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Carboxylic acids and carboxylic acid derivatives Carboxylic acid The carboxyl group is the first complex functional group. It consists a C=O and OH, but due to their interactions it is not an oxo compound and not an alcohol. Carboxylic acids, compounds of the type Classification ● According to R group - unsubstituted / substituted - saturated / unsaturated / aromatic - linear / branched / cyclic Within the substituted carboxylic acids: halogen, hydroxy, oxo and amino acids (the most important) Other subgroups: 2- (-), 3- (β-), 4- (γ-), … ● According to the number of carboxyl groups mono-, di-, tri-, ..., polycarboxylic acids Carboxylic Acid Derivatives Summarized as follows: one oxygen atom substitution with other hetero atoms - visibly a lot of variations is possible! The most important ones are: Nomenclature of Carboxylic Acids and their Derivatives 1. Carboxylic Acids Nowhere in organic chemistry are common names used more often than with the carboxylic acids. monocarboxylic acids: C1 = formic acid (acidum formicum), C2 = acetic acid (acidum aceticum), …, C4 = butyric acid (acidum butiricum), … dicarboxylic acids: C2 = oxalic acid (acidum oxalicum), C3 = malonic acid (acidum malonicum), C6 = glutaric acid (acidum glutaricum), … substituted carboxylic acids– natural sources: hydroxy carboxylic acids Systematic names: Substitutive nomenclature acyclic compounds - The name of the corresponding hydrocarbon base + „oic acid” ending (alkanoic acid) --- In case of dicarboxylic acid "diacid" ending– Systematic names for carboxylic acids are derived by counting the number of carbons in the longest continuous chain that includes the carboxyl group and replacing the -e ending of the corresponding alkane by -oic acid. The first three acids. When substituents are present, their locations are identified by number; numbering of the carbon chain always begins at the carboxyl group. If there is a higher priority group / skeleton COOH prefix („carboxy”) Notice that compounds containing OH group are named as hydroxy derivatives of carboxylic acids, rather than as carboxyl derivatives of alcohols. We have seen earlier that hydroxyl groups take precedence over double bonds, and double bonds take precedence over halogens and alkyl groups, in naming compounds. Carboxylic acids outrank all the common groups we have encountered to this point. Double bonds in the main chain are signaled by the ending -enoic acid, and their position is designated by a numerical prefix. cyclic carboxylic acids or polycarboxylic acids (n ≥ 2) „ carboxylic acid” suffix connected to main hydrocarbon chain - In this case the group COOH is not numbered! When a carboxyl group is attached to a ring, the parent ring is named (retaining the final -e) and the suffix -carboxylic acid is added. Compounds with two carboxyl groups are distinguished by the suffix -dioic acid or dicarboxylic acid as appropriate. The final –e in the base name of the alkane is retained. Nomenclature of Carboxylic Acid Derivatives In naming carboxylic acid anhydrides in which both acyl groups are the same, we simply specify the acyl group and add the word “anhydride.” When the acyl groups are different, they are cited in alphabetical order. Substitutive IUPAC names for nitriles add the suffix -nitrile to the name of the parent hydrocarbon chain that includes the carbon of the cyano group. Nitriles may also be named by replacing the -ic acid or -oic acid ending of the corresponding carboxylic acid with -onitrile. Alternatively, they are sometimes given functional class IUPAC names as alkyl cyanides. 