Polyfunctional compounds

Polyfunctional compounds contain two or more functional groups. These

compounds are named using the IUPAC system, which prioritizes one
functional group as the parent (suffix) and treats others as substituents
(prefixes). The parent chain or ring is determined by the highest priority
functional group.

1,2-Dicarbonyl compounds are organic molecules containing two carbonyl groups

(C=O) located on adjacent carbon atoms. This proximity significantly influences their
chemical reactivity compared to monocarbonyl compounds.
Major types of 1,2-dicarbonyls include:

● 1,2-Dialdehydes:

The simplest example is glyoxal, also called ethanedial (IUPAC)(CHO-CHO),

which mainly exists as hydrates and oligomers. Glyoxal readily condenses with
amines and serves as a precursor to heterocycles like imidazoles.
● 1,2-Diketones: The principal compound is diacetyl

(2,3-butanedione)(IUPAC) . These diketones can be formed by oxidation of diols

and are notable for their relatively long C–C bond between the carbonyl carbons
due to charge repulsion. Examples like 2,3-butanedione and benzil (diphenyl
derivative) are found in foods and used as aroma components. They react with
bifunctional nucleophiles to form heterocycles and with aromatic amines to form
diketimines.
● 1,2-Ketoaldehydes: Compounds like methylglyoxal
 (pyruvaldehyde) fall into this class, also called α-ketoaldehydes.
● 1,2-Diesters and Diacids:

Oxalic acid and its esters are typical members, produced industrially by oxidation
of sugars and found naturally in plants. These can form cyclic diamides with
diamines.
● α-Ketoacids and Esters:
 Pyruvic acid is a well-known α-ketoacid important in metabolism (citric acid
cycle).
1,2-Dicarbonyl compounds are also important in food chemistry, formed during thermal
processing like caramelization and Maillard reactions, contributing to flavor and aroma
but also implicated in disease processes due to their reactivity.
In synthetic organic chemistry, 1,2-dicarbonyls are versatile intermediates, undergoing
cyclization reactions (e.g., aza-Prins reaction) and serving as building blocks for
heterocycles.
Summary Table:

Class Example Characteristics & Uses

Compound( common name)

1,2-Dialdehydes Glyoxal Exists as hydrate; precursor to

 heterocycles

Found in foods; aroma

1,2-Diketones Diacetyl (2,3-butanedione) compounds; heterocycle
precursors

α-Ketoaldehydes; reactive
1,2-Ketoaldehydes Methylglyoxal
species

Industrially produced; natural

1,2-Diesters/Diacids Oxalic acid in plants; cyclic diamides
formation

Metabolically important; citric

α-Ketoacids/Esters Pyruvic acid
acid cycle component

These compounds have distinct chemical behavior due to the adjacency of the carbonyl
groups, influencing bond lengths and reactivity patterns. They are significant both
biologically and industrially.

PROPERTIES OF ETHANEDIAL AND DIPHENYL DIKETONE

Diphenyl diketone structure
Ethanedial (also known as glyoxal) and diphenyl diketone (also known as
benzil) have distinct properties. Ethanedial is a colorless, flammable gas at
room temperature, while diphenyl diketone is a yellow crystalline solid.
Ethanedial is soluble in water and organic solvents, whereas diphenyl
diketone is soluble in ethanol and ether but insoluble in water.

Ethanedial (Glyoxal):

● Molecular Formula: C₂H₂O₂

● Molecular Weight: 58.04 g/mol
● Physical State: Colorless gas at room temperature
● Solubility: Soluble in water and organic solvents
● Flammability: Highly flammable
● Reactions: Undergoes combustion and has low chemical reactivity

Diphenyl Diketone (Benzil):

● Molecular Formula: C₁₄H₁₀O₂

● Molecular Weight: 210.23 g/mol
● Physical State: Yellow crystals
● Melting Point: 95 °C
● Boiling Point: 346-348 °C (decomposition)
 ● Solubility: Soluble in ethanol and ether, insoluble in water

Use: Pharmaceutical intermediates, UV curing resin photosensitizer

● Reactions: Benzoin is generated during reduction

Properties and Reactions of 1,2-Dicarbonyl Compounds

Properties
● Structure: 1,2-Dicarbonyl compounds have two carbonyl groups (C=O) on
adjacent carbons. A distinctive feature is the relatively long C–C bond (about
1.54 Å) between the carbonyl carbons, longer than typical C–C bonds due to
repulsion between partial positive charges on the carbonyl carbons2.
● Physical Appearance: Most 1,2-dicarbonyls are yellow solids or liquids. For
example, ethanedial (glyoxal) is yellow in liquid form and green in vapor4.
● Reactivity: The adjacent carbonyls increase electrophilicity, making these
compounds highly reactive toward nucleophiles. Glyoxal readily forms hydrates
and oligomers in water and condenses with amines to form heterocycles such as
imidazoles25.
● Biological and Food Chemistry: 1,2-Dicarbonyls form during thermal
processing of foods (caramelization and Maillard reactions), contributing to flavor
but also potentially leading to advanced glycation end-products implicated in
disease67.

Reactions
● Condensation with Amines: 1,2-Dicarbonyls readily condense with 1,2-
diamines to form heterocyclic compounds, a key route to synthesize nitrogen-
containing rings58.
 ● Aza-Prins Reaction: Under acidic conditions, 1,2-dicarbonyls react with amino-
containing substrates (e.g., vinyltetrahydroquinolines) to form tricyclic
benzazocines with high regio- and stereoselectivity1. The acetyl carbonyl group
is typically more reactive than benzoyl or ester carbonyls in unsymmetrical
dicarbonyls.
● Cannizzaro Reaction (for dialdehydes): Ethanedial undergoes internal
Cannizzaro reaction under alkaline conditions to yield hydroxy acids like glycolic
acid4.
● Benzilic Acid Rearrangement: 1,2-Diketones such as diphenylethanedione
(benzil) undergo base-induced rearrangement to form α-hydroxy acids (benzilic
acid), involving carbon skeleton rearrangement4.
● Condensation with Bifunctional Nucleophiles: 1,2-Diketones react with
compounds like urea or thiourea to form heterocycles.
● Electrophilic Aromatic Substitution: Under strong acid catalysis, 1,2-
dicarbonyls can react with arenes (e.g., benzene) to form gem-diphenylated
ketones9.
● Reduction and Other Transformations: Diphenyl diketone (benzil) can be
reduced to benzoin and participates in various nucleophilic addition reactions2.

