Carboxylic acids and carboxylic acid derivatives

Carboxylic acidThe 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.

● 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

Classification

Carboxylic acids, compounds of the type

Carboxylic Acid DerivativesSummarized 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 Derivatives1. Carboxylic Acids Nowhere in organic chemistry are common names used more often than with the carboxylicacids. ➢ 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. When substituents are present, their locations are identified by number; numbering of the carbon chain always begins at the carboxyl group.

➢ 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!

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 theirposition is designated by a numerical prefix.

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, wesimply specify the acyl group and add the word “anhydride.” When the acyl groups aredifferent, 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 acidsUsual name: acylTrivial name: „Latin base" + "YL" suffixIn case of systematic name: name– ”acid” + „oyl” – 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”

+ Beginning with the cation

name!!

4. Carboxylic acid halides- Trivial name: „Latin base" + "YL" suffix- systematic name: - ”acid” + „oil” suffix- cyclic systems:„carboxylic acid” suffix +„carbonyl halogenide”

Prefix: „halogen formyl” (eg. bromoformyl)Br

O

5. Carboxylic acid anhydrides

5.1. The simplest case: symmetric unsubstituted anhydridesany type of nomenclature: „anhydride” suffix (propionic anhydride, heptanoic anhydride, cyclopentane carboxylic acid anhydride)5.2. Symmetric unsubstituted anhydridesbis(X-carboxylic acid)anhydride

5.3. Mixed acid anhydrides: name of component acids in alfabetic order + „anhydride” ending. Pl. acetic formic anhydride

bis(chloro acetic acid) anhidrid

6. Carboxylic acid esters

6.1. Traditional names= „salt like”, formaly carboxylate6.2. Ester of the given carboxylic acid6.3. Higher priority group in the chain

acyloxy (RCOO-) or alkoxy/aryloxy carbonyl (ROCO-) prefix

7. Carboxylic acid amides7.1. 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

R OH

O + model, + M effect (conjugative interaction with nonbonding e-pair and -bond) three-center, four-electron bond

Delocalized bonding system – resonance structure! Important consequences :- C=O bond distance increases,- C-O bond distance is shortened, bond order is

increases- „ carbonyl” O high electron density

(basic/nucleophile) center

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

Generally:

LCAO-MO description similarity to NO2

group!!

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:

The effect of quality of heteroatom :Y 1. EN (Cl > O > N)2. Ability for + M effect (it basically depends on the size; Cl > Br, O > S)The electron distribution (the share of resonance structures) is the resultant of the two factors, it is determining the stability of the carboxylic acid derivatives and their reactivity.1. example: carboxylic acid anhydride vs. carboxylic acid ester

For carboxylic anhydride bidirectional electron shift,

smaller stabilization

2. example: carboxylic acid amides

The 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!!!

The physical properties of carboxylic acids and their derivatives1. Carboxylic acids

Boiling point values:

H-bond~ 0.10 nm

Intermolecular H-bridge, "dimeric" structure

PhCOOH; mp: 122 oC, bp: 250 oC

Special case: carboxylate ion– fully balanced electronic structure, equivalent resonance structures, symmetric charge distribution

stable anion dC-O = 0.127 nm

Double H-bond

Apparently, the Mp. curve not monotonic increasing, Bp. is monotonic increasing

induced dipole-induced dipole

dipole-dipole

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 solubleCH3CONH2 acetamide 82 222 solubleCH3CH2CONH2 propionamide 81 213 solubleCH3CH2CH2CONH2 butyramide 115 216 solubleC6H5CONH2 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, estersMp, bp is lower than RCOOH, RCONHR1 – only dipole-dipole interaction

AcOH AcNH2 Ac2O AcOMe AcCl

Bp. (oC) 118 222 138-140 57-58 52

Mw 60.05 59.07 102.09 74.08 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 acidity1.1. Carboxylic acids

Due to the high stability of the carboxylate: significant acidity

HCOOH CH3COOH C(2-5)COOH

pKa 3.75 4.76 4.81-4.88

Incorporation of an alkyl group reduces the acidity – EDG group! decreasing anion stability

The effect of the substituents of alkyl group – EWG substituents increasing the stability of the carboxylate ion increasing acidity

Ionisation Constant pKa

CF3COOH – pKa = 0.23!! (acidity of inorganic acids)EtCHClCOOH – pKa = 2.86, MeCHClCH2COOH – pKa = 4.05, Cl(CH2)3COOH – pKa = 4.76

The acidic strength increase depends on

the numbers and position of EWG

substituents

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 decrease or increase 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.alkali-

soluble

1.3. Acidity of carboxylic acid esters / carboxylic acid anhydrides – C-H acidityAnalogy: C-H acidity of aldehydes/ketones (-deprotonation)The formed carbanion: „enolate” form is very stable

R alkyl H COOQ COQ

pKa 24-25 20 13 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. Acyl Nucleophilic Substitution of carboxylic acid and its 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

G

reaction coordinateReagents

tetrahedral intermediate

Products

Fundamental issue (free) enthalpy changes in the reaction –the energy relations of products and starting materials

RCOHlg < (RCO)2O < RCOSR < RCOOR1 ~ RCOOH < RCONH2 + other amides < RCOOƟ

increasing stability!

increasing reactivity!

Mostly spontaneous reactions! In the opposite direction specific reagents / conditions

Acylation of Nu unit!

