The document summarizes various types of oxidation reactions that can occur with carbon-heteroatom systems, including C-N, C-O, C-S, and others. It describes two main types of reactions: 1) hydroxylation of the α-carbon directly attached to the heteroatom, forming an unstable intermediate that cleaves the C-X bond, and 2) hydroxylation of the heteroatom itself (for N and S), forming derivatives like N-oxides. Specific compounds and pathways are discussed for tertiary, secondary, and primary amines, amides, alcohols, aldehydes, and others.
The document summarizes various types of oxidation reactions that can occur with carbon-heteroatom systems, including C-N, C-O, C-S, and others. It describes two main types of reactions: 1) hydroxylation of the α-carbon directly attached to the heteroatom, forming an unstable intermediate that cleaves the C-X bond, and 2) hydroxylation of the heteroatom itself (for N and S), forming derivatives like N-oxides. Specific compounds and pathways are discussed for tertiary, secondary, and primary amines, amides, alcohols, aldehydes, and others.
The document summarizes various types of oxidation reactions that can occur with carbon-heteroatom systems, including C-N, C-O, C-S, and others. It describes two main types of reactions: 1) hydroxylation of the α-carbon directly attached to the heteroatom, forming an unstable intermediate that cleaves the C-X bond, and 2) hydroxylation of the heteroatom itself (for N and S), forming derivatives like N-oxides. Specific compounds and pathways are discussed for tertiary, secondary, and primary amines, amides, alcohols, aldehydes, and others.
The document summarizes various types of oxidation reactions that can occur with carbon-heteroatom systems, including C-N, C-O, C-S, and others. It describes two main types of reactions: 1) hydroxylation of the α-carbon directly attached to the heteroatom, forming an unstable intermediate that cleaves the C-X bond, and 2) hydroxylation of the heteroatom itself (for N and S), forming derivatives like N-oxides. Specific compounds and pathways are discussed for tertiary, secondary, and primary amines, amides, alcohols, aldehydes, and others.
Carbon-Heteroatom systems oxidation - Tertiary amines: - Oxidative removal of alky group (oxidative N-dealkylation) by P- 450. Started by -carbon hydroxylation to form carbinolamine intermediate, then cleavage of C-N bond to secondary amine and carbonyl moiety (Aldehyde or ketone).
C-N system oxidation
- Small alky groups are normally removed quickly, and the first is removed faster.
C-N system oxidation Methadone to pyrrolidine ring cyclization - Complete dealkylation reactions will lead to oxidation of primary amine to carboxylic acid. - t-butyl moiety is not possible to be removed because no alpha H to be hydroxylated with the exception of t-butyl-norchlorcyclazine, which occur through oxidation of terminal CH 3 to carboxylic acid then decarboxylated to produce H at alpha carbon.
C-N system oxidation Cl N N Cl N N OH Cl N N COOH Cl N N
- Tertiary alicyclic amines usually form Lactams (nicotine).
C-N system oxidation - Secondary amines: Undergo oxidative N-dealkylation, oxidative deamination, and N- oxidation reactions. - Oxidative N-Dealkylation: Carbinolamine pathway which produces primary amine (the same as for tertiary amines). - Examples:
C-N system oxidation propranolol methamphetamine norketamine - Secondary amines: - Oxidative Deamination: process by which a molecule loses the primary amine group by the same carbinolamine intermediate.
- In general, the first step is N-dealkylation, then deamination
- There is an exception such as propranolol in which the oxidative deamination can occur directly through the oxidation of the alpha- carbon of its secondary amine.
C-N system oxidation
- Metabolic oxidation reactions of Propranolol:
C-N system oxidation - Norketamine does not undergo N-deamination. (why?)
- Norketamine can only undergo oxidative N-dealkylation
C-N system oxidation - Also some alicyclic secondary amines are transformed to their corresponding lactams (phenmetrazine, methylphenidate).
- N-oxidation also happens but to less extent to form N- hydroxylamine that is prone to form nitrone derivative C-N system oxidation - Primary amines: - Primary amines normally undergo oxidative deamination or N- oxidation. (endogenous compounds such as neurotransmitters oxidized via monoamine oxidase [MAOs]).
C-N system oxidation - The possibility of alpha carbon oxidation depends on the availability of alpha hydrogen (eg. Phentermine).
C-N system oxidation -Decarboxylation step could happen first then deamination occur (methyldopa). amphetamine phentermine
- Primary aliphatic amines which are not possible to be oxidized at alpha position will be N-hydroxylated and further oxidation produced nitroso and nitro compounds. (phenteramine, amantadine).
C-N system oxidation
- Primary aliphatic amines with alpha hydrogen can be N- hydroxylated also.
- N-hydroxylation could occur first then converted to imine by water loss, then converted to oxime which will be converted to ketone (amphetamine).
