Preparation and Reactions of Carboxylic Acids 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 Acid base definitions First Theory : Brønsted–Lowry acid–base theory Acid Base It donates hydrogen ions (H+) It accepts hydrogen ions (H+) such as HCl, HNO3 such as NH3, CH3COO-, OHCH3COOH Acid + Base HA + B CH3COOH + H2O conjugate base + conjugate acid ACH3COO- + BA+ + H3O + 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 1. simple anions, such as OH-, CN, RCOO- and F2. lone-pair containing species, such as H2O, NH3, CO 3. electron rich π-system Lewis bases, such as pyridine and benzene 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 Because electrophiles accept electrons, they are Lewis acids Examples : 1. Cations such as H+ and NO+ 2. Neutral molecules such as HCl, Cl2 and Br2, 3. Carbon in alkyl halides, acyl halides, and carbonyl compounds ( e.g keton and ester) 1. Carbon electrophiles in alkyls -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 nucleophiles donate electrons, they are by definition Lewis bases Examples 1. Anions, such as Cl-, CN-, and F2. lone-pair containing species, such as NH3 3. Carbon nucleophiles in the Grignard reagent (CH3 – MgBr) and organolithium reagent (CH3 – Li). 4. Oxygen nucleophiles are H2O, OH-, RCOO−, 5. Sulfur nucleophiles: H2S,RSH, RS6. Nitrogen nucleophiles include ammonia, azide N3-, amines, and nitrites. Common electrophiles and nucleophiles Chemical group proton (H3O+) alkyl halide (CH3-Br) alcohol (CH3-OH) aldehyde (CH3 - CHO) ketone (CH3 - CO - CH3) acid chloride (CH3 - CO - Cl) Type electrophile electrophile electrophile electrophile electrophile electrophile ester (CH3 - CO - OCH3) boron trifluoride (BF3) thionyl chloride (Cl - SO - Cl) phosphorous trichloride (PCl3) chloride ion (Cl-) 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) electrophile electrophile electrophile electrophile nucleophile nucleophile nucleophile nucleophile nucleophile nucleophile nucleophile nucleophile nucleophile 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. Examples of electrophile-electrophile reactions 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 Synthesis of Carboxylic acids (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 | CH3—CH2 O [O] || [O] CH3—C—H ethanol (ethyl alcohol) ethanal (acetaldehyde) O || CH3—C—OH ethanoic acid (acetic acid) 11 (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 CH3 CH3CHCH2-OH + KMnO4 isobutyl alcohol 2-methyl-1-propanol` CH3 CH3CHCOOH isobutyric acid 2-methylpropanoic acid (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 13 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. (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 15 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. 2. CH3-Br CH3-CN CH3COOH + NH4+ Learning Check What alcohol could be used to prepare the following: 1. butanoic acid 2. propanoic acid 17 Solution What alcohol could be used to prepare the following: [O] 1. butanol [O] butanal [O] 2. propanol acid butanoic acid [O] propanal propanoic 18 Reactions of Carboxylic Acids 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 1.Neutralization O RCOH O + HO– RCO– + H2O weaker acid stronger acid salt Fatty Acids; Carboxylic Acids (R-CO2H) where R group contains 12-18 carbons. Soaps/detergents; Salts of long chain fatty acids 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 23 Micelles O O CH3(CH2)16C OH + NaOH nonpolar – CH3(CH2)16CO Na+ + H2O polar 2.Reduction Reduction to a 1° alcohol Use strong reducing reagent: LiAlH4. It reduces carboxylic acid to alcohol. 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 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 4. Decarboxylation Decarboxylation: is loss of carbon dioxide, Reaction type: Elimination Simple carboxylic acids do not decarboxylate readily O RCOH RH + CO2 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 4. Decarboxylation 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 O O HOCCH2COH 150°C O CH3COH + CO2 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).