Summary:

Aspect Description

Adjacent carbonyl groups with long C–C bond

Structure
(~1.54 Å)

Physical State Usually yellow solids/liquids

Reactivity Highly electrophilic; forms hydrates, oligomers

 Condensation with amines; aza-Prins;
Key Reactions Cannizzaro; benzilic acid rearrangement;
heterocycle formation

Formed in food processing; involved in

Biological Relevance
glycation

Building blocks for heterocycles and complex

Synthetic Utility
molecules

These properties and reactions make 1,2-dicarbonyl compounds versatile intermediates

in organic synthesis and important species in food and biological chemistry.

Examples of 1,3-Dicarbonyl Compounds

1,3-Dicarbonyl compounds have two carbonyl groups separated by one carbon atom (β-
dicarbonyls).
Common examples include:

● 1,3-Dialdehydes:
○ Malondialdehyde

Propanedial
 ○ (CH₂(CHO)₂) — the parent 1,3-dialdehyde, usually handled as hydrates
or oligomers.
● 1,3-Diketones (β-Diketones):
○ Acetylacetone (pentane-2,4-dione, CH₃C(O)CH₂C(O)CH₃) — a key
example, often predominantly existing in the enol form.
○ Dimedone (5,5-dimethyl-1,3-cyclohexanedione) — a cyclic 1,3-diketone.
○ 1,3-Indandione — a cyclic 1,3-diketone fused to a benzene ring.
○ 2,2,4,4-Tetramethylcyclobutanedione — a cyclic 1,3-diketone precursor to
diols.
● 1,3-Diesters and Diacids:
○ Malonic acid (CH₂(CO₂H)₂) — the parent 1,3-diacid.
○ Diethyl malonate — a common malonic ester used in organic synthesis.
● β-Ketoesters:
○ Ethyl acetoacetate — a β-ketoester widely used in synthesis.

These compounds are important in organic synthesis, often existing predominantly in

enol forms and serving as versatile intermediates for heterocycle formation and metal
complexation.
Summary Table:

Class Example Compound Notes

Usually handled as
1,3-Dialdehydes Malondialdehyde
hydrates/oligomers

Predominantly enol form; key

1,3-Diketones Acetylacetone
β-diketone

Dimedone Cyclic 1,3-diketone

 Benzene-fused cyclic
1,3-Indandione
diketone

1,3-Diesters/Diacids Malonic acid Parent 1,3-diacid

Diethyl malonate Common malonic ester

β-Ketoesters Ethyl acetoacetate Widely used β-ketoester

These examples illustrate the diversity and synthetic utility of 1,3-dicarbonyl

compounds.
2,4-Pentanedione and 1,3-Dicarbonyl Compounds

Properties of 2,4-Pentanedione (Acetylacetone)

Physical Properties
-Molecular formula: C₅H₈O₂
-Molecular weight: 100.12 g/mol
-Appearance: Colorless to pale yellow liquid
-Boiling point: 140-141°C
-Melting point: -23°C
-Density: 0.975 g/cm³ at 20°C
-Solubility: Miscible with water, alcohol, ether, and most organic solvents
-Odour: Pleasant, characteristic sweet odor

Chemical Properties
- Acidic nature: Shows acidic behavior due to the active methylene group (-CH₂-)
between two carbonyl groups
-pKa: Approximately 9.0 (relatively acidic for a ketone)
-Keto-enol tautomerism: Exists in equilibrium between keto and enol forms
-Chelating ability: Forms stable chelate complexes with metal ions
-Nucleophilic substitution: The methylene protons are highly acidic and can be
easily deprotonated

Electronic Properties
-Resonance stabilization: The enolate anion is stabilized by resonance between
the two carbonyl groups
-Conjugation: In the enol form, there is extended conjugation across the molecule
-Electron-withdrawing effect The two carbonyl groups make the central carbon
highly electrophilic

Tautomers of 2,4-Pentanedione

Keto Form (Diketone)

O O
‖ ‖
CH₃-C-CH₂-C-CH₃

- Less stable form in solution

- Predominant in gas phase
- No intramolecular hydrogen bonding

Enol Form (Enolic)

O O
‖ ‖
CH₃-C-CH=C-CH₃
|
H

- More stable in solution (approximately 85% at room temperature)

- Stabilized by intramolecular hydrogen bonding
- Forms a six-membered ring through hydrogen bonding
- Shows characteristic enol properties

Equilibrium
-in solution: Enol form predominates (~80% enol, ~20% keto)
-In gas phase: Keto form is more stable
-Factors affecting equilibrium:
- Solvent polarity
- Temperature
- pH of the medium
- Presence of metal ions
Uses of 1,3-Dicarbonyl Compounds

Industrial Applications
-Metal extraction and purification: Used as chelating agents for extracting and
purifying metals
- Catalysis: Serve as ligands in organometallic catalysts
-Solvent systems: Used in specialized extraction processes

Pharmaceutical Industry
-Drug synthesis: Important intermediates in the synthesis of various
pharmaceuticalsn.
- Antimicrobial agents: Some derivatives show antibacterial and antifungal
properties
- Anti-inflammatory compounds: Used in the synthesis of anti-inflammatory
drugs

Chemical Synthesis
- Organic synthesis: Key building blocks for complex organic molecules
- Heterocyclic chemistry: Precursors for pyrazoles, isoxazoles, and other
heterocycles
- Condensation reactions: Participate in Knoevenagel, Claisen, and Michael
reactions

Analytical Chemistry
- Complexometric titrations: Used as complexing agents in analytical procedures
- Spectrophotometric analysis: Form colored complexes with metal ions for
quantitative analysis
- Chromatographic applications: Used in separation techniques
Coordination Chemistry
- Metal complexes: Form stable chelate complexes with transition metals
- Coordination polymers: Building blocks for extended coordination structures
- Bioinorganic chemistry: Models for metalloenzyme active sites

Agricultural Applications
- Pesticide synthesis: Intermediates in the production of certain pesticides
- Plant growth regulators: Some derivatives used as growth modulators
- Soil treatment: Metal complexes used for soil conditioning

Materials Science
- Polymer synthesis: Monomers or crosslinking agents in specialized polymers
- Surface modification: Used in surface treatment and coating applications
- Nanomaterials: Precursors for metal oxide nanoparticles

