Organic chemistry

Organic chemistry is one of the most important subfields of chemistry, dealing with the structure, properties, and transformations of carbon compounds, also known as organic compounds. The division into organic and inorganic chemistry dates back to a time when it was believed that living matter was fundamentally different from inanimate matter. Over 10 million of these organic substances are known, in contrast to "only" about 100,000 inorganic ones. This diversity is based on the special bonding properties of carbon: Carbon atoms have four valence electrons, allowing them to form up to four stable covalent bonds, including bonds to other carbon atoms. This results in short and long carbon chains, branched structures, or even ring-shaped structures.

In addition to carbon, organic compounds mostly contain hydrogen and oxygen, but also sulfur, nitrogen, phosphorus, and the halogens fluorine, chlorine, bromine, and iodine. These elements often occur in so-called "functional" groups, which exhibit distinct properties and reaction behaviors. Organic compounds are classified into different substance classes according to these groups. This article primarily deals with the organic compounds common in biological systems and thus in medicine. These are mainly molecules from the substance classes of alcohols, aldehydes and ketones, carboxylic acids, amines, and thiols.

Strictly speaking, hydrocarbons are compounds that consist exclusively of carbon (C) and hydrogen (H). In practice, the term "hydrocarbons" is sometimes used more broadly to include compounds that contain functional groups in addition to carbon and hydrogen. Functional groups bind to a C atom instead of a hydrogen atom, "replacing" it. This is the origin of the term "substituents" for these groups. The term "substituent" can also be applied to H atoms themselves.

Hydrocarbons form chains, rings, or combinations of both and are divided into different groups according to their structure. Hydrocarbons that contain only carbon and hydrogen (e.g., alkanes) are nonpolar and therefore dissolve poorly in water (hydrophobic) but well in other nonpolar solvents.

• Acyclic (open-chain) hydrocarbons are compounds consisting exclusively of carbon (C) and hydrogen (H) that do not form ring structures.
• They are categorized by their degree of saturation:
  • Saturated (alkanes): contain only single bonds; they hold the maximum number of hydrogen atoms possible
  • Unsaturated (alkenes/alkynes): contain double or triple bonds, meaning they have fewer hydrogens than the maximum capacity

Alkanes

Alkanes are hydrocarbons containing only single (σ) bonds. They are considered saturated because they contain the maximum number of hydrogen atoms possible for their carbon skeleton.

• Molecular formula
  • C_nH_2n+2 (for acyclic alkanes)
• Homologous series: form a sequence of compounds where each member differs by a specific structural unit (a -CH₂- group)
• Physical properties: nonpolar; boiling points increase with chain length due to increased London dispersion forces, but decrease with branching due to reduced surface area

Structure

• Alkanes are categorized by their chain structure
  • n-alkanes (normal): consist of unbranched "straight" carbon chains with CH₃ end groups and CH₂ linking groups
  • i-alkanes (iso-alkanes): consist of branched carbon chains; branching requires a minimum of four carbon atoms

Nomenlature

Spatial structure (conformers)

In acyclic alkanes, rotation around single bonds allows for different spatial arrangements called conformational isomers.

• Staggered conformation (anti): substituents on adjacent carbons are 180° apart → minimizes steric and torsional strain
  • Most stable (lowest energy) form
• Eclipsed conformation: substituents on adjacent carbons are aligned (0° apart)
  • Least stable (highest energy) form due to maximal steric and torsional strain
• Gauche conformation: a type of staggered conformation where two large substituents on adjacent carbons are 60° apart
  • More stable than eclipsed but less stable than the anti-staggered conformation (where large groups are 180° apart)

Reactions

• Alkanes are generally unreactive due to their strong, nonpolar C-C and C-H bonds.
• Under specific conditions (like high heat or UV light), they can undergo:
  • Combustion: an exothermic redox reaction with O_2, producing CO₂ and H₂O
  • Free-radical halogenation: replacement of an H with a halogen (Cl or Br). Reactivity follows the stability of the radical intermediate: 3° > 2° > 1° > methyl.

Alkenes

Unsaturated hydrocarbons that have at least one C-C double bond. The C atoms connected by a double bond are sp²-hybridized and typically bond to two other atoms.

• Molecular formula: C_nH_2n
• Nomenclature: corresponds to that of alkanes, but with the ending "-ene" (ethene, propene, butene, etc.)
• Typical reactions: electrophilic addition across the double bond
  • E.g., bromination (both carbons of the double bond each receive a bromine substituent)

Polyethylene
Chain polymerization of alkenes produces polyolefins, which are saturated polymers. For example, ethene is used to produce polyethylene, the most widely used plastic in the world. Due to its durability and biocompatibility, it is also used in medicine for implants and surfaces of endoprostheses.

Alkynes

Unsaturated hydrocarbons that have at least one C-C triple bond.

• Molecular formula: C_nH_2n-2
• Nomenclature: corresponds to that of alkanes, but with the ending "-yne" (ethyne, propyne, butyne, etc.)