Carboxylic acid derivatives:

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

irreversible (cf. stability of

carboxylate!)

starting material of heterocycles

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 formation2. Heating of solid

ammonium salts primary amides can be obtained.

Reactions of carboxylic acid derivatives with C nucleophilesSpecial 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 ☺)secondary reactions:

ketone will react further

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)

Rather an industrial method!

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. -HalogenationHalogenation 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, oxidativeconversion 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 derivatives1. Carboxylic acidsDue 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-synthesis1.4. ,β-unsaturated carboxylic acids – Perkin-, Knoevenagel-syntheses

2. Carboxylic acid derivativesBasically from carboxylic acid derivative with interconversion – from the more reactive derivative a more stable product can be easily obtainedQ: 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

Substituted (OH, Hlg) carboxilyc acids: classification,

nomenclature, synthesis, and physical and chemical

properties.

Classification and nomenclature of oxo-carboxilyc acids:

synthesis and physical and chemical properties.

Synthetic application of β-oxo and β-dicarboxylic acid.

Substituted carboxylic acids I.1. Halogenated carboxylic acids

Most important properties:

• Increased acidity (see earlier: acid - base properties of carboxylic acid)

• C-Hlg bond is highly polarized, electrophilic C atom → SN and EN reactions are more

favorable esspecially in the of - and -substituted derivatives.

• Opportunity of intramolecular substitution (SNi)

• Hydrolisis (H2O; MOH/H2O; M2CO3/H2O) – the structure of the products are depend

from the position of halogene

• -halo carboxylic acids: increased SN reactivity:

• -halo carboxylic acids: increased EN reactivity:

• In the case of - or -halo carboxylic acids the ring closing, the lactone formation is

preferable (SNi reaction)

E2 mechanism, the more acidic proton is

cleaved – stabilized anion!

n = 1; -lactone

n = 2; -lactone

2. Hydroxy carboxylic acids:

Increased acidity (see earlier: acid - base properties of carboxylic acid)

General properies: typical reactivity of hydroxy and carboxyl groups (e.g.: ether ,ester

formation, etc.) but some special reactivities are also known!

• -Hidroxy carboxylic acids

• -Hidroxy carboxylic acids: increase elimination ability

• -Hidroxy carboxylic acids: lactone formation

R: H, alkyl, aryl

n = 1; -lactone

n = 2; -lactone

Substituted carboxylic acids II.

3. Oxocarboxylic acids

The α- and β-oxocarboxylic acids are more important, because of the interaction of oxo-

and carboxyl group.

3.1. α-Oxocarboxylic acids

Increased reactivity (AdN) on the carbonyl group: e.g. stable hydrates

Glyoxylic acid, pyruvic acid: reducing activity

Easy decarbonylation

Substituted carboxylic acids III.

3.2. β-Oxocarboxylic acids and their esters

Key Features:

● strong intramolecular hydrogen bond with high enol content

● high C-H acidity

(see eaelier: stability of the carbanion/enolate)

The enolate is ambident nucleophile (C- és O-nukleofil)! Thermodinamically the enol form

is less because of the high stability of C=O bond!

Outcome: It can react as C-nucleophile, but it is depend from the electrophilic partners:

C-nucleophile is a soft nucleophilr/soft electrophile; O-nucleophile: hard nucleophile/hard

electrophile! E.g.: (CH3)3SiCl – hard electrophile – silylenol-ether is formed.

R O

O OH

R OH

O OH

R OR1

O O :B

R OR1

O O

R OR1

O O

R OR1

O O

pKa = 11

3-oxocarboxylic acids (and 1,3-dicarboxylic acids, like malonic acid) can decarboxylate (lost

CO2) under mild circumstance (70-100 oC)

Importnat synthetic methods were developed based on their C-H acidity and

decarboxylation – Malonic ester - and acetoacetic ester synthesis

Substituted carboxylic acids IV.

3.3. Synthetic application of β-dicarbonyl derivatives

In the -dicarbonyl derivatives there is a methylene group binding to two C=O groups. This

structural element cause that increased acidity of the methylene moiety, and it is stabilized

the formed anion (rezonance stabilized carbanion).

Water Methanol Ethnol Acetone Ethyl

acetate

Diethyl

malonate

Ethyl

acetoacetate

pKa 15,7 15,5 15,9 20 24 13 11

The spontaneus decarboxylation of -dicarbocxylic acids and -ketocarboxylic acids under

mild condition (heating at 70 – 100 C) gives substituted acetone and acetic acid derivatives.

Substituted carboxylic acids V.

Malonic ester - and acetoacetic ester synthesis: important synthesis methodsBased on the CH acidity and the easy decarboxylation of dicarboxylic compounds

Malonic ester synthesis

Synthesis of 2-monosubstituted or 2,2-disubstituted acetic acid derivatives

Possibilities: Synthesis of - and - oxo carboxylic acid derivatives

C-C bond formation reactions

diethyl malonate or

malonic acid's diethyl ester

Synthesis of 1-monosubstituted or 1,1-disubstituted derivatives of acetoneCyclic compound also can be formed if R-R1 is cyclic

Possibilities: Formation of - and - diketones

Acetoacetic ester synthesis

ethyl acetoacetate

BUT! ACIDs also can be prepared by acetoacetic ester synthesis – using concentrated (cc.) base!

Synthesis of heterocyclic compounds

Reactions of β-dicarbonyl derivatives as 1,3-dielectrophiles with 1,2- or 1,3-dinucleophiles

give five- or sixmemberd heterocyclic compounds (see later in details).