Module 3 Organic Intermediate (1)-Converted

ORGANIC INTERMEDIATES

MOD No. 3 VIT-Vellore-14

Reaction Intermediates

Most of the organic reaction occur through the involvement of certain chemical species. These are generally short – lived (10-6 second to a few seconds ) and highly reactive and hence cannot be isolated. These short –lived highly reactive chemical species through which the organic reactions occur are called reactive intermediates.

Some examples of reaction intermediates are,

Carbocations, Carbanions, Free Radicals, Carbenes and Nitrenes ⮚There are four types of organic species in which a carbon atom has a valence of only 2 or 3. ⮚They are usually very short-lived- mostly existing only as intermediates that are quickly converted to more stable molecules. However, some are more stable than others and fairly stable examples have been prepared of three of the four types. ⮚The four types of species are carbocations, free radicals, carbanions, and carbenes. ⮚Of the four, only carbanions have a complete octet around the carbon. ⮚There are many other organic ions and radicals with charges and unpaired electrons on atoms other than carbon-but we will discuss only nitrenes (E), the nitrogen analogs of carbenes.

Carbocation A group of organic species having a positively charged carbon atom bearing only six bonded electrons are called carbocations. For example,

Structure: • The central carbon atom of a carbocation (or carbonium ion) is sp2 hybridized. • The three sp2 orbitals are utilized in making bonds to three substituents. In order to minimize repulsion between the bonding electron pairs (I.e. to afford maximum separation of these electron pairs) a carbocation possesses a planar configuration with bond angles of 120o. The empty p orbital is perpendicular to the plane.

Carbocations very highly reactive species, because of having a strong tendency to complete the octet of the electron-deficient carbon.

Classification: Carbocations are classified as primary (1o), secondary(2o), and tertiary (3o) on the basis of the number of the number of carbon atoms (one, two, or three) directly attached to the positively charged carbon. For example,

The factors responsible for carbocation stability are – (i) Inductive effect, (ii) Hyperconjugative effect, (iii) Resonance effect, (iv) Steric effect and (v) constituting an aromatic system. (i) Inductive effect A charge-dispersing factor stabilizes an ion. The electron-releasing inductive effect (+I) exerted by an alkyl group attached to the positive carbon of a carbocation neutralizes the charge partially. As a consequence, the charge becomes dispersed over the alkyl groups and the system becomes stabilized. For example, the methyl groups in isopropyl cation stabilize the system through their +I effects. The stabilities of carbocations increase with increasing the number of alkyl groups attached to the positive carbon.

(ii) Hyperconjugative effect An alkyl group may also reduce the positive charge of a carbocation by hyperconjugative electron- release. The charge becomes dispersed over the a-hydrogens and consequently, the system becomes stabilized. Hyperconjugation in ethyl cation, for example, occurs as follows:

As the number of α-hydrogens, i.e., the number of hyperconjugative forms increases, the stability of carbocations increases. Hence, the order of stabilities of methyl substituted carbocations is :

(iii) Resonance effect Resonance is a major factor influencing the stability of carbocations. When the positive carbon of a carbocation is a to a double bond, effective charge delocalization with consequent stabilization occurs. Allyl and benzyl cations, for examples, are found to be highly stabilized by resonance.

(iv) Steric effect Steric effect causes an increase in stability of tertiary carbocations having bulky alkyl groups. For example, the substituents in tri-isopropyl cation (having planar arrangement with 120° angles) are far apart from each other and so there is no steric interference among them. However, if this carbocation is added to a nucleophile, i.e., if a change of hybridization of the central carbon atom from sp2 (trigonal) to sp3 (tetrahedral) takes place, the bulky isopropyl groups will be pushed together. This will result in a steric strain (B strain) in the product molecule. Because of this, the carbocation is much reluctant to react with a nucleophile, that is, its stability is enhanced due to steric reason.

(v) constituting an aromatic system The vacant p orbital of a carbocation may be involved in constituting a planar (4n +2)π electron system. where n = 0,1,2.... etc., i.e., a carbocation may be stabilized by constituting an aromatic system. Cycloheptatrienyl cation, for example, is unusually stable because it is a planar 6π electron system and aromatic.

Question: Arrange the following carbocations in order of their increasing stability with reasoning:

Ans: The carbocation I is stabilized by the +I effects of three -CH3 groups and hyperconjugative effect involving nine c-H atoms. The carbocation III is similarly stabilized by +I effect of three ring bonds. However, it is not stabilized by hyperconjugation because formation of a double bond at the bridgehead position is not possible (Bredt's rule). Again, the carbocation suffers from angle strain because the angle between bonds is somewhat less than the sp2 bond angle, i.e., 120". So, the carbocation II, although a 3° one, is less stable than the 3° carbocation I. The carbocation II is the most stable one because it is highly stabilized by resonance and also by both inductive and hyperconjugative effects of two methyl groups.