Ionic hydrocarbons

Hydrocarbons can exist as ions, which often play a role as reactive intermediates in multi-step reaction mechanisms. These ions are typically more reactive (less stable) than their neutral parent molecules.

• Carbanion
  • Carries a negative charge on a C atom
  • The C atom has a lone pair of electrons and forms three bonds
  • Example: the hydride anion (CH₃⁻)
• Carbocation
  • Carries a positive charge on a C atom
  • Carbenium ion: a carbocation where the C atom has three bonds and an empty p-orbital, totaling six valence electrons
  • Carbonium ion: a less common term, sometimes used for non-classical carbocations where the charge is delocalized over more than two atoms, often involving five-coordinate carbon intermediates
  • Stabilization (of carbocations)
    • Degree of substitution: stability increases with more alkyl substituents on the positively charged carbon: primary < secondary < tertiary.
    • Conjugation (so-called mesomerism or resonance): through delocalization of pi electrons (e.g., from adjacent double bonds), the positive charge is distributed over several atoms, which stabilizes the ion
      • The larger the system of conjugated double bonds, the more delocalized the electrons are.
        • This delocalization can lower the energy gap for electronic transitions, sometimes shifting light absorption into the visible spectrum and giving the molecule color.
      • Charges in the α-position to a double bond (allylic position) are resonance-stabilized.
      • Charges in the α-position to an aromatic ring (benzylic position) are also resonance-stabilized.
    • Steric shielding: If the carbocation has bulky substituents that physically block potential reaction partners from accessing the positive charge, the ion is kinetically stabilized (less reactive), though not necessarily thermodynamically more stable.
  • Special case of stable carbocations: Ions that are so stable they can be isolated (e.g., "bottled") are rare. An example is the trityl cation (triphenylmethyl cation), which is highly stabilized by resonance.

Open-chain hydrocarbons can form cyclic hydrocarbons. There are cyclic alkanes, alkenes, and alkynes. Among the cyclic hydrocarbons, two particularly important groups are aromatic hydrocarbons and heterocycles.

• Definition: hydrocarbon compounds that consist of cyclically arranged atoms
• Nomenclature: prefix "cyclo-" added to the root name of the n-alkane with the same number of C atoms in the ring (cyclopentane, cyclohexane, cycloheptane, etc.)

General structure

• Ring size
  • An alkane must have at least three C atoms to form a ring.
  • C3 (cyclopropane) and C4 (cyclobutane) rings are highly strained (angle strain) and therefore less stable.
  • C5 (cyclopentane) and C6 (cyclohexane) rings are very stable.
  • Larger rings are generally stable and not strained, but can have transannular strain.
• Multiple bonds: Alkenes and alkynes form cyclic compounds less easily than alkanes. The ideal bond angle for a triple bond (180°) introduces extreme strain in small rings.

Cyclohexane (C₆H₁₂)

A cyclic hydrocarbon with 6 carbon atoms, each forming single bonds to two adjacent C atoms in the ring and two further bonds to substituents (in cyclohexane itself, these are H atoms).

Spatial structure

Exists in different conformations, the most stable and common of which is the chair form.

• Chair form: a non-planar conformation that eliminates angle strain (all C-C-C angles are ∼109.5°) and minimizes torsional strain
  • Most stable and most common conformation
  • Substituents
    • Each C atom in the ring binds to two substituents.
    • These substituents occupy two distinct types of positions to minimize steric strain.
    • These positions can be interconverted by a ring inversion (ring flip).
      • Equatorial (eq): Substituents that point "outward" from the ring, roughly parallel to the "equator" of the molecule.
      • Axial (ax): Substituents that point perpendicularly "up" or "down," parallel to the main axis of the ring.
• Boat form: A less stable conformation where two opposite carbons are "flipped up." It has significant torsional and steric strain.
• Twist-boat form: A conformation intermediate in energy between the chair and boat forms, which is more stable than the boat form.

Aromatics

In certain cyclic molecules with conjugated double bonds , the pi electrons are not localized between specific atoms. For example, in a benzene 6-ring, the pi electrons are "delocalized" over the entire ring. Cyclic, planar molecules with a specific number of delocalized pi electrons (like benzene) are called aromatics. They are particularly stable and have unique reactivity.

• Definition (according to Hückel's rule): Aromatic compounds are cyclic, planar, fully conjugated, and have (4n+2) delocalized pi electrons (where n=0, 1, 2...; e.g., 2, 6, 10, 14 electrons).
• Properties: Exceptionally stable and tend to undergo substitution reactions rather than the addition reactions typical of alkenes.

