3.7. Synthesizing Heterocycles
Most heterocycles are synthesized using the same methods as their non-cyclic counterparts. For example, the secondary amine piperidine can be synthesized using reductive amination or reduction of an amide (Scheme 3.16).
Scheme 3.16 – Syntheses of Piperidine Using Reductive Amination or Reduction of an Amide.
However, the synthesis of aromatic heterocycles (heteroaromatics) requires different reactions and, in some instances, specialized approaches.
3.7.1. Reaction: Acid-Catalyzed Cyclization for Aromatic Heterocycles
A common approach to synthesize aromatic heterocycles is to use acid catalysis to cyclize a compound that contains two carbonyls (or carbonyl-equivalents with atoms other than oxygen). The reaction itself is very similar to an acid-catalyzed aldol condensation except that the alkene is not the nucleophile (see Sections 3.7.1.1.1 and 3.7.1.2.1).
Because the reaction is a condensation it releases water. Until the step where aromaticity is gained every mechanistic step is reversible (in equilibrium). To favour product formation and speed up the reaction a desiccant is normally added. A desiccant is a compound that absorbs (or adsorbs, or irreversibly reacts with) water from the area around it. This removes the water from the reaction mixture and drives equilibrium towards the products.
Common desiccants are phosphorus pentoxide (P2O5, sometimes written as P4O10), sodium sulfate (Na2SO4), and magnesium sulfate (MgSO4). Exactly how each of these compounds removes water from the reaction mixture varies and lies outside the scope of this text. However, recognizing them as desiccants can aide in recognizing the type of reaction occurring.
3.7.1.1. 5-Membered Aromatic Heterocycles
It is possible to synthesize a 5-membered aromatic heterocycle by cyclizing a 1,4-dicarbonyl using acid catalysis (Scheme 3.17). The carbonyls are most commonly aldehydes and/or ketones, though some other combinations also afford heteroaromatic rings. Because a desiccant is added to remove water the acid catalyst can be any of the common strong acids (sulfuric acid (H2SO4), phosphoric acid (H3PO4), nitric acid (HNO3), hydrochloric acid (HCl), etc.).
Scheme 3.17 – Generalized Reaction Equation for Acid-Catalyzed Synthesis of 5-Membered Aromatic Heterocycles.
The mechanism is very similar to that of acid-catalyzed aldol condensations (Scheme 3.18).
The strong acid reacts with the solvent to form a cationic oxygen (an oxonium, step not shown). This is the active catalyst. First, acid-catalyzed keto-enol tautomerism occurs. The oxygen of one of the carbonyls (base/nucleophile) removes a hydrogen from the acid catalyst. This creates a resonance-stabilized cation. The conjugate base of the acid then acts as a base/nucleophile to remove a hydrogen from the carbon adjacent to the same carbonyl. This regenerates the acid catalyst and creates the enol tautomer.
Then, the oxygen of the remaining carbonyl (base/nucleophile) removes a hydrogen from the acid catalyst. This greatly increases its electrophilicity. The oxygen of the enol (nucleophile) attacks activated carbonyl (electrophile). The solvent then removes a proton from the oxygen (the former nucleophile) and places it on the other oxygen (the former electrophile). This greatly increases its leaving group ability. These steps may be viewed as regeneration of the catalyst and another acid-catalyzed activation. Then the lone pair of the oxygen forms a new π bond with the carbon, ejecting the leaving group (water). This will be removed by the desiccant (not shown). Finally, the solvent removes a proton from the carbon adjacent to the oxonium, regenerating the catalyst and forming the product.
Scheme 3.18 – Generalized Reaction Mechanism for Acid-Catalyzed Formation of 5-Membered Aromatic Heterocycles.
3.7.1.1.2. Changing the Heteroatom
It is possible to synthesize other 5-membered aromatic heterocycles by first changing one of the oxygens to a nitrogen/sulfur and then cyclizing a “1,4-dicarbonyl” using acid catalysis (Scheme 3.19). Both nitrogen and sulfur are more nucleophilic than oxygen. As a result, during the cyclization this heteroatom (nitrogen/sulfur) reacts as the nucleophile and is incorporated into the ring.
Scheme 3.19 – Generalized Reaction Equations for Acid-Catalyzed Synthesis of 5-Membered Aromatic Heterocycles with Nitrogen or Sulfur as the Heteroatom.
