Heterocycles 1.pptx Heterocyclic Chemistry PDF

Heterocyclic Chemistry PH1015 Heterocyclic Chemistry Recommended Reading: Organic Chemistry Clayden, Greeves, Warren, Wothers Oxford University Press, 2001. Heterocycles in Life and Society Pozharskii, Soldatenkov, Katritzky John Wiley & Sons, 1997. Heterocyclic Chem...

Heterocyclic Chemistry PH1015 Heterocyclic Chemistry Recommended Reading: Organic Chemistry Clayden, Greeves, Warren, Wothers Oxford University Press, 2001. Heterocycles in Life and Society Pozharskii, Soldatenkov, Katritzky John Wiley & Sons, 1997. Heterocyclic Chemistry Joule, Mills, Smith Chapman & Hall, 3rd Ed., 1995. Heterocyclic Chemistry Sainsbury RSC, 2001.  Objectives To selectively illustrate the importance of heterocyclic rings in the structure of drugs and naturally occurring biologically active molecules. Course Content Lecture 1: Introduce heterocyclic molecules, namely saturated, monocyclic and aromatic. Lecture 2: Five membered aromatic systems & their properties. Monocyclic systems containing more than one heteroatom. Lecture 3: Fused ring systems with one heteroatom Lecture 4: Fused ring systems with more than one heteroatom.  What is a Heteroatom? A Heteroatom is any atom in an organic molecule other than C or H. Eg. Nitrogen, Oxygen, Sulfur What is a Heterocycle? A Heterocycle is a ring system containing one O or more heteroatoms. N Me EtO HN N N CO2Me N O S N Me O N O viagra N O N Me nicotine cocaine  Saturated Heterocycles Nitrogen containing saturated heterocycles Behave as secondary amines Lone pair of e-’s are free to react with protons, H+ Act as nucleophiles in addition & substitution reactions Are slightly stronger bases than their acyclic amines – R groups are “tied back” into ring, resulting in less steric hindrance for lone pair of e-’s on N to attack N N H H pKa = 11.0 pKa = 11.2  Examples N N N H H pyrrolidine piperidine quinuclidine pKa = 11.3 pKa = 11.2 pKa = 11.0 Quinuclidine is 60X faster than its acyclic equivalent, triethylamine when it is acting as a nucleophile.  Piperidine H H H H H H H H N H HH H N HH H H H H H H H H Slightly more stable A B Each C atom is sp3 hybridized - tetrahedral The N is also sp3 hybridized with the lone pair of e-’s in an sp3 orbital – also tetrahedral The bond angles are all close to 109.5° This gives rise to two chair conformations of piperidine – (A) where the H on N is equatorial, & (B) where the H on N is axial  Piperidine as a Base It is the lone pair of e-’s on N that allow it to act as a base – much the same as an aliphatic amine acts as a base. H H H H H H H H H H H N HH H N + HH H H H H H H H H+ Soluble in hydrocarbons Soluble in aqueous media  Drugs Containing Piperidine O O O N H O N Pethidine (Demerol) - analgesic Methylphenidate (Ritalin) - psychostimulant for ADHD O N N F Melperone - antipsychotic Phenylcyclohexylpiperidine (PCP) - hallucinogenic Other Saturated Heterocycles O O tetrahydrofuran tetrahydropyran THF THP S S tetrahydrothiophene thiane  Aromatic Heterocycles Heteroaromatic compounds are the most important group of heterocycles Approximately 2/3 organic compounds belong to this class Involved in an extraordinarily wide range of reaction types They may be acids or bases, may produce stable complexes with metals  Aromaticity & Pyridine 5 sp2 C atoms 6 sp2 C atoms N 1 sp2 N atom 6 H atoms 5 H atoms 6 p-electrons 6 p-electrons N benzene pyridine Hückel’s Rule: planar, fully conjugated cyclic systems containing (4n+2) p-electrons show added stability over that anticipated for the theoretical system composed of formal alternate single and double bonds - AROMATICITY  How Pyridine Differs from Benzene Pyridine has a distorted hexagonal shape C-N bonds are shorter than C-C bonds – (0.134nm versus 0.139 nm) This is because N is more electronegative than C and causes a permanent dipole towards the N. 1.40Å 1.39Å dipole N 1.34Å  How Pyridine Differs from Benzene + + - - - + N N N N N Because of the permanent dipole towards N, the ortho and para carbons have fractional positive charges. This electron deficiency means that pyridine & similar heterocycles are electron poor, or p- deficient. One H (on benzene) is replaced by a lone pair of electrons It is this lone pair which is responsible for the basic properties of pyridines  Pyridine as a Base + H+ N N H 1H-pyridinium cation N The lone pair can not be delocalized around the ring This is because the lone pair are orthogonal to the p- cloud They are available for bonding and therefore make pyridine a base pKa = 5.23 (conjugate acid is as strong as a carboxylic acid The pyridinium cation is still aromatic!  Properties of Pyridine Pyridine is a liquid (b.p. 115 °C) It is polar aprotic (does not H-bond) Is miscible with water & organic solvents The ring does not undergo electrophilic substitution E H E X N N Undergoes nucleophilic substitution with ease (better than benzene) Nu Nu N X N X N Nu Drugs Containing Pyridine N N N nicotine AcO OAc bisacodyl (laxative) N N N N O NH2 O mepyramine nicotinamide (Nam) (antihistamine) (constituent in NAD+- found in all living cells)