Structure

• Ring size
  • Compounds based on the aromatic C6 ring (benzene) are very important in medicine.
  • Example benzene: If a benzene ring is a substituent on a larger molecule, it is called a phenyl group.
• Spatial structure: Because of the delocalized pi system, aromatic rings are planar.
• Ring positions
  • For disubstituted aromatic rings (like benzene), the relative position of one substituent to another is specified.
  • Four relative positions are distinguished (relative to a reference substituent):
    • ipso-position: the position bearing the reference substituent itself
    • ortho-position: the positions directly adjacent to the reference point (1,2-disubstituted)
    • meta-position: the positions separated by one C atom from the reference point (1,3-disubstituted)
    • para-position: the position directly opposite the reference point (1,4-disubstituted)

Representation

The delocalized electrons and the resulting equivalence of all C-C bonds in benzene are often represented by a circle drawn inside the ring.

Heterocycles

Cyclic compounds, whether aromatic or not, can contain elements other than carbon. If these other atoms (heteroatoms) are part of the ring itself, the compounds are called heterocycles.

• Definition: cyclic compounds in which at least one ring atom is not carbon; these are often nitrogen, oxygen, or sulfur

Larger ring systems (organic chemistry)

Both aromatic and non-aromatic rings can be connected in a molecule, forming larger ring systems.

Fused rings

• Definition: rings that share at least one atomic bond (i.e., two atoms)
• Formation: can be formed by the condensation of (hetero)cyclic compounds
• Examples
  • Aromatic, fused rings: e.g., naphthalene
  • Non-aromatic, fused rings: e.g., sterane (gonane)
  • Heterocyclic, fused rings: e.g., indole , purine
• Properties
  • The pi electrons of aromatic, fused rings are delocalized over the entire fused system.
  • Fusion in non-aromatic rings prevents rotation around the shared bond, which can create rigid structures and possibilities for cis/trans isomers at the ring junction.

Bridged rings

• Definition: a system where two rings share two non-adjacent atoms (bridgehead atoms)
• Formation: can be viewed as a cyclic hydrocarbon with a "bridge" of one or more atoms connecting two non-adjacent C atoms of the ring
• Example molecules: adamantane, norbornane
• Properties
  • The C atoms shared by the rings are called “bridgehead atoms.”
  • Bridgehead atoms can be stereocenters.
  • Bridged rings can be saturated or contain multiple bonds, but due to strain (Bredt's rule), a double bond at a bridgehead atom is highly unstable in small systems.

Adamantane derivatives are used in antiviral medications, particularly for treating influenza (e.g., amantadine).

Spiro compounds

• Definition: cyclic compounds in which two rings share exactly one atom
• Formation: two rings joined at a single atom
• Example molecule: spironolactone (= aldosterone antagonist)
• Properties
  • The atom shared by both ring systems is called a spiro atom.
  • Spiro atoms are typically C atoms but can be heteroatoms.
  • Substituted spiro compounds can be chiral (exhibiting axial chirality) even without a traditional chiral center.

Functional groups are specific groups of atoms within a molecule that replace hydrogen atoms on a hydrocarbon framework and largely determine the molecule's chemical properties and reactivity. Hydrocarbons are grouped into substance classes based on their primary function.

Rules for the nomenclature of hydrocarbons with functional groups

Hydrocarbons with functional groups are named according to IUPAC rules as follows:

1. Find the longest continuous C chain (the parent chain) that contains the principal functional group (the one with the highest priority). The name of the corresponding alkane (meth-, eth-, prop-, but-, etc.) forms the base of the name.
2. Identify all other hydrocarbon chains (branches) and functional groups attached to this parent chain.
   • Location of substituents: Number the parent chain, starting from the end that gives the principal functional group the lowest possible number. If there's a tie, number to give other substituents the lowest possible numbers.
     • Special case: older nomenclature
       • Sometimes C atoms are named with Greek letters (α, β, γ...), starting with the C atom adjacent to the carbon bearing the principal functional group.
   • Name of substituents: Name all groups attached to the parent chain.
     • C side chains: named according to their length with the suffix -yl (e.g., methyl, ethyl)
     • Functional groups: named using standard prefixes or suffixes (see table above)
       • The single highest-priority group is named with its suffix. All other lower-priority groups are named with their prefixes.
   • Order of substituents: List all prefixes (side chains and lower-priority functional groups) alphabetically (ignoring prefixes like di-, tri-, sec-, tert‑).
3. Assemble the final name: List the prefixes alphabetically (with their location numbers), followed by the parent chain name, and finally the suffix of the principal functional group (with its location number, if needed).

The functional group of alcohols is the hydroxyl group (-OH group). Alcohols are formed by the substitution of at least one hydrogen atom on an sp³-hybridized carbon with a hydroxyl group. If the hydroxyl group is attached directly to an aromatic ring, the compound is called a phenol.

