The greater acidity of pyrroles and indoles is a consequence of. There are 6 nucleophilic substitution mechanisms encountered with aromatic systems. A clean, mild and sustainable method for the functionalization of pyridines and their analogues is reported. A simple introduction to the type of nucleophilic substitution reactions that are possible with pyridine. S n ar reactions of 2 or 4halopyridines comprise a sitespecific method to synthesize substituted pyridines. Y by an electrophile e such that e becomes bonded to y by the electron pair of the xy bond. This includes an explanation of c2 and c4 attack, the use of electron withdrawing groups.
Pyridine is more reactive than benzene because the presence of nitrogen enables pyridine to react with nucleophiles. Synthesis of ringfused pyridinium salts by intramolecular. It therefore enters less readily electrophilic aromatic substitution reactions, which are characteristic of benzene derivatives. Reactivity in the nucleophilic aromatic substitution. A comprehensive mechanism for aromatic nucleophilic substitution in aprotic solvents. Why nucleophilic substitution in pyridine favours at. Compare the reactivity of pyridine to that of benzene in nucleophilic aromatic substitution. Energy consideration aside, theres another problem given by the nitrogen atom. This can be explained by presence of the aromatic lone pair owing to nitrogen in pyrrole makes the aromatic system more electron rich, and you can get a hint of it by looking at the electron pushing mechanism.
At the beginning of this article an indepth comparison of electrophilic and nucleophilic aromatic and heterocyclic substitution processes examines their scopes of applicability in a new light. A zincbased lewis acid is used to activate pyridine and its analogues towards nucleophilic aromatic substitution, conjugate addition, and cyclization reactions by binding to the nitrogen on the pyridine ring and activating the pyridine ring core towards further. Pathways for the electrophilic aromatic substitution of pyridines. Electrophilic aromatic substitution furan, thiophene, and pyrrole, like benzene and naphthalene, undergo electrophilic aromatic substitution reactions. Electrophilic aromatic substitution is an organic reaction in which an atom that is attached to an aromatic system usually hydrogen is replaced by an electrophile. Benzene undergoes substitution reactions instead of addition. We can picture this in a general way as a heterolytic bond breaking of compound x. Electrophilic reagents attack preferably at the natom and at the bcatoms.
Therefor, metasubstitution is preferred in electrophilic attack on pyridine so electrophilic attack on pyridine will produce metasubstituted pyridines. Electrophilic aromatic substitution is the most typical reaction of benzene and its derivatives. Acidity of pyrrole and indole pyrrole and indole are weak acids. The element effect in nucleophilic aromatic substitution reactions s n ar is characterized by the leaving group order, l f no 2 cl. Chemistry ii organic heteroaromatic chemistry lecture 6. Why is pyrrole more reactive than pyridine and benzene for. One of the three diazines sixmembered heterocyclics with two nitrogen atoms in the ring, it has the nitrogen atoms at positions 1 and 3 in the ring 250 the other diazines are pyrazine nitrogen atoms at the 1 and 4 positions and pyridazine nitrogen atoms at the 1 and 2 positions. Pyridine is the simplest heterocycle of the azine type.
Electrophilic aromatic substitution the most characteristic reaction of aromatic compounds is electrophilic aromatic substitution, in which one of the ring hydrogens is substituted by a halogen, nitro group, sulfonic acid group, alkyl or acyl group. The nucleophilic addition at the nitrogen atom leads to a further deactivation of the aromatic properties and hindering of the electrophilic substitution. Intramolecular cyclization using nacyliminium ions. As you learn about other electrophilic substitution reactions, it will. Nucleophilc substitution in pyridine favours not only position 2 but also position 4. Nucleophilic aromatic substitution snar as an approach. King chapter 18 electrophilic aromatic substitution i. Some of the most important electrophilic aromatic substitutions are aromatic nitration, aromatic halogenation, aromatic sulfonation, and alkylation and alkylating friedelcrafts reaction. A nucleophilic aromatic substitution reaction is a reaction in which one of the substituents in an aromatic ring is replaced by a nucleophile a meisenheimer complex is a negatively charged intermediate formed by the attack of a nucleophile upon one of the aromaticring carbons during the course of a nucleophilic aromatic substitution reaction. However, unlike benzene and its derivatives, pyridine is more prone to nucleophilic substitution and metalation of.