Research Applications
- Model compounds: Used to study keto-enol tautomerism and hydrogen bonding
- Mechanistic studies: Help understand reaction mechanisms in organic chemistry
- Structural studies: Important for understanding molecular recognition and self-
assembly
Examples of 1,4-Dicarbonyl Compounds

Simple Aliphatic 1,4-Dicarbonyl Compounds

1. Succinaldehyde (Butanedial)
- Structure: CHO-CH₂-CH₂-CHO
- Formula: C₄H₆O₂
- Properties: Colorless liquid, highly reactive
- Uses: Organic synthesis intermediate

2. Glutaraldehyde (pentanedial)
Structure CHO-CH₂-CH₂-CH₂-CHO

- Formula: C₅H₈O₂
- Properties: Colorless liquid, pungent odor
- Uses: Disinfectant, crosslinking agent, biological fixative

3. Adipaldehyde (Hexanedial)
- Structure: CHO-CH₂-CH₂-CH₂-CH₂-CHO
- Formula: C₆H₁₀O₂
- Properties: Crystalline solid at room temperature
- Uses: Polymer synthesis, chemical intermediate

4. 2,5-Hexanedione
- Structure: CH₃-CO-CH₂-CH₂-CO-CH₃

- Formula: C₆H₁₀O₂
- Properties: Colorless liquid, neurotoxic
- Uses: Industrial solvent, chemical intermediate

5. 1,4-Butanedione (Diacetyl)
- Structure: CH₃-CO-CO-CH₃
- Formula: C₄H₆O₂
- Properties: Yellow liquid, butter-like odor
- Uses: Food flavoring agent, chemical intermediate

Mixed Carbonyl 1,4-Dicarbonyl Compounds

6. 4-Oxobutanoic acid (Succinic semialdehyde)

- Structure: CHO-CH₂-CH₂-COOH

- Formula: C₄H₆O₃
- Properties: Crystalline solid, water-soluble
- Uses: Biochemical intermediate, pharmaceutical precursor

7. 5-Oxopentanoic acid (Glutaric semialdehyde)

- Structure: CHO-CH₂-CH₂-CH₂-COOH
- Formula: C₅H₈O₃
- Properties: Solid, hygroscopic
- Uses: Organic synthesis, biochemical studies

8. Levulinic acid (4-Oxopentanoic acid)

- Structure: CH₃-CO-CH₂-CH₂-COOH
- Formula: C₅H₈O₃
- Properties: White crystalline solid
- Uses: Pharmaceutical intermediate, renewable chemical feedstock

Aromatic 1,4-Dicarbonyl Compounds

9. Terephthalaldehyde (1,4-Benzenedicarboxaldehyde)
- Structure: CHO-C₆H₄-CHO

(para-substituted)
- Formula: C₈H₆O₂
- Properties: White crystalline solid
- Uses: Polymer synthesis, liquid crystal precursors

10. 1,4-Diacetylbenzene
- Structure: CH₃CO-C₆H₄-COCH₃

(para-substituted)
- Formula: C₁₀H₁₀O₂
- Properties: Crystalline solid
- Uses: Organic synthesis, materials chemistry

11. 1,4-Benzoquinone (para-Quinone)

- Structure: Cyclic diketone with C₆H₄O₂
- Formula: C₆H₄O₂
- Properties: Yellow crystalline solid, strong oxidizing agent
- Uses: Photographic developer, tanning agent, oxidizing agent

Cyclic 1,4-Dicarbonyl Compounds

12. Succinic anhydride

- Structure: Cyclic anhydride with 1,4-relationship
- Formula: C₄H₄O₃
- Properties: White crystalline solid
- Uses: Chemical intermediate, resin production

13. Glutaric anhydride

- Structure: Six-membered cyclic anhydride
- Formula: C₅H₆O₃
- Properties: Crystalline solid
- Uses: Polymer synthesis, pharmaceutical intermediate

Heterocyclic 1,4-Dicarbonyl Compounds

14. Maleic anhydride

- Structure: Unsaturated cyclic anhydride

- Formula: C₄H₂O₃
- Properties: White crystalline solid, highly reactive
- Uses: Polymer production, chemical synthesis

15. Phthalic anhydride

- Structure: Aromatic cyclic anhydride
- Formula: C₈H₄O₃
- Properties: White crystalline solid
- Uses: Plasticizer production, dye synthesis

Substituted 1,4-Dicarbonyl Compounds

16. 2,2-Dimethyl-3,5-hexanedione
- Structure: Branched diketone with methyl substituents
- Formula: C₈H₁₄O₂
- Properties: Liquid, less volatile than parent compound
- Uses: Specialty solvent, organic synthesis

17. 2-Methyl glutaraldehyde

- Structure: CHO-CH(CH₃)-CH₂-CH₂-CHO
O O
|| ||
H–C–CH(CH₃)–CH₂–CH₂–C–H

- Formula: C₆H₁₀O₂
- Properties: Liquid, similar reactivity to glutaraldehyde
- Uses: used in aqueous solutions and exhibits antimicrobial properties, making it
useful for sterilization and preservation.
Biological 1,4-Dicarbonyl Compounds

18. α-Ketoglutaric acid

- Structure: HOOC-CO-CH₂-CH₂-COOH
- Formula: C₅H₆O₅
- Properties: White crystalline solid, important metabolite
- Uses: Biochemical research, nutritional supplements

19. Oxaloacetic acid

- Structure: HOOC-CO-CH₂-COOH

- Formula: C₄H₄O₅
- Properties: Unstable in solution, biological intermediate
- Uses: Biochemical studies, metabolic research

Special Properties of 1,4-Dicarbonyl Compounds

Chemical Reactivity
- Cyclization reactions: Can undergo intramolecular aldol condensations
- Michael additions: Act as dienophiles in Diels-Alder reactions
- Reduction reactions: Can be selectively reduced to diols or partially reduced
- Nucleophilic additions: Both carbonyl groups can react with nucleophiles
Biological Activity
- Crosslinking agents: Many dialdehydes are used as protein crosslinkers
- Antimicrobial properties: Some exhibit antibacterial and antifungal activity
- Metabolic intermediates: Several are important in cellular metabolism
- Toxicity: Some show neurotoxic effects (e.g., 2,5-hexanedione)

DIALKANOIC ACIDS

Introduction

Organic acids are a significant class of compounds in chemistry and biochemistry

due to their structural diversity and wide applications. Among them, dialkanoic
acids (also called dicarboxylic acids) form an important group of compounds that
contain two carboxyl (-COOH) functional groups in their molecular structure.
Their unique properties make them useful in industry, polymer chemistry, and
biological systems. Dialkanoic acids occur naturally in living organisms and are
also synthesized in the laboratory for commercial purposes.