Alcohols

• Formation
  • By reduction of aldehydes, ketones, or carboxylic acids
  • By hydration (addition of water) to the double bond of alkenes
• Nomenclature: name of the organic parent structure + suffix "-ol" (butane → butanol)

Classification

• By number of OH groups: monohydric (one OH group) or polyhydric (multiple OH groups)
  • E.g., ethanol is monohydric , glycerol is a trihydric alcohol
• By degree of substitution: classified by the number of other carbon atoms attached to the carbon bearing the hydroxyl group
  • Primary alcohol: one other C atom
    • Special case: Methanol (CH₃OH) is also considered a primary alcohol.
  • Secondary alcohol: two other C atoms
  • Tertiary alcohol: three other C atoms

Properties

• More water-soluble than corresponding alkanes (due to hydrogen bonding with water)
• Higher boiling point than corresponding alkanes

Typical reactions

• Dehydration: In the presence of strong acids, alcohols can be dehydrated (lose water) to form alkenes (intramolecularly) or ethers (intermolecularly).
  • Ethers: are formed when two alcohol molecules react (condensation) with the elimination of water, typically acid-catalyzed; an ether has an oxygen atom bonded to two alkyl residues (R-O-R').
    • Nomenclature: named by the two alkyl groups attached to the oxygen (e.g., diethyl ether)
    • Properties: boiling point is lower than that of corresponding alcohols
  • Esters: are formed from the reaction of an alcohol with a carboxylic acid (or its derivative), with the elimination of water
  • Alkenes: are formed from alcohols (ease of dehydration: tertiary > secondary > primary) by acid-catalyzed elimination of water
• Oxidation: Alcohols can be oxidized with suitable oxidizing agents (in biochemistry, often by enzymes like dehydrogenases).
  • The oxidation of primary alcohols produces aldehydes (which can be further oxidized to carboxylic acids).
  • The oxidation of secondary alcohols produces ketones.
  • Tertiary alcohols are resistant to oxidation (without C-C bond cleavage).
• Acid-base reaction: Alcohols are very weak acids (similar to water).

Ethers and esters should not be confused. Ethers are formed from two alcohols (R-O-R'). Esters are formed from an alcohol and a carboxylic acid (R-COO-R').

Phenols

• Classification: by number of OH groups - monohydric (e.g., phenol) or polyhydric (e.g., hydroquinone)
• Properties: often crystalline solids; boiling point increases with the number of hydroxyl groups

Typical reactions

• Oxidation: The oxidation of phenols (e.g., hydroquinone, which has OH groups para to each other) can produce quinones.
• Acid-base reaction: Phenols are significantly more acidic than alcohols (but still weak acids) because the resulting phenoxide ion is stabilized by resonance.
• Substitution: The hydroxyl group is a strong activating group for electrophilic aromatic substitution, directing new substituents to the ortho- and para-positions.

The functional group of aldehydes and ketones is the carbonyl group (C=O). They differ in the position of the carbonyl group in the molecule.

Aldehydes

• Definition: hydrocarbon derivative with a terminal carbonyl group (an "aldehyde group")
• Formation: by oxidation of primary alcohols
• Nomenclature: name of the organic parent structure + suffix "-al" (butane → butanal)

Ketones

• Definition: hydrocarbon derivative with a non-terminal (internal) carbonyl group (a "keto group")
• Formation: by oxidation of secondary alcohols
• Nomenclature: name of the organic parent structure + suffix "-one" (butane → butanone) or prefix "oxo-" (e.g., 2-oxoglutarate)

Typical reactions of carbonyls

Since the chemical structure of aldehydes and ketones is similar, their typical reactions are also similar. The carbonyl group is polarized: The electronegative oxygen atom pulls electron density towards itself, acquiring a partial negative charge (δ‑). The carbon atom becomes electron-poor, acquiring a partial positive charge (δ+). This makes the carbon atom electrophilic (reacts with nucleophiles) and the oxygen atom nucleophilic (reacts with electrophiles, especially protons).

• Oxidation
  • Aldehydes are easily oxidized to carboxylic acids.
  • Ketones are resistant to oxidation (except under harsh conditions that break C-C bonds).
• Aldol reaction (aldehydes and ketones)
  • Aldols are molecules that have both an aldehyde (or keto) function and an alcohol function.
  • They are formed by the reaction of two carbonyl compounds (one acting as a nucleophile via its enolate, the other as an electrophile).
• Hemiacetal and acetal formation
  • Hemiacetal: functional group R–CH(OH)(OR') (from an aldehyde), hemiketal: functional group R–CR'(OH)(OR'') (from a ketone)
    • Formation by the nucleophilic addition of an alcohol to the carbonyl group of an aldehyde or ketone.
  • Acetal or ketal: functional group R-CH(OR')₂ or R-CR'(OR'')₂
    • Formation by reaction of a hemiacetal or hemiketal with another alcohol molecule (acid-catalyzed).
  • Cyclic hemiacetals/hemiketals: are formed when a carbonyl and a hydroxyl group within the same molecule react with each other
• Schiff base reaction
  • The reaction of aldehydes or ketones with a primary amine produces an imine (R₂C=NR'), also called a Schiff base, with the elimination of water.
• Keto-enol tautomerism
  • Carbonyl compounds with an α-hydrogen (a hydrogen on the adjacent carbon) can interconvert to form an isomer called an enol (an alcohol adjacent to a C=C double bond).
  • In aqueous solution, both forms (keto and enol) exist in an equilibrium called "tautomerism." For simple ketones and aldehydes, the keto form is overwhelmingly favored.
  • Process: involves the transfer of a proton from the α-carbon to the carbonyl oxygen, with a corresponding shift of the pi bond from C=O to C=C; this is catalyzed by acid or base
    • Base-catalyzed: A base removes an acidic α-proton to form an enolate ion (a resonance-stabilized nucleophile).
    • Protonation: The enolate can be protonated on the carbon (returning to the keto form) or on the oxygen (forming the enol).