Hence, the order of their increasing stability is:

Carbanion The species containing negatively charged carbon atom are known as carbanions. For example,

Structure: • The central carbon atom of a carbanion is sp3 hybridized. • it is surrounded by three bonding pairs and one unshared pair of electrons which occupies an sp3 orbital. Thus, a carbanion is expected to have the tetrahedral shape. • However, the shape is not exactly that of a tetrahedron. It is found to have the pyramidal shape. Since the repulsion between the unshared pair and any bonding pair is greater than the repulsion between any two bonding pairs, the angle between two bonding pairs (i.e., two sp3- σ bonds) is slightly less than the normal tetrahedral value of 109.5° and because of this, a carbanion appears to be shaped like a pyramid with the negative carbon at the apex and the three groups at the corners of a triangular base.

However, the resonance-stabilized carbanions, such as allylic and benzylic carbanions are sp2 hybridized and they assume trigonal planar structure.

The factors responsible for carbanion stability are The structural features responsible mainly for the increased stability of carbanions are : (i) the amount of s character of the carbanion carbon atom, (ii) inductive electron withdrawal, (iii) conjugation of the non-bonding electron pair with an unsaturated system, and (iv) constituting an aromatic system. (i) The amount of s character of the carbanion carbon atom An s orbital is closer to the nucleus than the p orbital in a given main quantum level and it possesses lower energy. An electron pair in an orbital having large s character is, therefore, more tightly held by the nucleus and hence of lower energy than an electron pair in an orbital having small s character. Hence, a carbanion at an sp hybridized (50% s character) carbon atom is more stable than a carbanion at an sp2 hybridized (33.33% s character) carbon atom, which in turn is more stable than a carbanion at an sp3 hybridized (25% s character) carbon atom. Thus, the order of carbanion stability is:

(ii) inductive electron withdrawal Groups having electron-withdrawing inductive effects (H) stabilize a carbanion by dispersing the negative charge. In a nitrogen ylide, for example, the carbanion is stabilized by the -i effect of the adjacent positive nitrogen.

(iii) Conjugation of the non-bonding electron pair with an unsaturated system Where there is a double or triple bond a to the carbanion carbon atom, the anion is stabilized by delocalization of its negative charge with the t orbitals of the multiple bond. Thus, allylic and benzylic carbanions and the carbanions attached to the functional groups such as -NO2, -C≡N, >C=O, etc. are stabilized by resonance.

(iv) constituting an aromatic system The unshared pair of a carbanion may be involved in constituting a planar (4n + 2)π electron system where n=0, 1, 2... etc., i.e., a carbanion may be stabilized by constituting an aromatic system Cyclopentadienyl anion, for example. is unusually stable because it is a 6π electron system and aromatic.

Question: Give the order of stability of the following simple carbanions :

Ans: Because of the destabilizing influence of the electron-donating inductive effect of alkyl groups, the order of stabilities of these simple carbanions is as follows:

Question: Arrange the following carbanions in each of the following series in order or increasing stability:

Ans: The order of increasing stability of these carbanions is:

continue

The electron-releasing methyl groups of isopropyl anion (I) intensify the negative charge on carbon and make it less stable than methyl anion (III) where there is no possibility of charge intensification. The external orbitals (orbitals directed to the outside bonds) in cyclopropane have larger (33%) s character i.e., they are approximately sp2 orbitals. Because of this, the unshared pair in cyclopropyl anion (IV) is more tightly held with the carbon nucleus than the electrons in methyl anion (III) that occupies an sp3 orbital (25% s character). Consequently, the former anion is more stable than the latter. In vinyl anion (VI), the unshared pair occupies a sp orbital (33.33% s character) and so this anion is somewhat more stable than cyclopropyl anion (IV). The charge in allyl anion (II) is delocalized by resonance with the adjacent double bond and so it is more stable than vinyl anion (VI) in which the charge is localized. Since the unshared pair in cyclopentadienyl anion (V) is involved in forming an aromatic system, charge delocalization and consequent stabilization is far greater for this anion than for allyl anion.

Radical Homolytic cleavage of covalent bonds leads to the formation of neutral species possessing an unpaired electron. These are known as free radicals. Free radicals containing odd electrons on carbon atoms are collectively called carbon radicals or simply free radicals. For example, methyl radical (CH), phenyl radical (Ph), etc.

