moles of the
starting material shown below.
a. 2 moles of the starting material are used to prepare a lithium dialkylcuprate reagent. Draw this
reagent in the box provided, showing a full -1 charge on C.
 b. This LiR2Cu reagent is added back to the rest of the starting material. Assume an SN2 mechanism
and use curved arrows to show how the final step might occur.

Note: Lithium dialkyl cuprate (LiR2Cu) reagents are much better than lithium or Grignard
reagents for SN2 reactions with alkyl halides to form C-C bonds.

3. Carbanion reagents are extremely strong bases. Upon making a bond to H+ they release a large
amount of energy (you may assume about 50 pKa units, but actually the value is closer to 35-40 pKa
units of energy). Recall that the pKa of an alcohol is about 16. (Requires 16 pKa units of energy to
remove an H+.)

a. In the reaction below, the moment a molecule of Grignard reagent is formed, it immediately
undergoes an acid-base reaction with a second molecule of starting material. Use curved arrows
to show this unwanted side reaction, and draw the products.

H2 H2
H C Br
Mg metal H C MgBr bond to H+releases
O C O CH2 -35 pKa units
H2 ?
starting alkyl halide H2 side-reaction
H C Br
O C
H2
requires +16
pKa units to break starting alkyl halide is
in excess in the reaction mixture

b. Construct an explanation for why preparation of carbanion reagents cannot be performed with
an alkyl halide containing an acidic H (pKa < 35).
Model 3: Nucleophilic Addition to a Carbonyl (C=O)

Review: nucleophile = “nucleus (+) lover” nucleophilic = “nucleus (+) loving”

electrophile = “electron (–) lover” electrophilic = “electron (–) loving”

spectator counter ion "carbonyl oxygen"

H
O "carbonyl group" H3C O Li
H C Li C
C "carbonyl carbon"
spectator
H H H H counter ion
H
formaldehyde

4. Draw a + and a - on appropriate atoms of formaldehyde to show the polarity of the C=O
bond.
5. Use curved arrows to show a mechanism for the reaction in Model 3.

6. Draw the alcohol product that results when an aldehyde or ketone is…
i. treated with a Grignard or Lithium reagent (strong nucleophile)
ii. then neutralized with dilute acid

O R" MgBr
or dilute
C R" Li H Cl
R R'

(aldehyde when R or R' = H)

Note: Lithium dialkyl cuprate (LiR2Cu) reagents do not react with aldehydes or ketones to
form alcohols.
Model 3: Alkyne Carbanions
Recall the hybridization effect: an electron pair in an sp hybrid orbital is lower in potential energy
than an electron pair in an sp2 hybrid orbital. This is because the sp orbital has more “s character” (50%
vs 33%), and s orbitals are lower in energy. An interesting result is that a C-H bond in acetylene is both
shorter and weaker than a C—H bond in ethene or ethane.

H
Critical Thinking Questions
H C C H
7. Label each lone pair in Model 3 with the
H H name of the hybrid orbital in which it
resides.
H a) Which is most acidic: acetylene,
C C
H C C H H pKa = 50
ethene or ethane [circle one]?
pKa = 44
pKa = 25 H
b) Which has the shortest C-H bond:
H H H
H acetylene, ethene or ethane [circle
C C C C H
H C C H
H H H one]?
acetylene (ethyne) ethene ethane H

8. A strong base such as NaNH2 (Na+ H2N-) cannot pull an H off of propene or propane (Rxn I) but can
pull off the terminal H of an alkyne (Rxn II). The resulting conjugate base is another type of carbon
nucleophile.

H H

H3C
C C

H
N

H
H
X
Rxn I
No Reaction

H3C C C H
SN2
H3C C C C Br
Rxn II H3C C C CH3
H Rxn III
N H H N H H 2-butyne
H H add methyl bromide

a. Use curved arrows to show the mechanism of Rxn III, an SN2 reaction.
b. Label the new C-C  bond in the product, 2-butyne.
 9. SN2 reactions (such as in Rxn III) only give a reasonable yield of product when a methyl, primary, or
secondary electrophile is used.
Good rule to remeber: A bulky nucelophile is better than a bulky electrophile.

a) Explain why each of the following reactions will not give a good yield of the product.
b) Under each reaction draw a pair of reagents that would give the product shown.

Cu Br H3C C CNa
i) Cl Li ii) (CH3)2CuLi iii) Br H3 C C C

Hint: use NaC C as your nucleophile

Exercises
1. The synthesis on the first page of this ChemActivity can be accomplished in four steps. Fill in empty
boxes for reagents and products.
 2. Design a synthesis of the following target molecule using the starting material given and… (You
may use any non-carbon containing reagents in either synthesis.)
a. any alkyne (hint: a reduction reaction is also necessary to achieve the target).
b. any lithium di-alkyl cuprate reagent.

Br

target
starting material

3. Which of the following are acceptable alkyl halides for making Grignard or lithium reagents? If they
are not acceptable, show the side-reaction that would occur if each were treated with Li or Mg.
Cl
H
N
HC HO
I
Br Br

Rule of Thumb: In general, an alkyl halide with any other functional group will not work for making a
Grignard or lithium reagent.

4. Explain why the synthesis in Exercise 1 would not work if you started with 4-amino-1-
bromobenzene instead of 4-nitro-1-bromobenzene. Draw the side reaction that completely
consumes the carbon anion before it can be used in the desired second step.
 5. Consider the following acid-base reactions.
a. Use curved arrows to show each reaction.
b. Draw the products of each reaction.
c. Hrxn using pKa values from Model 3.
d. Which reaction is downhill (favorable) and which reaction is uphill (unfavorable)?
e. Explain why the methyl H's were not removed in either case.

H H
N H
C C
H
H3C H

H3C C C H N H

6. One method of preparing an alkyne is to heat a geminal dihalide in the presence of a base (such as
hydroxide). (“Geminal dihalide” comes from Gemini meaning “twin” and refers to a carbon with
two halides.) Construct a reasonable mechanism for the following reaction.

H Cl

H 3C C C H 2 H2O
O H H 3C C CH
2 Cl
H Cl

7. Alkyl bromides are the most common starting materials for preparing Grignard, lithium, and
lithium dialkyl cuprate reagents, but Cl and I also work. Draw the products of each of the following
reactions and show the products as ions to emphasize the polarization of the C–M bond (M =
metal).