Ketones (non-terminal carbonyl groups) cannot be easily oxidized further without breaking the carbon skeleton!

The functional group of carboxylic acids is the carboxyl group (-COOH group). Carboxylic acids play a major role in biochemical processes and are widespread in nature.

Carboxylic acids

• Formation: by oxidation of primary alcohols or aldehydes
• Nomenclature: name of the organic parent structure + suffix "-oic acid" (e.g., methanoic acid, ethanoic acid)

Classification

• By number of carboxyl groups (monocarboxylic acids = one, dicarboxylic acids = two, tricarboxylic acids = three)
• By other functional groups (e.g., hydroxy acids, keto acids, amino acids)
  • E.g., α-amino acid: has an amino group on the α-carbon (the C atom adjacent to the carboxyl group)
• Long-chain monocarboxylic acids (typically C4 or more) are also referred to as "fatty acids."

Typical reactions

• Acid-base reaction: Carboxylic acids are weak acids; they donate a proton in aqueous solution to form a resonance-stabilized carboxylate anion (R-COO^-).
• Dehydration: At high temperatures, two carboxylic acid molecules can condense (with loss of water) to form a carboxylic acid anhydride.
• Decarboxylation: elimination of the COOH group as CO₂

Di- and tricarboxylic acids (polyprotic acids) have multiple pK_a values. The first proton is donated most easily (lowest pK_a), the second less easily, and so on.

The -OH group of the carboxylic acid is part of the carboxyl functional group and behaves very differently from the hydroxyl group of an alcohol.

Important representatives of carboxylic acids

Carboxylic acid derivatives

Carboxylic acid derivatives are organic compounds whose functional group is derived from a carboxyl group (e.g., by replacing the -OH).

Esters

• Definition: compounds containing the functional group R-COOR' (a carboxyl group where the H is replaced by an alkyl/aryl group)
• Esterification: Esters are formed from the reaction of carboxylic acids and alcohols, typically acid-catalyzed, with the elimination of water (carboxylic acid + alcohol ⇄ ester + H₂O).
  • Molecules with both an alcohol group and a carboxylic acid group can polymerize to form polyesters.
• Ester hydrolysis: cleavage of an ester bond by reaction with water
  • Acid-catalyzed ester hydrolysis: the reverse of Fischer esterification; it is an equilibrium-controlled, reversible process
  • Base-catalyzed ester hydrolysis (saponification): hydrolysis of an ester using a strong base (e.g., NaOH); this reaction is irreversible because the base deprotonates the carboxylic acid product, forming a carboxylate salt
    • Product: the alcohol and the carboxylate salt of the carboxylic acid

Acid-catalyzed ester hydrolysis is reversible, while base-catalyzed ester hydrolysis (saponification) is irreversible.

Esters of inorganic acids

• Definition: compounds formed from an inorganic acid (e.g., phosphoric acid, H₃PO₄, or sulfuric acid, H₂SO₄) and an alcohol
  • Phosphoric acid esters (phosphate esters): contain the structural motif R-O-PO₃^2- (e.g., glucose-6-phosphate) or can form di- and triesters (like in DNA, ATP).
    • Phosphorylation: the formation of a phosphate ester, often by transferring a phosphate group from ATP to an alcohol (e.g., the OH group of serine, threonine, or tyrosine side chains in proteins).

Lactones

• Definition: cyclic carboxylic acid esters
• Lactone formation: formed by the intramolecular esterification of a molecule that contains both a carboxylic acid function and an alcohol function (a hydroxy acid)

Amides (carboxamides)

• Definition: compounds containing the functional group R-CONR'₂ (where R' can be H or an alkyl/aryl group); a key biochemical example is the peptide bond linking amino acids
• Structural feature: The amide group exhibits resonance, with a significant contribution from a resonance structure that has a C=N double bond and a C-O single bond.
  • This resonance gives the C-N bond partial double-bond character (restricting rotation) and makes the nitrogen lone pair much less basic than in an amine.
• Amide formation: formed by the reaction of a carboxylic acid (or derivative) with an amine, often requiring activation (e.g., in protein synthesis)

Lactams

• Definition: cyclic amides
• Lactam formation: formed by the intramolecular reaction of a molecule containing both a carboxylic acid function and an amino function (an amino acid)
• Medical relevance: The β-lactam ring (a four-membered lactam) is the core structural component of β-lactam antibiotics, such as penicillins and cephalosporins.