C-N system oxidation C-N system oxidation Aromatic amines and heterocyclic Nitrogen compounds
- Tertiary and secondary aromatic amines are not common in medicinal drugs while the primary amines are abundant (from enzymatic reduction of aromatic nitro compounds, reductive cleavage of azo compounds and hydrolysis of aromatic amides).
- Tertiary aromatic amines will undergo N-dealkylation and N-oxide formation.
C-N system oxidation Aromatic amines and heterocyclic Nitrogen compounds
C-N system oxidation Aromatic amines and heterocyclic Nitrogen compounds
- Secondary amines undergo N-dealkylation and N-oxidation to give N-hydroxyl amines which will oxidized again to give nitrone derivatives, which they may hydrolyze to primary hydroxylamines.
C-N system oxidation Aromatic amines and heterocyclic Nitrogen compounds
- Primary aromatic amines first produce hydroxyl derivative, then to nitroso.
C-N system oxidation - Aromatic N-oxidation is considered a minor constitute compared to N-acetylation and aromatic hydroxylation.
- Methemoglobinemia is a common side effect of aromatic amines (dapsone) when they are converted to N-hydroxyl derivatives. The N-hydroxyl derivatives are able to oxidize the Fe +2 to Fe +3 in hemoglobin which will prevent oxygen transport (suffocation).
C-N system oxidation
- Aromatic amines are considered carcinogenic: activated by N- oxidation to make them highly electrophilic and alkylated by DNA, RNA. C-N system oxidation N N NH N N N OH N N N OSO 3 - N N N + nitreniumion N N N GLG - N-oxidation of N atoms inside heterocycle occur less common to produce N-Oxide metabolite, (trimethoprim, cotinine and metronidazole).
C-N system oxidation - Oxidative C-N cleavage (- carbon hydroxylation) and N- hydroxylation reactions. - Oxidative dealkylation occur through carbinolamide intermediate, unstable, fragmentation to form N-dealkylated product (Diazepam).
Amides Amides Flurazepam chlorpropamide
- Lactams, in the same way by forming carbinolamide that lead to C-N breakage (Cotinine).
Amides Cotinine
- Cyclophosphamide has many metabolites, see book page 73. - Aromatic amides, minor extent, toxicological importance, 2-acetyl aminoflourene (AFF) [N-oxidation, sulfonation, then nitrinum ion production]. Amides Cyclophosphamide
-Aromatic amides, minor extent, toxicological importance, 2-acetyl aminoflourene (AAF) [N-oxidation, sulfonation, then nitrinum ion production]. Amides - Acetaminophen: Amides HN CH 3 O O H Renal excretion HN CH 3 O O N-acetylamindoquinone HN CH 3 O O HN CH 3 O O Glucuronide SO 3 O - Cause covalent binding with livercells, necrosis - Performed via microsomal mixed function oxidases. - Oxidation involve -oxidation to form hemiacetal or hemiketal, followed by C-O bond breakage (phenol, alcohol) and (ketone or aldehyde).
C-O System Oxidation R 1 H OH OR 2 R 1 R 3 OH OR 2 Hemiacetal hemiketal
-Small alkyl groups removed first.
C-O System Oxidation morphine - Mescaline where the 3-O demethylation is favored.
C-O System Oxidation - Undergo S-dealkylation, desulfuration, and S-Oxidation. The first two involve C-S bond cleavage. - S-dealkylation is proceeded in the same way as C-O and C-N dealkylation by oxidizing the -carbon.
- Examples are 6-(methylthio)-purine produced 6-mercaptopurine.
C-S System Oxidation N N N H N S N N N H N SH
C-S System Oxidation HN N H S O O S COOH CF 3 S - Desulfuration: Conversion of thiono (C=S) or (P=S) to (C=O) or P=O respectively. -Thiopental to pentobarbital
-and parathion to paraoxon.
C-S System Oxidation - S-Oxidation reactions: - Sulfide to sulfoxide to sulphone. C-S System Oxidation
- Alcohol is produced from different metabolic pathways such as oxidation of benzylic, allylic, alicyclic or aliphatic oxidation. - If the OH is not conjugated, it will further oxidized. - Primary alcohol and aldehydes give facile oxidation to carboxylic acid. - Less important, secondary alcohol to ketone, not that important as it may be reduced again to alcohol as it is easier to be conjugated. - The enzyme called alcohol dehydrogenase perform reversible reaction that converts alcohol to aldehyde and ketone, using NAD + as a coenzyme. - Further oxidation of aldehyde to COOH, is done by aldehyde oxidaze and xanthine oxidize. Oxidation of Alcohols and Aldehydes - Oxidative aromatization, as in norgestrol.
Other Oxidation Reactions
-Chloroform produce phosgene (hepato and nephrotoxicty).
Other Oxidation Reactions Other Oxidation Reactions - Normally dehalogenation reactions produce toxic acylhalides.