Definition and General Structure

Dialkanoic acids are aliphatic dicarboxylic acids derived from alkanes by

replacing two hydrogen atoms with carboxyl groups. Their general formula is:

HOOC-(CH2)n-COOH

where n represents the number of methylene (-CH₂-) groups separating the two
carboxyl groups.

Examples include:
 ● Oxalic acid (n = 0): HOOC–COOH
● Malonic acid (n = 1): HOOC–CH₂–COOH
● Succinic acid (n = 2): HOOC–(CH₂)₂–COOH
● Adipic acid (n = 4): HOOC–(CH₂)₄–COOH

Thus, dialkanoic acids can range from the simplest oxalic acid to higher
homologues with long carbon chains.

Classification of Dialkanoic Acids

Dialkanoic acids can be classified according to:

1. Chain length

○ Lower dicarboxylic acids (C2–C5): oxalic, malonic, succinic, glutaric.

○ Higher dicarboxylic acids (C6 and above): adipic, pimelic, suberic,
sebacic, etc.
2. Position of carboxyl groups

○ α,ω-dicarboxylic acids (terminal carboxyl groups): e.g., adipic acid.

○ Substituted dicarboxylic acids (additional functional groups
present): e.g., malic acid (hydroxyl group) and tartaric acid.
3. Saturation

○ Saturated: succinic, adipic.

○ Unsaturated: maleic and fumaric acids.
○ Aromatic: phthalic, isophthalic, terephthalic acids.

Natural Occurrence

Dialkanoic acids occur widely in plants and animals.

 ● Succinic acid is found in amber and occurs in the Krebs cycle as an
intermediate.
● Oxalic acid is present in rhubarb leaves, spinach, and some legumes.
● Adipic acid is found in trace amounts in beets and sugarcane.
● Many long-chain dicarboxylic acids occur in fatty acid metabolism and are
significant in biochemical energy production.

Methods of Preparation

Several methods are used to prepare dialkanoic acids:

1. Oxidation of alkanes or alkenes

○ Oxidation of cyclohexanol or cyclohexanone yields adipic acid.

○ Oxidation of alkenes with potassium permanganate produces
dicarboxylic acids.
2. Hydrolysis of nitriles

○ Dinitriles (e.g., adiponitrile) undergo hydrolysis to yield dicarboxylic

acids.

NC-(CH₂)_4-CN \xrightarrow[H₂O]{H⁺/heat} HOOC-(CH₂)₄-COOH

3. From malonic ester synthesis

○ Diesters of malonic acid can be alkylated and then hydrolyzed to form

substituted dicarboxylic acids.
4. Fermentation and biological synthesis
 ○ Microorganisms produce succinic acid via fermentation of
glucose.→

Properties and Reactions of Dialkanoic Acids

Physical Properties

1. State and Appearance

○ Lower members (C2–C6) → colorless crystalline solids (e.g.,

oxalic, malonic, succinic).
○ Higher members → waxy, greasy solids, similar to fatty acids.
2. Melting and Boiling Points

○ Relatively high melting points due to hydrogen bonding between –

COOH groups.
○ Melting point increases with chain length, but even–odd effect may
occur (even-numbered dicarboxylic acids have higher melting points
than odd-numbered ones).
3. Solubility

○ Lower members are highly soluble in water (due to hydrogen

bonding).
○ Solubility decreases as chain length increases.
4. Acidity

○ They are dibasic acids (can donate two protons).

 ○ First ionization constant (Ka₁) > second ionization constant (Ka₂)
because removal of the second proton is less favorable due to
electrostatic repulsion.

Chemical Properties and Reactions

A. Acidic Reactions

1. Reaction with Bases

○ React with alkalis (NaOH, KOH) → salts of dicarboxylic acids.
○ Example:

HOOC–(CH₂)_2–COOH + 2NaOH→

NaOOC–(CH₂)_2–COONa + 2H₂O

2. Reaction with Carbonates and Bicarbonates

○ Release CO₂ gas.
○ Example:

HOOC–COOH + Na₂CO₃→

NaOOC–COONa + CO₂ + H₂O

B. Decarboxylation Reactions

● Malonic acid and some others undergo thermal decarboxylation (loss of

CO₂).
● Example:

HOOC–CH₂–COOH heat→

CH₃–COOH + CO₂
C. Formation of Anhydrides

● Heating some dicarboxylic acids → cyclic anhydrides (if carboxyl groups

are suitably positioned).
● Example:
○ Succinic acid → Succinic anhydride on heating.
○ Phthalic acid → Phthalic anhydride.

D. Esterification

● React with alcohols in presence of H₂SO₄ (acid catalyst) → diesters.

● Example:

HOOC–(CH₂)_4–COOH + 2CH₃OH →CH₃OOC–(CH₂)_4–COOCH₃ +

2H₂O

E. Reduction

● Reduction with LiAlH₄ → glycols (diols).

● Example:

HOOC–(CH₂)_4–COOH LiAlH₄ →HOCH₂–(CH₂)_4–CH₂OH

F. Oxidation

● Some dicarboxylic acids can undergo further oxidation.

● Example: Oxalic acid oxidizes easily to CO₂ and H₂O with strong oxidizers
(e.g., KMnO₄).

G. Substitution Reactions
 ● Hydrogen atoms on the α-carbon (next to the –COOH group) are reactive.
● Example: Malonic acid derivatives are used in the malonic ester synthesis
because of the acidity of α-hydrogens.

Summary of Reactions

● With bases → salts.

● With carbonates/bicarbonates → CO₂ + salts.
● On heating (decarboxylation) → monocarboxylic acids + CO₂.
● On heating (dehydration) → cyclic anhydrides.
● With alcohols → esters/diesters.
● With LiAlH₄ → diols.
● With oxidizing agents → CO₂, H₂O (esp. oxalic acid).

Industrial and Biological Applications

Dialkanoic acids are versatile compounds with wide-ranging applications:

1. Polymer industry

○ Adipic acid is a major raw material in the production of nylon-6,6.