Thioesters

• Definition: sulfur analogs of esters; the most common type in biochemistry is a thiol ester
• Thiol esters: The singly bonded oxygen atom of an ester is replaced by a sulfur atom (R-CO-SR').
  • The cleavage (hydrolysis) of thiol esters is highly exergonic (releases a lot of energy). They play a major role in metabolism as "high-energy" compounds and acyl group carriers (e.g., acetyl-CoA, malonyl-CoA).
• Thionoesters: The C=O double bond oxygen is replaced by sulfur (R-CS-OR').
• Dithioesters: Both oxygen atoms are replaced by sulfur (R-CS-SR').

Carboxylic anhydride

• Definition: Carboxylic anhydrides contain the functional group R-CO-O-CO-R', formed from two carboxylic acid groups linked via an oxygen atom (with loss of water).
• Anhydride formation: formed by the condensation (dehydration) of two carboxylic acids
• Mixed acid anhydride: anhydride formed from two different acids, e.g., a carboxylic acid and an inorganic acid like phosphoric acid (forming an acyl phosphate, another "high-energy" compound)

Thiols are the sulfur analogs of alcohols; their functional group is the thiol group (-SH), also called a sulfhydryl group.

• Nomenclature: name of the organic parent structure + suffix "-thiol" or prefix "sulfanyl-" (or "mercapto-")
• Properties: do not form strong hydrogen bonds (like alcohols), so their boiling point is lower than that of the corresponding alcohols
• Typical reactions
  • Oxidation
    • Thiols are easily oxidized.
    • Disulfides: mild oxidation links two thiols (R-SH) to form a disulfide (R-S-S-R)
    • Sulfonic acids
      • Strong oxidation of thiols produces sulfonic acids (R-SO₃H).
      • Amides of sulfonic acids (sulfonamides, R-SO₂NR'₂) are important in pharmacology (e.g., sulfa antibiotics, sulfonylurea antidiabetics).
  • Thioether formation: Thioethers (sulfides, R-S-R') can be formed, for example, by the reaction of a thiolate (R-S^-) with an alkyl halide (analogous to Williamson ether synthesis).
  • Sulfoxide formation: Oxidation of thioethers (R-S-R') leads to the formation of sulfoxides (R-S(=O)-R').
  • Acid-base reaction: Thiols are more acidic than the corresponding alcohols (the S-H bond is weaker than the O-H bond) and can be deprotonated by bases to form thiolate anions (R-S^-).

General

Amines are organic derivatives of ammonia (NH₃). Their functional group is the amino group.

• Formation: in living systems, often by decarboxylation of amino acids or transamination reactions
• Nomenclature: name of the organic parent structure + suffix "-amine" or prefix "amino-"
• Classification: classified by the number of organic residues attached to the nitrogen atom.
  • Primary amine (R-NH₂): one hydrogen of ammonia is replaced
  • Secondary amine (R₂NH): two hydrogens of ammonia are replaced
  • Tertiary amine (R₃N): three hydrogens of ammonia are replaced
• Properties
  • The boiling point is higher than for corresponding hydrocarbons (primary and secondary amines can hydrogen-bond with themselves) but lower than for corresponding alcohols.
  • Short-chain amines are readily soluble in water.
• Typical reactions
  • Acid-base reaction: Amines are weak bases. The lone pair of electrons on the nitrogen can accept a proton (H⁺) to form an ammonium ion (e.g., R-NH₃⁺).
    • Basicity in aqueous medium: Alkylamines are generally stronger bases than ammonia.
  • Nucleophilic reaction: The lone pair makes amines good nucleophiles (e.g., in reactions with aldehydes/ketones to form imines/Schiff bases).

Biogenic amines

Biogenic amines are biologically active compounds formed in organisms, often by the decarboxylation of amino acids. They play important roles as neurotransmitters, hormones, and coenzymes.

Substitution and elimination reactions

These reactions are fundamental in organic chemistry, describing how a leaving group (an atom or group that detaches) is replaced by a nucleophile (substitution) or how a double bond is formed (elimination). Common substrates include alkyl halides or alcohols (which must first be protonated to make the -OH group a good leaving group, H₂O).