2. Group names derived from carboxylic acids Usual name: acyl Trivial name: „Latin base" + "YL" suffix In case of systematic name: name– ”acid” + „oil” – functional group name does NOT exist!! Name of polyacids / cyclic acid– „ carboxylic acid” suffix+ carbonyl ending 3. Carboxylic acid salts / carboxylate ions - Trivial name: „Latin base" + „ate" suffix - systematic name: - „acid” ending+ „oate” suffix - In case of a cyclic systems : - „carboxylic acid” suffix+ „ carboxylate” 4. Carboxylic acid halides - Trivial name: „Latin base" + "YL" suffix - systematic name: - ”acid” + „oil” suffix - cyclic systems: „carboxylic acid” suffix +„carbonyl halogenide” O Prefix: „halogen formyl” (eg. bromoformyl) Br + Beginning with the cation name!! 5. Carboxylic acid anhydrides 5.1. The simplest case: symmetric unsubstituted anhydrides any type of nomenclature: „anhydride” suffix (propionic anhydride, heptanoic anhydride, cyclopentane carboxylic acid anhydride) 5.2. Symmetric unsubstituted anhydrides bis(X-carboxylic acid)anhydride bis(chloro acetic acid) anhidrid 5.3. Mixed acid anhydrides: name of component acids in alfabetic order + „anhydride” ending. Pl. acetic formic anhydride 6. Carboxylic acid esters 6.1. Traditional names= „salt like”, formaly carboxylate 6.2. Ester of the given carboxylic acid 6.3. Higher priority group in the chain acyloxy (RCOO-) or alkoxy/aryloxy carbonyl (ROCO-) prefix 7. Carboxylic acid amides 7.1. primary amides - In case of trivial name: „latin base” + „amide” suffix - In case of systematic name: carboxylic acid + amid suffix - In case of cyclic systems: instead of „carboxylic acid” suffix „carboxamide” 7.2. Secondary and tertiary amides – derivatives of N-(di)substituted of primary amides Bonding system of carboxylic acids and their derivatives O R O H + model, + M effect (conjugative interaction with nonbonding e-pair and -bond) three-center, four-electron bond sp2 hybridization of the hydroxyl oxygen allows one of its unshared electron pairs to be delocalized by orbital overlap with the system of the carbonyl group In resonance terms, this electron delocalization is represented as: Important consequences : Delocalized bonding system – resonance structure! The sp2 hybrid state and +M effect are proved by bond angles and distances! C(sp3)-OH bond distance~ 143 pm!! Bond angle: steric effects - C=O bond distance increases, - C-O bond distance is shortened, bond order is increases - „ carbonyl” O high electron density (basic/nucleophile) center Generally: LCAO-MO description similarity to NO2 group!! The effect of quality of heteroatom :Y 1. EN (Cl > O > N) 2. Ability for + M effect (it basically depends on the size, pl. Cl > Br, O > S) The electron distribution (the share of resonance structures) the resultant of the two factors, it is determining the stability of the carboxylic acid derivatives and reactivity. 1. example: carboxylic acid anhydride vs. carboxylic acid ester For carboxylic anhydride bidirectional electron shift, smaller stabilization 2. example: carboxylic acid amides Th electronegativity of N is small (relatively weak –I), good donation for nonbonding e-pair on N C=N double bond is dominant Stability is increasing (biological importance: peptides), high planarity, restricted rotation around the C-N bond existence of diastereomers Rotation Barrier - G‡ = 63 – 84 kJ/mole!!! Special case: carboxylate ion– fully balanced electronic structure, equivalent resonance structures, symmetric charge distribution stable anion dC-O = 0.127 nm The physical properties of carboxylic acids and their derivatives 1. Carboxylic acids Boiling point values: Intermolecular H-bridge, "dimeric" structure ~ 0.10 nm induced dipoledipole-dipole H-bond induced dipole Double H-bond PhCOOH; mp: 122 oC, bp: 250 oC Apparently, the Mp. curve not monotonic increasing, Bp. is monotonic increasing The water solubility of carboxylic acids: at lower number C is high, in homologous line decreases (cf. H-bridge solvation) 2. Carboxylic acid amides Name Mp (°C) Bp (°C) water solubility HCONH2 formamide 2 193 soluble CH3CONH2 acetamide 82 222 