○ Sebacic acid is used in making plasticizers, lubricants, and
biodegradable polymers.
2. Pharmaceuticals

○ Succinic acid is used in drug formulations and as an acidity regulator.

○ Oxalic acid has applications in cleaning and as a chelating agent.
 3. Food industry

○ Some dicarboxylic acids serve as acidulants, preservatives, and

buffering agents.
4. Biochemistry

○ Many dialkanoic acids (succinic, fumaric, malic acids) are

intermediates in the citric acid (Krebs) cycle, vital for energy
metabolism.
5. Other uses

○ Used in dyes, coatings, adhesives, and corrosion inhibitors.

MALONIC ESTER

Structure of Malonic Ester (Diethyl Malonate)

● Molecular formula: C₇H₁₂O₄
● IUPAC name: Diethyl propanedioate
● Structure:

CH₂(COOC₂H₅)₂

Expanded structure:

O O
|| ||
C₂H₅–O–C–CH₂–C–O–C₂H₅
 ● The CH₂ group lies between two ester carbonyl groups (–COOR).
● This position makes the hydrogens of the methylene group acidic because
the carbanion formed is stabilized by resonance with the two adjacent
carbonyl groups.

Tautomerism of Malonic Ester

Like many esters and β-dicarbonyl compounds, malonic ester shows keto–enol
tautomerism.

Keto Form (major form)

CH₂(COOC₂H₅)₂

Here the central carbon is bonded to two carbonyl groups. This is the more stable
form.

Enol Form (minor form)

By transfer of one hydrogen atom from the methylene group to one carbonyl
oxygen, the enol tautomer is formed:

CH=C(OH)–COOC₂H₅ (with the second ester group attached)

Generalized representation:

O OH
 || |
R–O–C–CH=C–O–R' ↔ R–O–C–CH₂–C(=O)–OR'

Keto–Enol Equilibrium

● The equilibrium usually favors the keto form (due to stronger C=O bonds).
● The enol form is stabilized by intramolecular hydrogen bonding and
conjugation, so it exists in small amounts.
● The enol form is important because it participates in condensation and
substitution reactions.

Summary:

● Structure: Diethyl ester of malonic acid CH₂(COOC₂H₅)₂.

● Tautomerism: Exhibits keto–enol tautomerism, with keto as the stable form
and enol as the reactive form in many reactions.

Preparation of Malonic Ester (Diethyl Malonate)

Malonic ester (commonly diethyl malonate) is prepared by the esterification of

malonic acid or by the ester exchange reaction. The most common laboratory
method is through esterification.

1. From Malonic Acid and Ethanol (Fischer Esterification Method)

● Reaction:

\text{HOOC–CH₂–COOH} + 2C₂H₅OH heatH₂SO₄→CH₂(COOC₂H₅)₂ +

2H₂O

● Steps:
 1. Malonic acid is dissolved in excess absolute ethanol.
2. A few drops of concentrated sulfuric acid (H₂SO₄) are added as a
catalyst.
3. The mixture is heated under reflux (to avoid loss of volatile ethanol).
4. After completion, the mixture is cooled and poured into water.
5. The ester layer (diethyl malonate) is separated, washed with sodium
carbonate solution (to remove unreacted acid), then dried.
6. The ester is purified by fractional distillation under reduced pressure.

2. From Chloroacetic Acid (Synthetic Method)

This is an industrial method.

● Reaction:

ClCH₂COOH + 2C₂H₅OH heat &H₂SO₄ →CH₂(COOC₂H₅)₂

Here, chloroacetic acid reacts with ethanol in presence of H₂SO₄ to form the
ester.

3. By Ester Exchange (Transesterification)

Malonic acid derivatives can also be converted to diethyl malonate by reacting

with ethyl alcohol in presence of an acid or base catalyst.

Summary:

● Laboratory preparation: Fischer esterification of malonic acid with

ethanol.
● Industrial preparation: From chloroacetic acid and ethanol.
● Purification: By distillation under reduced pressure.
Reactions and Synthetic Importance of
Malonic Ester

1. Acidity of Methylene Group

● In malonic ester, the methylene group (–CH₂–) between two ester groups is
highly acidic.
● Reason: The carbanion formed after losing a proton is stabilized by
resonance with both carbonyl groups.

CH₂(COOC₂H₅)₂ NaOEt→ CH⁻(COOC₂H₅)₂ + Na⁺

Thus, malonic ester easily undergoes reactions involving its methylene group.

2. Alkylation of Malonic Ester

● The carbanion formed above can act as a nucleophile.

● It reacts with alkyl halides (R–X) to give mono- or dialkyl substituted
malonic esters.

CH⁻(COOC₂H₅)₂ + R–X → R–CH(COOC₂H₅)₂

If two equivalents of alkyl halide are used, dialkyl derivatives form.

3. Hydrolysis and Decarboxylation

● Alkylated malonic ester undergoes hydrolysis with aqueous alkali to form a

malonic acid derivative.
 ● Upon heating, it undergoes decarboxylation, yielding a substituted acetic
acid.

R–CH(COOC₂H₅)₂ H⁺/OH⁻, H₂O→ R–CH(COOH)₂ heat -CO₂→ R–CH₂–

COOH

4. Synthetic Applications (Malonic Ester Synthesis)

This method is used to prepare a wide range of carboxylic acids.

(a) Preparation of Monocarboxylic Acids

● Example: Acetic acid

CH₂(COOC₂H₅)₂ hydrolysis/decarboxylation→ CH₃COOH

● Example: Propionic acid

CH₂(COOC₂H₅)₂ Alkylation (CH₃I)→ CH₃–CH(COOC₂H₅)₂

Hydrolysis/Decarboxylation}→ CH₃CH₂COOH

(b) Preparation of Dicarboxylic Acids

● Example: Succinic acid

CH₂(COOC₂H₅)₂ Alkylation (ClCH₂COOC₂H₅)→ HOOC–CH₂–CH₂–COOH

(c) Preparation of Substituted Acetic Acids

 ● By using appropriate alkyl halides, substituted acetic acids like isobutyric
acid, phenylacetic acid, etc. can be obtained.

(d) Preparation of Barbituric Acid

● Malonic ester condenses with urea to form barbituric acid, the parent
compound of many sedative drugs (barbiturates).

CH₂(COOC₂H₅)₂ + H₂N–CO–NH₂ → Barbituric Acid

Summary of Importance

● Provides a general method for synthesizing mono-, di-, and poly-

substituted carboxylic acids.
● Useful in the synthesis of pharmaceutical compounds (e.g., barbiturates).
● Demonstrates the importance of active methylene group chemistry in
organic synthesis.