Nucleophilic substitution

SN1 (nucleophilic substitution, unimolecular)

• Kinetics: first-order (rate = k × [substrate]); the rate-determining step involves only the substrate
  • k = rate constant or rate coefficient, [substrate] = concentration of substrate (mol/L)
• Mechanism: two-step reaction
  • The leaving group departs, forming a planar carbocation intermediate (slow, rate-determining step).
    1. The nucleophile attacks the planar carbocation.
• Substrate:: favored by substrates that form stable carbocations (tertiary > secondary; primary and methyl do not typically react via SN1)
• Stereochemistry: produces a racemic mixture (racemization)
• Nucleophile: favored by weak nucleophiles (e.g., H₂O, ROH).
• Solvent: favored by protic solvents (e.g., water, alcohols) which can stabilize the carbocation intermediate

SN2 (nucleophilic substitution, bimolecular)

• Kinetics: second-order (rate = k × [substrate] × [nucleophile])
  • Mechanism: one-step (concerted) reaction
    • The nucleophile attacks the carbon from the backside, simultaneously displacing the leaving group.
  • Substrate: favored by unhindered substrates due to steric hindrance: methyl > primary > secondary (tertiary substrates do not react via SN2)
  • Stereochemistry: results in an inversion of configuration at the stereocenter, often called a Walden inversion (like an umbrella flipping inside out)
  • Nucleophile: requires a strong nucleophile (e.g., OH^‑,CN^-)
  • Solvent: favored by polar aprotic solvents (e.g., acetone, dimethyl sulfoxide), which do not "cage" the nucleophile, leaving it more reactive

Elimination reactions

E1 (elimination, unimolecular)

• Kinetics: first-order (rate = k × [substrate])
  • Mechanism: two-step reaction, proceeding through the same carbocation intermediate as SN1
    1. Leaving group departs, forming a carbocation
    2. A base (often weak, like the solvent) removes a proton from an adjacent carbon to form a double bond
  • Competition: E1 and SN1 reactions always compete with each other.
  • Base: effective with weak bases (e.g., H₂O, ROH)
  • Regiochemistry: follows Zaitsev's rule; the major product is the most substituted (and thus most stable) alkene

E2 (elimination, bimolecular)

• Kinetics: second-order (rate = k × [substrate] × [base])
  • Mechanism: one-step (concerted) reaction
  • Base: requires a strong base (e.g., OH^-, OR^-).
  • Stereochemistry: requires an anti-periplanar arrangement
  • Regiochemistry: follows Zaitsev's rule (most substituted alkene) unless a sterically hindered (bulky) base is used, which favors the less substituted and less stable alkene (i.e., the Hofmann product)

SN1, SN2, E1, and E2 often compete, and the dominant pathway depends on the substrate, nucleophile/base strength, and solvent.

Adding heat (often shown as a "Δ" symbol) always favors elimination (E1/E2) over substitution (SN1/SN2).

The structure and geometry of molecules lead to structural relationships. Molecules with the same molecular formula but different arrangements of atoms are called isomers. This concept is crucial for understanding large biomolecules. To understand isomerism, one must first grasp the concept of chirality. Molecules are three-dimensional objects. This means that two molecules that look identical as two-dimensional drawings may in reality be non-superimposable mirror images of each other, like a left and a right hand. Such molecules are called "chiral" (from the Greek *cheir* = "hand") and the pair are called enantiomers.

• Chirality: a geometric property of a molecule (or object) that is non-superimposable on its mirror image
• Chirality center (also stereocenter): The most common source of chirality in organic molecules is a carbon atom bonded to four different substituents.
  • For each such stereocenter, there are two possible spatial arrangements (configurations) that are mirror images of each other.
  • A molecule with 'n' stereocenters can have up to 2ⁿ possible stereoisomers.
• Importance in biochemistry: Many biochemically relevant molecules are chiral, including amino acids (and thus proteins) and carbohydrates.

Effect of different enantiomers
The physiological properties of enantiomers can be completely different. For example, (+)-limonene smells of oranges, while (‑)-limonene smells of resin or pine. Chirality is particularly important in medicine: For example, only the (S)-(+)-ibuprofen enantiomer is the active anti-inflammatory agent (though the (R)-form is slowly converted to the (S)-form in the body). Sometimes, one enantiomer is therapeutic while the other is inactive or, in the worst case, harmful. The most infamous example is thalidomide, where one enantiomer had the intended sedative effect while the other was found to be teratogenic (causing birth defects).

Prochirality

“Prochiral” molecules are not chiral themselves but can become chiral in a single chemical step (e.g., by addition or substitution). Prochiral centers are often sp²-hybridized carbons (like in ketones or aldehydes) that can become chiral sp³ carbons upon an addition reaction.

• Example: Butanone is an achiral molecule. Reduction of its carbonyl group (at C2) with H₂/catalyst or NaBH₄ produces 2-butanol. The resulting C2 atom is now bonded to four different groups (-H, -OH, -CH₃, -CH₂CH₃) and is thus a chirality center.

Nomenclature of enantiomers

To distinguish between enantiomers, several nomenclature systems are used.

Classification by optical activity

Enantiomers have identical physical properties (boiling point, melting point, density) except for one: their interaction with plane-polarized light. A solution of a pure enantiomer will rotate the plane of polarized light.