soluble CH3CH2CONH2 propionamide 81 213 soluble CH3CH2CH2CONH2 butyramide 115 216 soluble C6H5CONH2 benzamide 132 290 limited Stronger associates than its carboxylic acids, therefore higher mp and bp. Solubility in water at low Cn unlimited or good. 3. Carboxylic acid halides, anhydrides, esters Mp, bp is lower than RCOOH, RCONHR1 – only dipole-dipole interaction Bp. (oC) Mw AcOH 118 60.05 AcNH2 222 59.07 Ac2O 138-140 102.09 AcOMe 57-58 74.08 AcCl 52 78.50 Chemical properties of carboxylic acids and their derivatives 1. Acidity of carboxylic acids and acid derivatives For acidic strength the stability of the resulting anion is determining O-H (S-H), N-H and C-H acidity 1.1. Carboxylic acids HCOOH CH3COOH pKa 3.75 4.76 Due to the high stability of the carboxylate: significant acidity C(2-5)COOH 4.81-4.88 Incorporation of an alkyl group reduces the acidity – EDG group! decreasing anion stabilty The effect of the substituents of alkyl group – EWG substituents increasing the stability of the carboxylate ion increasing acidity Ionisation Constant pKa The acidic strength increase depends on the numbers and position of EWG substituents CF3COOH – pKa = 0.23!! (acidity of inorganic acids) EtCHClCOOH – pKa = 2.86, MeCHClCH2COOH – pKa = 4.05, Cl(CH2)3COOH – pKa = 4.76 1.1. Acidity of carboxylic acids Dicarboxylic acids – two dissociation steps, two pKa Here already far the second COOH (1,4-position) and seven membered H-bond cycle… CH3COOH – pKa = 4.76 Aromatic carboxylic acids - 6 system and carboxylate anion 4 system has conjugation therefore increasing stability stronger acid o-/p-position EDG/EWG substituents can decreasing or increasing the acidity - I < +M - I, - M - I , M effect is negligible 1.2. Acidity of carboxylic acid amides – N-H acidity Amides exhibit increased acidity compared with the amines. Additional electron withdrawing / mezomeria stabilization functional groups increase the acidity. alkalisoluble 1.3. Acidity of carboxylic acid esters / carboxylic acid anhydrides – C-H acidity Analogy: C-H acidity of aldehydes/ketones (-deprotonation) The formed carbanion: „enolate” form is very stable R pKa alkyl 24-25 H 20 COOQ 13 COQ 11 Acetoacetate--- acetylacetone β-keto carboxylic acid esters can be deprotonated even in alkali /alcoholate solution 2. Basicity of carboxylic acids and acid derivatives C=O: oxygen has large electron density Brönsted-, Lewis-acids can attack Acid catalysed processes, increased electrophilicity of „carbonyl” C!! 3. Nucleophilic Acyl Substitution of carboxylic acid derivatives - carboxylic acid derivatives – Conversion of carboxylic acid derivatives into each other electrophilic character of „carbonyl” C → nucleophilic attack In the first step, "tetrahedral intermediate„ Its formation is analogous with the reactions of aldehydes and ketones, BUT! X is a good LG! Possibility for the formation of C=O, and even the formation of a stable CONu unit Acylation of Nu unit! G Fundamental issue (free) enthalpy changes in the reaction – tetrahedral the energy relations of products intermediate and starting materials Reagents Products reaction coordinate Carboxylic acid derivatives: RCOHlg < (RCO)2O < RCOSR < RCOOR1 ~ RCOOH < RCONH2 + egyéb amidok < RCOOƟ increasing stability! increasing reactivity! Mostly spontaneous reactions! In the opposite direction specific reagents / conditions Substitution reactions of carboxylic acid chlorides (halides) Similar reactions in the case of acid anhydrides, although slower reaction! (worse leaving group) The most important reactions of esters starting material of heterocycles irreversible (cf. stability of carboxylate!) The reactivity of esters can be increased if Q containing EWG group ("active esters") Reactions of carboxylic acids The similar stability of carboxylic acid and ester a reversible process - an acid catalysed reaction!!! (three different mechanisms) Q: reaction of carboxylic acids with nucleophiles?? Nu is a base it reacts with the acid (deprotonation!) – carboxylate ion is very stable – no further reaction with the Nu 1. Salt formation 2. Heating of solid ammonium salts primary amides can be obtained. Rather an industrial method! Reactions of carboxylic acid derivatives with C nucleophiles Special case - usually irreversible process. Conditions: ● no acidic H (O-H, N-H, S-H) ● sufficiently electrophilic C=O carbon Derivatives that may be relevant : acid halides, acid anhydrides, esters! 