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Heterocycles 2 Daniel Palleros Heterocycles 2 Daniel Palleros Heterocycles 1. Structures 2. Aromaticity and Basicity 2.1 Pyrrole 2.2 Imidazole 2.3 Pyridine 2.4 Pyrimidine 2.5 Purine 3. Π-excessive and Π-deficient Heterocycles 4. Electrophilic Aromatic Substitution 5. Oxidation-Reduction 6. DNA and RNA Bases 7. Tautomers 8. H-bond Formation 9. Absorption of UV Radiation 10. Reactions and Mutations Heterocycles 3 Daniel Palleros Heterocycles Heterocycles are cyclic compounds in which one or more atoms of the ring are heteroatoms: O, N, S, P, etc. They are present in many biologically important molecules such as amino acids, nucleic acids and hormones. They are also indispensable components of pharmaceuticals and therapeutic drugs. Caffeine, sildenafil (the active ingredient in Viagra), acyclovir (an antiviral agent), clopidogrel (an antiplatelet agent) and nicotine, they all have heterocyclic systems. O CH3 N HN O O N O CH 3 N H3C N N HN N OH O S O H N N N 2 N O N N O CH3 N CH3 caffeine sildenafil acyclovir Cl S N CH3 N N H COOCH3 nicotine (S)-clopidogrel Here we will discuss the chemistry of this important group of compounds beginning with the simplest rings and continuing to more complex systems such as those present in nucleic acids. Heterocycles 4 Daniel Palleros 1. Structures Some of the most important heterocycles are shown below. Note that they have five or six-membered rings such as pyrrole and pyridine or polycyclic ring systems such as quinoline and purine. Imidazole, pyrimidine and purine play a very important role in the chemistry of nucleic acids and are highlighted. Five-membered 3 N 4 3 N 4 N 5 5 2 2 O N S N O S 1 1 H H Furan Pyrrole Thiophene Imidazole Oxazole Thiazole O N S H Tetrahydrofuran Pyrrolidine Thiolane (THF) Six-membered N N N N N N N Pyridine Pyrimidine Pyridazine Pyrazine O N N H H Piperidine Morpholine Polycyclic 5 4 5 4 4 6 3 7 N 5 6 3 6 3 5 N 1 2 8 2 7 7 N 6 N N 2 N 9 4 N 2 1 3 8 1 8 1 7 H H Quinoline Isoquinoline Indole Purine 2. Aromaticity and Basicity Heterocycles are aromatic if they obey Hückel’s rules of aromaticity: a) The ring is planar. b) There is a continuous conjugated system (all atoms of the ring are sp2 hybridized). c) The number of pi electrons is equal to 4 n +2, where n = 0; 1; 2; 3; etc. According to these rules, pyrrole, imidazole, pyridine, pyrimidine and purine, just to mention a few, are aromatic heterocycles. We will discuss these five systems in some detail because they play an important role in the chemistry of nucleic acids and Heterocycles 5 Daniel Palleros pharmaceuticals. We will pay special attention to the hybridization and basicity of the nitrogen atoms. 2.1 Pyrrole The nitrogen atom is sp2 hybridized. The N electron pair is on a p orbital, perpendicular to the plane of the ring and overlapping with the other p orbitals. There are a total of 6 π electrons, which is a Hückel number (Hückel numbers are 2, 6, 10, etc.) and, therefore, the molecule is aromatic. sp2 N H H H N H nonbasic H H 6 pi electrons You may wonder why the hybridization of the nitrogen atom is sp2 and not sp3 as expected for a nitrogen attached to three other atoms. The answer to this question can be found in the fact that the sp2 hybridization makes the nitrogen coplanar with the rest of the molecule and places the lone electron pair on a p orbital parallel to the other p orbitals. This leads to aromaticity and further stability. If the nitrogen were sp3 hybridized, it wouldn’t be coplanar and the molecule couldn’t be aromatic. H H N sp3 H H H nonaromatic Heterocycles 6 Daniel Palleros Because the N electron pair is forming part of the aromatic system, it is not available for protonation (protonation would destroy the aromaticity), thus pyrrole is nonbasic. not available for protonation N H nonbasic This is demonstrated by an unusually low pKa value for the conjugate acid of pyrrole, which is 11 orders of magnitude more acidic than the conjugate acid of the nonaromatic counterpart, pyrrolidine. conjugate acid of pyrrole: conjugate acid of pyrrolidine: pKa = 11.3 pKa = 0.4 N N H H H H Let’s consider now the dissociation of pyrrole itself. pKa = 17.5 + H2O + H O+ N N 3 H sp2 The pKa of pyrrole (the dissociation of the H on the nitrogen) is 17.5. Compared to the pKa of pyrrolidine (≈ 35), it is about 20 orders of magnitude lower. Pyrrolidine pKa ! 