In order to understand why, we must first draw out the intermediate structures and take a look at the different resonance stabilized forms that it have. Pyridine structure and properties a liquid bp 115 c bond lengths, 1h and c nmr chemical shifts and coupling constants as expected for an aromatic system. Aromaticity nucleophilic aromatic substitution, benzyne. Lewis acid activation of pyridines for nucleophilic. Directing and activating effects in electrophilic aromatic substitution, use of electrophilic aromatic substitution in synthesis, nucleophilic substitution of aryl halides benzyne and addition. Is the nitrogen in pyridine electron withdrawing and what. Therefore, it matches all qualifications for an aromatic. A comprehensive mechanism for aromatic nucleophilic. The synthesis of nitrogen cationdoped polycyclic aromatic hydrocarbons pahs having a variety of counteranions is reported via the trimethylsilyl tmspromoted intramolecular aromatic nucleophilic substitution snar reaction of fluoroarenes and pyridine groups. In a nucleophilic substitution reaction, the substituting group acts as a nucleophile, or lewis base. Nitrogen is an electron withdrawing substituents enables the aromatic ring to participate in such reactions and the.
Pyridine is bad at electrophilic aromatic substitution the lower energy of the orbitals of pyridines. Synthesis of 2amino and 2arylazoazulenes via nucleophilic aromatic substitution of 2chloroazulenes with amines and arylhydrazines taku shoji, a shuhei sugiyama, a takanori araki, a akira ohta, a ryuta sekiguchi, a shunji ito, b shigeki mori, c tetsuo okujima d and masafumi yasunami e. Pyrimidine is an aromatic heterocyclic organic compound similar to pyridine. Cyanohydrin formation nucleophilic addition to the carbonyl group. Nucleophilic aromatic substitution snar as an approach to challenging carbohydrate. A series of preparatively interesting reactions on pyridine can be carried out by means of pyridine noxides such as the introduction of certain functions into the ring and sidechain which cannot be achieved in the parent system by direct methods. Its pi orbital system has p electrons that are delocalized all throughout the ring. On the other hand, freeradical and nucleophilic substitutions occur more readily in pyridine than in benzene. Pyridine itself is often used to neutralize acid formed in a reaction and as a basic solvent. Apr 20, 2015 ericminikel cambridge, ma chem20 these are my notes from lecture 29 of harvards chemistry 20. Conditions for the nucleophilic aromatic substitution of 2fluoropyridines. Pyridine is bad at electrophilic aromatic substitution the lower energy of the orbitals of pyridine s. Pyridine can be activated to electrophilic substitution by conversion to pyridinenoxides. Dont forget, in an electrophilic aromatic substitution the nucleophile is the aromatic ring.
The basicity of pyridine as measured by the dissociation constant of its conjugate acid, p k a 5. Electrophilic aromatic substitution on pyridine rings. A different leaving group order is observed in the substitution reactions of ringsubstituted nmethylpyridinium compounds with piperidine in methanol. Furthermore, it is planar due to all of its p orbitals being perpendicular to the ring. Chapter 3 n o s substitutions of aromatic heterocycles 1 m. Conversely pyridines are susceptible to nucleophilic attack. The nitrogen drains electron density, the homo is lower and therefore pyridine is a worse nucleophile than benzene and benzene itself is not that reactive. Derivation of the whole reaction scheme for third order in amine kinetic law cecilia e. Note too that in the case of nitration, the first thing that will happen is that the lone pair on nitrogen will be protonated by the strong acid and generate the pyridinium cation. Aromatic substitution reactions electrophilic nucleophilic. Pyridine pyridine is aromatic as there are six delocalized. It discusses the electrophilic aromatic substitution reactions of 5 membered heterocycles such as pyrrole, furan, and thiophene.
Carmen galan school of chemistry, university of bristol, cantocks close, bristol bs8 1ts, united kingdom s supporting information. Carmen galan school of chemistry, university of bristol, cantocks close, bristol bs8. Nucleophilic substitution conversion of a pyridine into the pyridinium salt greatly accelerates substitution relative rate 5. Pyridines undergo electrophilic substitution reactions s e ar more reluctantly but nucleophilic substitution s n ar more readily than benzene. Reagents that acquire an electron pair in chemical reactions are said to be electrophilic electronloving. Nucleophilic aromatic substitution for hydrogen reduction in chemical waste generation elimination of 74% of organic waste 99% of inorganic waste eliminates use of chlorine reduction in waste water more than 97% savings eliminates use of xylene a sara chemical improves process safety lower reaction temperatures. Additionelimination s nar groups which favor substitution no 2, cn, co.
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