Significance of the Active Methylene Group in the Reactions of Malonic

Ester

Structure of malonic ester (diethyl malonate):

CH2(COOC2H5)2

Why it is “active”:
The two carbonyl groups are strongly electron-withdrawing,
which makes the hydrogen atoms on the central methylene
carbon very acidic (pKa ≈ 13). This acidity is far greater than in
normal alkanes (pKa ≈ 50).

consequence:

In the presence of a base (e.g., sodium ethoxide, NaOEt), the acidic hydrogen is
easily removed to form a stabilized enolate ion.

CH2 (COOC2H5 )2 Base-→ CH(COOC2 H5 )2

Stabilization:

The negative charge is delocalized by resonance into the two carbonyl groups,
making the enolate highly stable and reactive.

Reactivity:

The enolate ion acts as a strong nucleophile and can undergo substitution
reactions with alkyl halides, acyl halides, etc. This property forms the basis of the
malonic ester synthesis.

In summary:
The active methylene group gives malonic ester its special reactivity, enabling
easy formation of carbon–carbon bonds, which is essential for building more
complex organic acids.

2. Application of Malonic Ester in the Synthesis of Other Acids

Malonic ester is widely used in organic synthesis, especially to prepare substituted

carboxylic acids. The general process is called the malonic ester synthesis:

Steps in Malonic Ester Synthesis

1. Formation of enolate:

Base removes an α-hydrogen from the methylene group.

2. Alkylation:

The enolate ion attacks an alkyl halide (R–X), introducing a new substituent.

-
CH(COOC2H5)2 + R–X → R–CH(COOC2H5)2

3. Hydrolysis and decarboxylation:

The diester is hydrolyzed to a dicarboxylic acid, which then undergoes

decarboxylation (loss of CO₂), yielding a mono-substituted carboxylic acid.
R–CH(COOC2H5)2 [heat]H3O+→ R–CH2–COOH

Examples of Applications

1. Synthesis of acetic acid derivatives

With methyl iodide (CH₃I) → Propionic acid (CH₃–CH₂–COOH).

2. Synthesis of higher fatty acids

Using long-chain alkyl halides.

3. Synthesis of aromatic acids

Reaction with benzyl chloride → Phenylacetic acid.

4. Synthesis of dicarboxylic acids

Double alkylation with two equivalents of alkyl halide → gives substituted

succinic acids.

5. Synthesis of α,β-unsaturated acids

Alkylation followed by elimination gives acids like crotonic acid.

6. Pharmaceutical intermediates

Used in preparing barbiturates, vitamins (B₁, B₆), and amino acid derivatives.

In essence:

The active methylene group is the reason malonic ester is reactive.

Its applications lie in the malonic ester synthesis, which is a versatile method for
preparing a wide variety of mono-, di-, and poly-substituted carboxylic acids.

Acetoacetic Ester

Structure of Acetoacetic Ester

Acetoacetic ester, also known as ethyl acetoacetate, is an important β-keto ester.

Its molecular formula is C₆H₁₀O₃, and its structure can be represented as:

CH₃–CO–CH₂–COOCH₂CH₃

It consists of three major parts:

A ketone group (–COCH₃) at the β-position.

An ester group (–COOCH₂CH₃) at the α-position.

A methylene group (–CH₂–) in between, which is highly reactive and is referred
to as the active methylene group.

2. Methods of Preparation of Acetoacetic Ester

Acetoacetic ester can be prepared by several methods:

(a) Claisen Condensation of Ethyl Acetate

Ethyl acetate is treated with sodium ethoxide (NaOEt) in ethanol.

One molecule of ethyl acetate is deprotonated at the α-hydrogen, which then

attacks the carbonyl group of another ethyl acetate molecule.

The product is ethyl acetoacetate (acetoacetic ester).

2 CH₃COOEt {NaOEt}→ CH₃COCH₂COOEt + EtOH

(b) From Acetyl Chloride and Ethyl Acetate

Acetyl chloride reacts with ethyl acetate in the presence of sodium ethoxide to
yield ethyl acetoacetate.

(c) Ketene Method

Ketene (CH₂=C=O) is reacted with ethanol, followed by acetic acid, to produce
acetoacetic ester.

Properties and Reactions of Acetoacetic Ester

(i) Physical Properties

Colorless liquid with a fruity odor.

Slightly soluble in water but miscible with organic solvents like alcohol and ether.

Boiling point: ~181 °C.

(ii) Chemical Properties

The properties of acetoacetic ester are due to the presence of both the ester and
ketone functional groups and the active methylene group.

(a) Tautomerism

Acetoacetic ester exists in equilibrium between two forms:

Keto form (CH₃–CO–CH₂–COOEt) – about 92%

Enol form (CH₂=C(OH)–CH₂–COOEt) – about 8%

This keto-enol tautomerism is important for its reactivity.

(b) Reactions due to the Ester Group

Hydrolysis and decarboxylation: On hydrolysis with dilute acid or alkali,

acetoacetic ester yields acetoacetic acid, which readily decarboxylates to form
acetone.

CH₃COCH₂COOEt \xrightarrow{H₂O/H⁺} CH₃COCH₂COOH \xrightarrow{Δ}

CH₃COCH₃ + CO₂

(c) Reactions due to the Active Methylene Group

The methylene hydrogens (–CH₂–) are acidic and can be easily removed by bases
like NaOEt to form carbanions, which undergo alkylation or acylation.

(d) Reactions due to the Keto Group

The carbonyl group can undergo nucleophilic addition reactions (e.g., with
hydroxylamine, hydrazine, etc.).

Significance of the Active Methylene Group

The active methylene group (–CH₂–) between the carbonyl groups (–CO– and –
COOR) is highly acidic because:
The negative charge after deprotonation is delocalized between the two carbonyl
oxygen atoms through resonance.

This makes it easy to form a stabilized carbanion, which is a powerful

nucleophile.

Thus, the active methylene group is the key to the reactivity of acetoacetic ester,
enabling it to undergo:

Alkylation with alkyl halides.

Acylation with acyl chlorides.

Condensation reactions.

Applications of Acetoacetic Ester in Organic Synthesis

(a) Synthesis of Methyl Ketones

When acetoacetic ester is hydrolyzed and decarboxylated, it produces methyl

ketones.