1. Reaction with Grignard reagent (you know these ) Using less reactive organometallic reagent (R2Cd) ketones can be prepared selectively. 2. Reactions with other C-nucleophiles (Z1, Z2 at least one is EWG) – both nucleophilic and electrophilic is derived from the same compound (analogy to the aldol dimerization) secondary reactions: ketone will react further It is a "crossed Claisen" version, four products can be formed BUT! If only one can be electrophile than two products will be formed. Reactions in -position 1. -Halogenation Halogenation only in -position! Significance: easy nucleophilic substitution (Nu = NH2, OH, CN, …) Different mechanisms depending on the quality of the halogen. -Bromination – via enol; Br2/PBr3/D = Hell-Volhard-Zelinsky Reaction 2. -Oxidation In biological systems it is important (Krebs cycle, glycolysis) R = Me (pyruvic acid, pyruvic acid) Oxidation and reduction of carboxylic acids and their derivatives The carboxylic acids are the highest oxidation state of the organic compounds, oxidative conversion of COX functional groups is not significant Due to the high stability of the COX group the reduction is difficult! Eg. Catalytic reduction is possible only in special cases, at high pressure and temperature. In practice: metal hydrides Similar reaction: RCOCl Thermal reactions of carboxylic acids The driving force is the high stability of CO2. Decarboxylation of alkane acid is less effective, requires high temperatures (melt). Easier from salts (eg. On the presence of solid NaOH). Aromatic carboxylic acids can loose CO2 easier. Dicarboxylic acids and β-oxocarboxylic acids can be decarboxylated already under 100 °C For produce simple alkanoic acid anhydride it is not a general reaction. For ,-dicarboxylic acids cyclic anhydrides can be formed, preferred formation process in case of 5- and 6-membered rings Preparation of carboxylic acids and their derivatives 1. Carboxylic acids Due the high oxidation state of the carboxylic acids predominantly oxidative processes Carboxylic acid mixture is formed. Low practical significance. Exception: symmetrical compounds (R = R1 or ring) Practical significance: adipic acid synthesis - Nylon 66 starting materials, E355 (flavour and gelling compound) 2.5 Mt/year! 1.1.2. Oxidation of aromatic compounds with alkyl side chain Any R results benzoic acid derivative ! Oxidising agents: KMnO4 or K2Cr2O7/H 1.1.3. Oxidation of alcohols – mainly, primary alcohols For secondary and tertiary alcohols: mixture!! 1.1.4. Oxidation of aldehydes – takes place easily with mild oxidizing agents Aldehyde synthesis: particularly from 1o alcohols 1.2. Substitution methods (C1 fragment incorporation) 1.3. Aromatic carboxylic acids – Kolbe and Kolbe-Schmidt-synthesis 1.4. ,β-unsaturated carboxylic acids – Perkin-, Knoevenagel-syntheses 2. Carboxylic acid derivatives Basically from carboxylic acid derivative with interconversion – from the more reactive derivative a more stable product can be easily obtained Q: Preparation of a highly reactive, unstable derivatives from carboxylic acids Reagents: SOCl2, SO2Cl2, PCl3, POCl3, PCl5, … Thermal activation + highly reactive reaction partner (inorganic acid chloride!!) + LeChatelier-Braun principle synthetically used reaction Preparation of carboxylic acid anhydrides eg. P2O5