Replacement of an oxygen with nitrogen typically uses ammonia (NH3) to form the imine and then proceeds as usual. Several different reagents may be used to form a thio-carbonyl. The most commonly used is phosphorus pentasulfide (P2S5, sometimes written as P4S10). Exactly how this exchange occurs lies outside the scope of this text.
3.7.1.2. 6-Membered Aromatic Heterocycles
It is possible to synthesize a 6-membered aromatic heterocycle by cyclizing a 1,5-dicarbonyl using acid catalysis AND THEN achieving aromaticity with a strong oxidation reaction (Scheme 3.20). The oxygen- and sulfur-containing 6-membered aromatic heterocycles are slightly unusual and not normally targeted; the nitrogen exchange is almost always performed. Other than the oxidation reaction all considerations are identical to the cyclization of 5-membered aromatic heterocycles: carbonyls are most commonly aldehydes and/or ketones; a desiccant is added; the acid catalyst can be any of the common strong acids; the heteroatom is exchanged to a nitrogen using ammonia (NH3).
Scheme 3.20 – Generalized Reaction Equation for Acid-Catalyzed Synthesis of 6-Membered Aromatic Heterocycles.
This occurs in three main parts (Scheme 3.21).
It starts with acid-catalyzed enamine formation. The strong acid reacts with the solvent to form a cationic oxygen (an oxonium, step not shown). This is the active catalyst. First, the electrophile (carbonyl) gets activated by the catalyst. This greatly increases its electrophilicity. Second, the amine (nucleophile) attacks the activated carbonyl (electrophile). This forms a new bond and adds a lone pair to the oxygen. The solvent then removes a proton from the nitrogen (the former nucleophile) and places it on the desired leaving group, the oxygen. This greatly increases its leaving group ability. A lone pair of the nitrogen forms a π bond with the carbon, ejecting the leaving group (water). This will be removed by the desiccant (not shown). The solvent then removes an alpha hydrogen, regenerating the acid catalyst.
Then, the oxygen of the remaining carbonyl (base/nucleophile) removes a hydrogen from the acid catalyst. This greatly increases its electrophilicity. The nitrogen of the enamine (nucleophile) attacks activated carbonyl (electrophile). The solvent then removes a proton from the nitrogen (the former nucleophile) and places it on the other oxygen (the former electrophile). This greatly increases its leaving group ability. These steps may be viewed as regeneration of the catalyst and another acid-catalyzed activation. Then the lone pair of the nitrogen forms a new π bond with the carbon, ejecting the leaving group (water). This will be removed by the desiccant (not shown). Finally, the solvent removes a proton from the carbon adjacent to the iminium, regenerating the catalyst and forming the product of cyclization.
The oxidation can occur using any of several different approaches (see Sections 3.7.1.2.2 to 3.7.1.2.4) each with a different mechanism. However, in all cases the net result is a hydrogen from the CH2 being removed and aromaticity being achieved.
Scheme 3.21 – Generalized Reaction Mechanism for Acid-Catalyzed Formation of 6-Membered Aromatic Heterocycles.
3.7.1.2.2. Achieving Aromaticity by Eliminating a Leaving Group Added After Cyclization
The oxidation step can be accomplished by adding a leaving group to the nitrogen and then eliminating it (Scheme 3.22). There are several possible ways of doing this. The classical approach is to form nitronium by mixing sulfuric and nitric acid. Then the heterocycle is added to the nitronium, which forms a leaving group and is eliminated to achieve aromaticity.
Scheme 3.22 – Generalized Reaction Equation for Acid-Catalyzed Synthesis of 6-Membered Aromatic Heterocycles Followed by Oxidation via Nitration-Elimination.
In this method two electrons of the nitrogen form a new bond to a leaving group. These electrons then leave during the elimination (loss of electrons is oxidation) which oxidizes the ring.
The sulfuric acid reacts with water to form hydronium (not shown). This is the active catalyst (Scheme 3.23). First, the electrophile (HNO3) gets activated by the catalyst. It then ejects water and forms a nitronium ion (NO2+). This greatly increases its electrophilicity. Then, the lone pair from the nitrogen (nucleophile) attacks the nitronium (activated electrophile). This creates a new N-N bond. Water (nucleophile/base) removes the hydrogen from the CH2 (electrophile/acid), which generates aromaticity, ejects the leaving group (nitrite, NO2–), and regenerates the catalyst. Finally, another molecule of water removes the proton from the nitrogen to produce the desired product.