Example: Ethyl acetoacetate → hydrolysis + decarboxylation → acetone.

CH₃COCH₂COOEt \xrightarrow{Hydrolysis, Δ} CH₃COCH₃ + CO₂

(b) Synthesis of Alkanoic Acids

By alkylating acetoacetic ester at the active methylene group, then hydrolyzing

and decarboxylating, higher alkanoic acids can be prepared.

Example: Reaction with ethyl iodide → hydrolysis + decarboxylation →

butanoic acid.

(c) Synthesis of Heterocyclic Compounds

Acetoacetic ester is used in the synthesis of pyridines, pyrazoles, and pyrimidines

through condensation reactions with amines or hydrazine.

(d) Synthesis of Pharmaceuticals and Dyes

Many drugs (e.g., barbiturates) and coloring agents are synthesized using
acetoacetic ester as an intermediate.

Conclusion

Acetoacetic ester (ethyl acetoacetate) is an important β-keto ester widely used in

organic synthesis. Its unique properties are due to the presence of both ester and
ketone functional groups, along with the reactive active methylene group. Its
applications in the synthesis of methyl ketones, alkanoic acids, and heterocycles
highlight its industrial and pharmaceutical importance.
Polyhydric Alkanols

Definition of Polyhydric Alkanols

Polyhydric alkanols, also called polyhydric alcohols or polyols, are organic

compounds that contain more than one hydroxyl (–OH) functional group attached
to saturated carbon atoms in their molecules. In other words, they are alkanols
with two or more hydroxyl groups. The simplest members include ethylene glycol
(a dihydric alcohol with two –OH groups) and glycerol (a trihydric alcohol with
three –OH groups).

They are generally classified based on the number of hydroxyl groups present:

Dihydric alcohols (e.g., ethane-1,2-diol, propane-1,3-diol).

Trihydric alcohols (e.g., glycerol).

Polyhydric alcohols with four or more hydroxyl groups (e.g., sorbitol, mannitol,
inositol).

Their presence of multiple hydroxyl groups gives them distinct physical and
chemical properties such as high solubility in water, high boiling points, and
strong hydrogen bonding.

General Methods of Preparation of Polyhydric Alkanols

Polyhydric alkanols can be prepared by several synthetic and natural methods:

(a) Hydration of Epoxides

Epoxides such as ethylene oxide undergo hydration in the presence of an acid

catalyst to yield dihydric alcohols.

C2H4 O + H2O → HO–CH2–CH2–OH

(b) Hydrolysis of Halogenated Alkanes

Vicinal dihalogen alkanes (e.g., ethylene dibromide) react with aqueous alkali to
give diols:

Br–CH2–CH2–Br + 2NaOH → HO–CH2–CH2–OH + 2NaBr

(c) Reduction of Aldehydes and Ketones

Reduction of aldehydes yields primary alcohols.

Reduction of dicarbonyl compounds (e.g., dialdehydes) or hydroxy aldehydes

leads to polyhydric alkanols.

For example, reduction of glyceraldehyde gives glycerol.

(d) Fermentation of Sugars

Natural polyols like glycerol and sorbitol are produced industrially from
fermentation of carbohydrates (glucose, sucrose, starch).

(e) Reduction of Carbohydrates

For instance, catalytic hydrogenation of glucose yields sorbitol (a hexahydric

alcohol).

C6H12O6 + H2 → C6H14O6

Properties and Reactions of Polyhydric Alkanols

Physical Properties

1. Hydrogen bonding: Due to multiple –OH groups, they exhibit extensive

hydrogen bonding, leading to:

High boiling and melting points.

High viscosity.

Strong hygroscopicity (ability to absorb moisture).

2. Solubility: Most lower polyols (e.g., ethylene glycol, glycerol) are highly
soluble in water due to hydrogen bonding.

3. Taste: Some polyhydric alcohols like glycerol and sorbitol are sweet-tasting.

Chemical Properties

1. Acidic character: The –OH groups can act as weak proton donors, forming
alkoxides with active metals such as sodium:

2ROH + 2Na → 2RONa + H2

2. Esterification: They react with carboxylic acids (or acid anhydrides) to form
esters. Glycerol forms triglycerides with fatty acids.

3. Oxidation:

Mild oxidants convert polyhydric alcohols into hydroxy aldehydes or hydroxy

acids.

Vigorous oxidants lead to complete oxidation (CO₂ + H₂O).

Example: Glycerol can be oxidized to glyceric acid or tartronic acid.

4. Dehydration: When heated with concentrated sulfuric acid, polyhydric
alcohols undergo dehydration, forming unsaturated compounds or cyclic ethers.

5. Formation of complex compounds: Glycerol reacts with copper(II) hydroxide

to form deep blue complexes due to the presence of adjacent –OH groups.

Uses of Polyhydric Alkanols

1. Antifreeze agent: Ethylene glycol is widely used in automobile radiators as an

antifreeze.

2. Manufacture of explosives: Glycerol is nitrated to produce nitroglycerin, a

key ingredient in dynamite.

3. Food industry: Sorbitol and mannitol are used as artificial sweeteners and
humectants in food products.

4. Cosmetics and pharmaceuticals: Glycerol is used in creams, lotions, syrups,

and cough mixtures as a solvent and moisturizer.

5. Polymer industry: Ethylene glycol is a major raw material for the production
of polyesters (e.g., PET for plastic bottles and fibers).

6. Tobacco industry: Glycerol is added to keep tobacco moist.

7. Laboratory and chemical synthesis: Polyols are used as intermediates in
organic synthesis and as solvents.

Method of Determining the Number of OH Groups in a Polyhydric Alkanol

The acetylation method is commonly employed:

1. The polyhydric alkanol is treated with an excess of acetic anhydride in the

presence of a catalyst (e.g., pyridine).

2. Each –OH group reacts with acetic anhydride to form an acetate ester.

3. The amount of acetic anhydride consumed (or acetic acid liberated) is measured
by titration.

4. From this, the number of hydroxyl groups per molecule can be determined.

Example reaction with glycerol:

C3H5(OH)3 + 3(CH3CO)2O → C3H5(OCOCH3)3 + 3CH3COOH

Alternatively, other methods such as reaction with Grignard reagents, acetyl

chloride titration, or infrared spectroscopy (–OH absorption bands) can also be
used.
Conclusion

Polyhydric alkanols are an important class of organic compounds with wide-

ranging industrial, pharmaceutical, and domestic applications. Their preparation
can be achieved by several synthetic and natural methods, while their properties
are largely influenced by the presence of multiple hydroxyl groups. Methods such
as acetylation are useful for determining the number of –OH groups, making them
indispensable in structural studies and industrial chemistry.

