1. Preparation and Reactions of Carboxylic Acids

2. Learning Objectives
1- Synthesis (preparation) of carboxylic acids by: 1.1 Oxidation of primary alcohol 1.2 Carboxylation of Grignard reagents 1.3 Hydrolysis of Nitriles 2-Reactions of carboxylic acids: 2.1 Neutralization 2.2 Reduction 2.3 Alkylation 2.4 Decarboxylation of β-dicarboxylic acids

3. Acid base definitions First Theory : Brønsted–Lowry acid–base theory
It donates hydrogen ions (H+)
such as HCl, HNO3 CH3COOH
It accepts hydrogen ions (H+)
such as NH3, CH3COO-, OH-
Acid + Base conjugate base + conjugate acid
HA + B A BA+
CH3COOH + H2O CH3COO H3O +

4. Second theory: Lewis definitions Acid Base
Lewis acid : electron pair Acceptor
Lewis Acids are Electrophilic
Lewis Base: Lone pair Donor
Lewis Bases are Nucleophilic
Examples
1. All cations are Lewis acids since they are able to accept electrons. (e.g., Cu2+, Fe2+ )
2. An atom, ion, or molecule with an incomplete octet of electrons can act as an Lewis acid (e.g., BF3, AlF3).
3. Molecules that have multiple bonds between two atoms of different electronegativities (e.g., CO2, SO2)
Examples of lewis base are electron pair donors which include
simple anions, such as OH-, CN-, RCOO- and F-
lone-pair containing species, such as H2O, NH3, CO
electron rich π-system Lewis bases, such as pyridine and benzene

5. Electrophile (El) Nucleophile (Nu)
Electrophile (El)
Nucleophile (Nu)
Electron deficient group accepting an electron pair
It can be neutral or positively charged
- It has affinity to bond to a Lewis base or a nucleophile
Electron rich group donating an electron pair
It can be neutral or negatively charged
It attacks the + charge on electrophile, or bonds to a Lewis acid
Because electrophiles accept electrons, they are Lewis acids
Because nucleophiles donate electrons, they are by definition Lewis bases
Examples :
Cations such as H+ and NO+
Neutral molecules such as HCl, Cl2 and Br2,
Carbon in alkyl halides, acyl halides, and carbonyl compounds
( e.g keton and ester)
Carbon electrophiles in alkyls
Examples
Anions, such as Cl-, CN-, and F-
lone-pair containing species, such as NH3
Carbon nucleophiles in the Grignard reagent (CH3 – MgBr) and organolithium reagent (CH3 – Li).
Oxygen nucleophiles are H2O, OH-, RCOO−,
Sulfur nucleophiles: H2S,RSH, RS-
Nitrogen nucleophiles include ammonia, azide N3-, amines, and nitrites.

6. Common electrophiles and nucleophiles
Chemical group
Type
proton (H3O+)
electrophile
alkyl halide (CH3-Br)
alcohol (CH3-OH)
aldehyde (CH3 - CHO)
ketone (CH3 - CO - CH3)
acid chloride (CH3 - CO - Cl)
ester (CH3 - CO - OCH3)
boron trifluoride (BF3)
thionyl chloride (Cl - SO - Cl)
phosphorous trichloride (PCl3)
chloride ion (Cl-)
nucleophile
hydroxide ion (OH-)
methoxide ion (CH3O-)
cyanide (CN-)
Organolithium compound (CH3 - Li)
Grignard reagent (CH3 - MgBr)
amine (N(CH3)3)
phosphine (P(CH3)3)
pi bond (H2C = CH2)

7. Example : Decide if each molecule or ion shown below will react as a nucleophile or electrophile, or both.
Solution :
a. Bromide ion:  This atom has four lone pairs and a formal negative charge, suggesting it is electron-rich and can therefore function as a nucleophile.  If it has none of the features that would suggest it might behave as an electrophile.
b. Ammonium ion: This ion has a formal positive charge, suggesting it is electron-poor and can therefore function as an electrophile.  It has no lone pairs or negative charge, suggesting it will not function as a nucleophile.
c. Water: The oxygen atom of water has two lone pairs and a δ - charge (oxygen is more electronegative than hydrogen).  This suggests that water can behave an a nucleophile.  Each hydrogen atom bears a δ + charge, so the molecule can behave as an electrophile as well. 
Many molecules can be both nucleophiles and electrophiles.  How they behave depends upon what they react with. For example, if water is reacted with an electrophile, the water will behave as a nucleophile.

8. Examples of electrophile-electrophile reactions

9. Leaving Group LG
It is a group that tends- or favours -to leave with a pair of electrons
It can be neutral ( e.g NH3 & H2O) or anions ( OH-, halides)
What makes a Good Leaving Group ( LG)?
As for acidity, the more stable A- is, the more the equilibrium will favour dissociation, and release of H meaning that HA is more acidic.
For the leaving group, the more stable LG- is, the more it favours "leaving“, meaning that the better leaving group LG- is .
Examples of Leaving groups

10. Synthesis of Carboxylic acids

11. (1) oxidation of 1o alcohols
Carboxylic acids can be prepared by oxidizing primary alcohols or aldehydes. The oxidation of primary alcohols leads to the formation of aldehydes that undergo further oxidation to yield acids.
The oxidation of ethanol produces ethanoic acid (acetic acid).
OH O O
| [O] || [O] ||
CH3—CH CH3—C—H CH3—C—OH
ethanol ethanal ethanoic acid
(ethyl alcohol) (acetaldehyde) (acetic acid)