Scheme 3.23 – Reaction Mechanism for Oxidation via Nitration-Elimination to Generate Aromaticity in 6-Membered Heterocycles.
3.7.1.2.3. Achieving Aromaticity by Eliminating a Leaving Group Added During Cyclization
The oxidation step can be accomplished by adding a leaving group to the nitrogen during the cyclization and then eliminating it (Scheme 3.24). There are several possible ways of doing this. The classical approach is to use hydroxylamine (NH2OH) instead of ammonia during the cyclization. Then the heterocycle is added to a strong acid, which forms a leaving group and eliminates to achieve aromaticity.
Scheme 3.24 – Generalized Reaction Equation for Acid-Catalyzed Synthesis of 6-Membered Aromatic Heterocycles Followed by Oxidation via Elimination of a Pre-Existing Group.
In this method two electrons of the nitrogen are already in a bond to a leaving group. These electrons then leave during the elimination (loss of electrons is oxidation) which oxidizes the ring.
The strong acid catalyst can be any of the strong acids. Sulfuric acid is the most commonly used.
The sulfuric acid reacts with water to form hydronium (not shown). This is the active catalyst (Scheme 3.25). The oxygen of the heterocycle gets activated by the acid catalyst. This greatly increases its leaving group ability. Water (nucleophile/base) removes the hydrogen from the CH2 (electrophile/acid), which generates aromaticity, ejects the leaving group (water), and regenerates the catalyst.
Scheme 3.25 – Reaction Mechanism for Oxidation via Elimination of a Pre-Existing Group to Generate Aromaticity in 6-Membered Heterocycles.
3.7.1.2.4. Achieving Aromaticity by Using a Powerful Hydride Acceptor
The oxidation step can be accomplished by using a very powerful hydride acceptor (Scheme 3.26). There are several different molecules that may be used for this. The classical approach is to use 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (often abbreviated as DDQ). The heterocycle attacks DDQ by releasing a hydride as a “leaving group”, which achieves aromaticity.
Scheme 3.26 – Generalized Reaction Equation for Acid-Catalyzed Synthesis of 6-Membered Aromatic Heterocycles Followed by Oxidation via Hydride Acceptor.
In this method two electrons of the nitrogen remain. Instead, two electrons from a hydrogen of the CH2 leave as part of a hydride. These electrons leave (loss of electrons is oxidation) which oxidizes the ring.
For most molecules ejecting a hydride as a nucleophile/leaving group is functionally impossible. This normally requires an incredibly large amount of energy because H– is a very poor leaving group. As a result, it is highly unfavourable. Hydride acceptors are an unusual class of compounds that are very (very very) strong electrophiles. Often they become aromatic after being attacked by a hydride. This makes them even more electrophilic AND selectively electrophilic for hydrides; the product after being attacked by a hydride is much more stable because it gains aromatic stabilization energy. Because both the heterocycle AND the hydride acceptor are becoming aromatic (and gaining aromatic stabilization energy) the amount of energy needed for the hydride to leave is drastically reduced to the point where it is possible.
The mechanism for this oxidation is relatively straightforward (Scheme 3.27). The lone pair of the nitrogen forms a π bond to an adjacent carbon, which pushes electrons to the carbon of the CH2. This generates aromaticity and ejects the leaving group (hydride, H–). The hydride (nucleophile) attacks a carbon adjacent to a carbonyl on the hydride acceptor (electrophile). This pushes electrons towards the opposite oxygen and breaks the C-O π bond, forming a lone pair. The other carbonyl undergoes keto-enol tautomerism, generating aromaticity. This tautomerism proceeds through several different mechanisms (e.g. solvent-mediated, dimer-mediated) concurrently. A standard acid-catalyzed mechanism is shown. Finally, the anionic oxygen (nucleophile/base) removes the proton from the nitrogen (electrophile/acid) generating the final product.
Scheme 3.27 – Reaction Mechanism for Oxidation via Hydride Acceptor to Generate Aromaticity in 6-Membered Heterocycles.