Amino Acid

Definition of Amino Acid

An amino acid is an organic compound that contains both an amino group (–

NH₂) and a carboxyl group (–COOH) attached to the same carbon atom, known
as the α-carbon. Amino acids are the basic building blocks of proteins and play
vital roles in metabolism, enzyme activity, and cellular function. They are
amphoteric in nature, meaning they can act as both acids and bases.

General Formula of Amino Acids

The general formula of an α-amino acid is:

H2N-CHR-COOH

Where:

● –NH₂ = amino group

● –COOH = carboxyl group
● –H = hydrogen atom
 ● R = side chain (which differs among amino acids and determines their
specific properties)

3. Examples of Amino Acids

Some common examples of amino acids include:

1. Glycine (Gly) – the simplest amino acid with hydrogen (H) as the R-group.

H_2N-CH_2-COOH

2. Alanine (Ala) – with a methyl (–CH₃) side chain.

H_2N-CH(CH_3)-COOH

3. Valine (Val) – with an isopropyl group.

H_2N-CH(CH(CH_3)_2)-COOH

4. Leucine (Leu) – with an isobutyl side chain.

H_2N-CH(CH_2CH(CH_3)_2)-COOH

5. Phenylalanine (Phe) – with a benzyl side chain.

H_2N-CH(CH_2–C_6H_5)-COOH

6. Glutamic acid (Glu) – with a carboxyl group in the side chain.

H_2N-CH(CH_2CH_2COOH)-COOH

7. Lysine (Lys) – with an amino group in the side chain.

H_2N-CH(CH_2CH_2CH_2CH_2NH_2)-COOH
 8. Serine (Ser) – with a hydroxyl group in the side chain.

H_2N-CH(CH_2CH_2CH_2CH_2NH_2)-COOH

4. Essential Amino Acids

Essential amino acids are amino acids that cannot be synthesized by the human
body in sufficient quantities and therefore must be obtained through diet. They
are vital for growth, tissue repair, enzyme formation, and overall health.

The essential amino acids in humans are:

1. Histidine – important for growth and the production of histamine.

2. Isoleucine – involved in muscle metabolism and hemoglobin synthesis.
3. Leucine – stimulates muscle protein synthesis and regulates blood sugar.
4. Lysine – essential for collagen formation, calcium absorption, and immune
function.
5. Methionine – a sulfur-containing amino acid important in methylation
reactions and antioxidant functions.
6. Phenylalanine – precursor of tyrosine, dopamine, norepinephrine, and
epinephrine.
7. Threonine – plays a role in collagen and elastin formation, as well as fat
metabolism.
8. Tryptophan – precursor of serotonin and niacin (Vitamin B3).
9. Valine – important for muscle repair and energy production.

5. Optical Isomerism in Amino Acids

Most amino acids (except glycine) exhibit optical isomerism because the α-carbon
atom (the central carbon) is attached to four different groups:

● an amino group (–NH₂)

● a carboxyl group (–COOH)
 ● a hydrogen atom (–H)
● a side chain (–R)

This makes the α-carbon a chiral center, and the amino acid can exist as two non-
superimposable mirror images (enantiomers), called the D- and L- forms.

● L-amino acids are the naturally occurring ones in proteins.

● D-amino acids are rare, but they occur in some bacterial cell walls and
antibiotics.

These enantiomers rotate plane-polarized light in opposite directions: one to the

left (levorotatory) and the other to the right (dextrorotatory).

6. Difference Between Basic and Acidic Amino Acids

Feature Basic Amino Acids Acidic Amino Acids

Side chain Contains additional Contains additional

amino (–NH₂) group(s) carboxyl (–COOH)
group(s)

Charge at physiological Positively charged Negatively charged

pH (cationic) due to (anionic) due to
protonation of –NH₂ ionization of –COOH

Nature Proton acceptors Proton donors (acidic in

(alkaline in solution) solution)
7. Examples
● Acidic Amino Acids (extra carboxyl group in side chain):

1. Aspartic acid (Asp, D) – has –CH₂–COOH

2. Glutamic acid (Glu, E) – has –CH₂–CH₂–COOH
● Basic Amino Acids (extra amino group in side chain):

1. Lysine (Lys, K) – has –(CH₂)₄–NH₂

2. Arginine (Arg, R) – has guanidinium group
3. Histidine (His, H) – has imidazole group

Acidic Amino Acids

1. Aspartic Acid (Asp, D)

H2N-CH(CH2COOH)-COOH

H O

| ||

H2N—C—C—O⁻

CH2

COOH

● Has an extra –COOH group on the side chain.

2. Glutamic Acid (Glu, E)

H2N-CH(CH2CH2COOH)-COOH

H O

| ||

H2N—C—C—O⁻

CH2—CH2—COOH

● Has an extra –CH₂–COOH group.

Basic Amino Acids

1. Lysine (Lys, K)

H2N-CH(CH2CH2CH2CH2NH2)-COOH

H O

| ||

H2N—C—C—O⁻

(CH2)4—NH2

● Extra amino group makes it strongly basic.

2. Arginine (Arg, R)

H2N-CH(CH2CH2CH2–NH–C(=NH)NH2)-COOH

H O

| ||

H2N—C—C—O⁻

(CH2)3—NH—C(=NH)NH2

● Contains a guanidinium group, very strongly basic.

3. Histidine (His, H)

H2N-CH(CH2–C₃H₃N₂)-COOH

H O

| ||

H2N—C—C—O⁻

CH2—(Imidazole ring)
 ● Contains an imidazole ring that can accept or donate protons.

8. Isoelectric Point (pI) of an Amino Acid

The isoelectric point (pI) is the pH at which an amino acid exists as a zwitterion
(i.e., has both positive and negative charges) but carries no net electrical charge.

● At low pH (acidic conditions): the amino acid is positively charged

(cation).
● At high pH (basic conditions): the amino acid is negatively charged
(anion).
● At the isoelectric point (pI): the amino acid has equal positive and negative
charges, so it does not move in an electric field.

The pI is important in protein purification techniques such as electrophoresis and

isoelectric focusing.