12. (1) oxidation of 1o alcohols
All strong oxidizing agents (potassium permanganate KMnO4 , potassium dichromate K2Cr2O7, and chromium trioxide CrO₃) can easily oxidize the aldehydes that are formed.
CH3CH2CH2CH2-OH CrO3  CH3CH2CH2COOH
n-butyl alcohol butyric acid
1-butanol butanoic acid
CH CH3
CH3CHCH2-OH KMnO4  CH3CHCOOH
isobutyl alcohol isobutyric acid
2-methyl-1-propanol` methylpropanoic acid

13. (2) Carboxylation of Grignard Reagents
Grignard reagents are strong nucleophiles reacting with electrophiles such as carbonyl compound
Grignard Reagents Increase the carbon chain by one carbon.
Grignard reagents are also very strong bases and will react with acidic hydrogens (such as alcohols, water, and carboxylic acids).
Grignard reagents react with carbon dioxide to yield acid salts, which, upon acidification, produce carboxylic acids.
hydrolysis
Gringard reagent

14. NUCLEOPHILIC ADDITION OF RMgX TO CARBON DIOXIDE
( carbon in Gringard reagent is partly negative and magnesium is partly positive because the C is more elctronegative than Mg)
Step 1: The nucleophilic C in the Grignard reagent adds to the electrophilic C in the polar carbonyl group, electrons from the C=O move to the electronegative O creating an intermediate magnesium carboxylate complex.
Step 2:
Protonation of the carboxylate oxygen creates the carboxylic acid product from the intermediate complex.

15. (3) Hydrolysis of Nitriles
Nitriles are compounds which contain cyanide ion CN- attached to a hydrocarbon group (R).
Cyanide ion is an excellent nucleophile and will react with alkyl halides to give nitriles. This reaction involves 2 steps and results in an increase in the length of the carbon chain because of the extra carbon in the -CN group. The nitrile can be hydrolyzed to a carboxylic acid
General Example
nitrile
hydrolysis

16. Step 1. Nitriles are prepared by SN2 (Nucleophilic substitution ) reactions of alkyl halids ( R-X) with Sodium cyanide NaCN
Step 2. Hydrolysis of the nitriles yields a carboxylic acids (-C≡N is converted to –COOH)
Specific Examples 1.
CH3-Br
CH3-CN
CH3COOH + NH4+ 2.

17. Learning Check What alcohol could be used to prepare the following:
butanoic acid
propanoic acid

18. Solution What alcohol could be used to prepare the following:
[O] [O]
1. butanol butanal butanoic acid
[O] [O]
2. propanol propanal propanoic acid

19. Reactions of Carboxylic Acids

20. 1.Neutralization
Salts of Carboxylic Acids
Carboxylic acids are neutralized by strong bases to give carboxylate salts.
as long as the molecular weight of the acid is not too high, sodium and potassium carboxylate salts are soluble in water

21. 1.Neutralization O O RCOH + HO– RCO– + H2O weaker acid stronger acid
salt 16

22. Fatty Acids; Carboxylic Acids (R-CO2H) where R
group contains carbons.
Soaps/detergents; Salts of long chain fatty acids

23. Micelles: substances with polar (hydrophilic) head groups and hydrophobic tail groups form aggregates in water with the carboxylate groups on the outside and nonpolar tails on the inside.
Steric acid

24. Micelles CH3(CH2)16C O CH3(CH2)16CO O Na+ – OH + NaOH + H2O nonpolar18

25. 2.Reduction Reduction to a 1° alcohol
Use strong reducing reagent: LiAlH4.
It reduces carboxylic acid to alcohol.

26. Difficult to stop reduction at aldehyde.
Reduction to Aldehyde
Difficult to stop reduction at aldehyde.
Use a more reactive form of the acid
(an acid chloride) and a weaker reducing agent, lithium aluminum tri(tbutoxy)hydride.
benzaldehyde

27. 3.Alkylation to Form Ketones
React 2 equivalents of an organolithium reagent (e.g CH3-Li) with a carboxylic acid to produce keton.
CH2CH3
Benzoic acid
Ethyl phenyl ketone

28. 4. Decarboxylation RCOH O + CO2 RH
Decarboxylation: is loss of carbon dioxide, Reaction type: Elimination
most carboxylic acids, if heated to a very high temperature, undergo thermal decarboxylation
most carboxylic acids, however, are quite resistant to moderate heat and melt or even boil without decarboxylation
Simple carboxylic acids do not decarboxylate readily
RCOH O +
CO2 RH

29. 4. Decarboxylation HOCCH2COH O CH3COH O 150°C + CO2
Carboxylic acids with a carbonyl group at the 3- (or β-) position readily undergo thermal decarboxylation, e.g. derivatives of malonic acid.
The reaction proceeds via a cyclic transition state giving an enol intermediate that tautomerizes to the carbonyl
HOCCH2COH O
CH3COH O
150°C +
CO2 28

30. 4. Decarboxylation
Step 1: Remember curly arrows flow.... Start at the protonation of the carbonyl, break the O-H bond and form the p bond, break the C-C and make the C=C. Note the concerted nature of this reaction and the cyclic transition state.
Step 2: Tautomerization of the enol of the carboxylic acid leads to the acid product (not shown here).