35 + H O 2 + H O+ N N 3 H sp3 The higher acidity of pyrrole is due to the sp2 hybridization of its N; sp2 hybridized atoms have more s-character, hold electrons tighter and, in general, are more tolerant of negative charges than sp3 hybridized atoms and thus yield more stable anions. 2.2 Imidazole The imidazole ring is aromatic. Both N atoms are sp2 hybridized. The N attached to H (N1) has the electron pair on a p orbital, perpendicular to the plane of the ring. This electron pair forms part of the six-electron aromatic cloud and, like in the case of pyrrole, Heterocycles 7 Daniel Palleros is not available for protonation. The double-bonded nitrogen (N3), on the other hand, has the electron pair on an sp2 hybrid orbital which lies outside the ring and, thus, does not form part of the aromatic system. This electron pair is available for protonation. 2 outside the ring sp available for protonation (basic N) 2 N 3 N H 1 4 5 inside the ring; aromatic not available for protonation (nonbasic N) available for protonation H not available for protonation N N H H H 6 pi electrons It is worth mentioning that once the basic N gets protonated, both N atoms become indistinguishable because of resonance: H H N N HA N A- N N N H H H Protonated imidazole is often represented by the following structure that clearly shows that both N atoms are identical. The pKa of the conjugate acid of imidazole is 6.95. H N + pKa = 6.95 N H Heterocycles 8 Daniel Palleros The pKa of imidazole itself is 14.2, about three order of magnitude lower than the pKa of pyrrole (pKa = 17.5). This is due to the extra N atom in imidazole which is electron- withdrawing and thus stabilizes the negative charge in the conjugate base. electron withdrawing: stabilizes the negative charge N N pKa = 14.2 + H O 2 + H O+ N N 3 H The imidazole ring is present in histidine, a basic amino acid, and histamine, a biologically active amine involved in immune responses. O H N N O NH2 NH3 N N H H histidine histamine 2.3 Pyridine The N atom is sp2 hybridized. The N electron pair lies outside the ring on an sp2 hybrid orbital and is available for protonation, making pyridine a basic heterocycle. The pKa of the conjugate acid of pyridine is 5.25. N pKa = 5.25 N outside the ring H available for protonation (basic N) 2.4 Pyrimidine Both N atoms are equivalent and sp2 hybridized. Both electron pairs lie outside the aromatic ring on sp2 hybrid orbitals. Both N are slightly basic. Pyrimidine is less basic than pyridine because of the inductive, electron-withdrawing effect of the second N atom. The pKa of the conjugate acid of pyrimidine is 1.3. Heterocycles 9 Daniel Palleros N N N N H pKa = 1.3 Note that pyrimidine is about six orders of magnitude less basic than imidazole. 2.5 Purine Purine consists of a pyrimidine ring fused with an imidazole ring. All four N atoms are sp2 hybridized. N1, N3 and N7 are basic but N9 is not. N7, being on the imidazole side of the molecule, is more basic than N1 and N3 on the pyrimidine side. less basic than imidazole 7 3 N 4 N 1 N 5 2 9 N N N 3 1 more acidic than H H imidazole nonbasic Purine Imidazole However, N7 less basic than the corresponding N in imidazole (N3) because the neighboring pyrimidine ring with two N atoms, which are electron-withdrawing, takes electron density away from the imidazole ring. Once N7 gets protonated both N7 and N9 become almost indistinguishable; they both have a pKa of 2.4, which makes them about four orders of magnitude more acidic than the protonated nitrogens in imidazole. H N H 7 N 1 N pKa = 2.4 N N 9 N 3 pKa = 6.95 H H The pyrimidine ring, because of the electron-withdrawing effect of the nitrogen atoms, also makes the H on N9 more acidic than the corresponding H in imidazole (on N1). 7 3 N N N 1 N N 1 9 N H 3 H pK = 8.9 pK = 14.2 a a It should be remarked that there are two important tautomers of purine. As you may recall, tautomers are constitutional isomers in rapid equilibrium with one another. Usually, they differ in the position of a hydrogen atom (tautomers are also treated in section 7). The only difference between the two tautomers of purine is in the position of the hydrogen on the imidazole ring. Heterocycles 10 Daniel Palleros 7 H N 7 N N N 9 N N 9 N N H H9 H7 In solution, both tautomers exist in equilibrium in equal amounts.
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