• (+)-Enantiomer (or dextrorotatory, d‑): rotates plane-polarized light clockwise (to the right)
• (‑)-Enantiomer (or levorotatory, l‑): rotates plane-polarized light counterclockwise (to the left)
• Racemate (or racemic mixture): an equal (50:50) mixture of both enantiomers; it is optically inactive because the rotations of the two enantiomers cancel each other out

R/S nomenclature (Cahn-Ingold-Prelog convention)

This system assigns an absolute configuration (R or S) to each stereocenter based on its 3D geometry, independent of its optical rotation.

To determine the R/S configuration:

1. Identify a stereocenter (e.g., a C atom with four different substituents).
2. Assign priorities (1 = highest, 4 = lowest) to the four substituents based on atomic number.
   • The atom directly attached to the stereocenter with the highest atomic number gets the highest priority (e.g., Br > Cl > O > N > C > H).
   • If there is a tie, move to the next atom along each chain until a point of difference is found. Multiple bonds count as multiple single bonds to that atom (e.g., C=O counts as C bonded to two O's).
3. Orient the molecule so that the lowest-priority group (4) points away from you (into the page, often shown with a dashed bond).
4. Trace the path from priority 1 → 2 → 3.
   • If the path is clockwise, the configuration is R (*rectus* = right).
   • If the path is counterclockwise, the configuration is S (*sinister* = left).

D/L nomenclature

This is an older system, still used in biochemistry for carbohydrates and amino acids. It relates the configuration of a molecule to that of a reference compound, glyceraldehyde.

• Procedure for carbohydrates
  • The molecule is drawn in a Fischer projection with the most oxidized carbon (e.g., aldehyde) at or near the top.
  • The stereocenter furthest from the most oxidized carbon is considered.
  • If the -OH group on this C atom points to the right, it is the D-form (from the Latin "dexter," meaning "right"). If it points to the left, it is the L-form (from the Latin "laevus," meaning "left").
• Procedure for amino acids: analogous, but the position of the amino group (-NH₂) on the α-carbon is considered

The 20 common proteinogenic amino acids (except achiral glycine) are all in the L-form.

The more atoms a molecule has, the more ways they can be linked. Molecules with the same molecular formula but different structures are called isomers. A distinction is made between different types of isomers:

Constitutional isomers (or structural isomers)

Molecules with the same molecular formula but a different connectivity (order in which atoms are bonded). E.g., n-butane and isobutane (C₄H₁₀), or dihydroxyacetone and glyceraldehyde (C₃H₆O₃).

Stereoisomers

Molecules with the same molecular formula and the same connectivity, but a different spatial arrangement of atoms.

Conformational isomers (or conformers)

Stereoisomers that can be interconverted simply by rotation around C-C single bonds. E.g., the chair and boat forms of cyclohexane, or the staggered and eclipsed conformations of ethane.

Configurational isomers

Stereoisomers that cannot be interconverted by simple bond rotation; breaking and reforming bonds is required. This occurs due to restricted rotation (e.g., double bonds, rings) or the presence of a stereocenter.

• Cis/trans isomers (geometric isomers): occur due to restricted rotation (e.g., around a double bond or in a ring)
  • Cis/trans nomenclature
    • cis-isomer: Similar substituents are on the same side of the double bond or ring.
    • trans-isomer: Similar substituents are on opposite sides.
  • E/Z nomenclature: a systematic method using Cahn-Ingold-Prelog priority rules (CIP) for naming geometric isomers, especially when "cis/trans" is ambiguous (e.g., in tri- or tetrasubstituted alkenes)
    • Procedure: assign priorities (high/low) to the two substituents on each carbon of the double bond using CIP rules
    • Z-isomer (*Zusammen* = together): The two high-priority groups are on the same side of the double bond or ring.
    • E-isomer (*Entgegen* = opposite): The two high-priority groups are on opposite sides of the double bond.
• Enantiomers
  • Configurational isomers that are non-superimposable mirror images of each other.
  • They have opposite configurations (R/S) at all existing chirality centers (e.g., D-glucose and L-glucose).
• Diastereomers
  • Configurational isomers that are not mirror images of each other.
  • This category includes molecules with multiple stereocenters that differ at some, but not all, of those centers (e.g., L-glucose and D-galactose). Cis/trans isomers are also a type of diastereomer.
  • Epimers
    • A sub-type of diastereomer. Epimers are molecules with multiple stereocenters that differ in configuration at exactly one stereocenter (e.g., D-glucose and D-galactose are C4 epimers).

Cis/trans and E/Z nomenclature are not interchangeable. Cis/trans is a simpler system that compares the relative positions of identical groups or the main carbon chain. E/Z is the rigorous IUPAC standard that uses Cahn-Ingold-Prelog (CIP) priority rules to compare the highest-priority groups on each carbon of the double bond. Because they use different rules, the two systems can conflict (e.g., an alkene can be cis but E), which is why E/Z is the unambiguous and universally preferred method.