They are classified as primary, secondary, and tertiary free radicals according to the number of carbon atoms (one, two or three) directly attached to the carbon atom bearing the unpaired electron. For example, ethyl radical (CH3ĊH2) is a primary, isopropyl radical (Me2ĊH) is a secondary and tertbutyl radical (Me3Ċ) is a tertiary radical. Stability: (i) Hyperconjugation: Free radicals become stabilized by hyperconjugation involving α-H atoms

As the number of a-H atoms increases, hyperconjugation becomes more effective and consequently, the radical becomes more stabilized. The relative stability of simple alkyl radicals is found to follow the sequence (most stable) R3Ċ (tertiary) > R2ĊH (secondary)> RĊH2 (primary) > ĊH3 (methyl) (least stable). For example, tert-butyl radical, Me3Ċ (with nine hyperconjugable α-H atom) is more stable than isopropyl radical, Me2ĊH (with six hyperconjugable α-H atom) which in turn is more stable than ethyl radical, MeĊH2 (with only three hyperconjugable α-H atom). The methyl radical, ĊH3 is least stable because the unpaired electron is not at all delocalized. (ii) Resonance:

Resonance is a major factor influencing the stability of tree radicals. When the carbon bearing the odd electron is a to a double bond, effective delocalization of the unpaired electron with the π orbital system with consequent stabilization occurs. Allyl and benzyl radicals, for example, are found to be particularly stable because of resonance.

(iii) Steric Strain: Another factor that is responsible for the increased stability of tertiary radicals is steric. There occurs considerable relief of steric strain when a sp2 hybridized tertiary radical is formed from an sp3 hybridized precursor and this is because repulsion between the bulky alkyl groups is relieved to a certain extent by an increase in bond angles from 109.5° to about 120°. Thus, the radical is much reluctant to react further, i.e., its stability is enhanced due to steric reason.

CARBENES: Stability and Structure

• Carbenes are highly reactive species, practically all having lifetimes considerably under 1 s in general. By entrapment in matrices at low temp. (77 K or less). • Carbenes are very short lived species in which one C atom possesses two bonds two electrons, • either paired or unpaired. • The simplest member of the class is methylene, a non-isolable of the formula H2C: beside this, • the most common carbene is :CCl2.

Carbenes There are two main methods by which carbenes can be formed:

By elimination reaction : Formation of dichlorocarbene by the action of alcoholic KOH on chloroform is an example of this method. This may also be obtained from trichloroacetate by the process of thermolysis.

By decomposition reaction: When diazomethane or ketene are pyrolyzed or irradiated with ultraviolet light, they give rise to carbenes:

Carbenes can be divided into two types: Spectroscopic investigations of a number of carbenes of differing structures have shown that they fall broadly into two groups: (1) those (which you will learn to call ‘triplets’) that ESR spectroscopy demonstrates have unpaired electrons and whose bond angles are 130–150° and (2) those (like the stable crystalline carbene above, and which you will learn to call ‘singlets’) that have bond angles of 100–110° but cannot be observed by ESR.

• An ingenious method of distinguishing between the two possibilities was developed by Skell, based on the common reaction of addition of carbenes to double bonds to form cyclopropane derivatives.

• If the singlet species adds to cis-2-butene, the resulting cyclopropane should be the cis isomer since the movements of the two pairs of electrons should occur either simultaneously or with one rapidly succeeding another.

• However, if the attack is by a triplet species, the two unpaired electrons cannot both go into a new covalent bond, since by Hund’s rule they have parallel spins. • So one of the unpaired electrons will form a bond with the electron from the double bond that has the opposite spin, leaving two unpaired electrons that have the same spin and therefore cannot form a bond at once but must wait until, by some collision process, one of the electrons can reverse its spin. • During this time, there is free rotation about the CC bond and a mixture of cis- and trans-1,2-dimethyl cyclopropanes should result.

• Experiments show that CH2 itself is usually formed as a singlet species, which can decay to the triplet state, which consequently has a lower energy. • molecular-orbital calculations and experimental determinations show that the difference in energy between singlet and triplet CH2 is 8–10 kcal mol1 or 33– 42 kJ mol1. • However, it is possible to prepare triplet CH2 directly by a photosensitized decomposition of diazomethane.

• The CH2 group is so reactive that it generally reacts as the singlet before it has a chance to decay to the triplet state. • As to other carbenes, some react as triplets, some as singlets, and others as singlets or triplets, depending on how they are generated. • There are, however, molecules that generate persistent triplet carbenes. • Indeed, remarkably stable diaryl triplet carbenes have been prepared.

Limitations of Stereo-specificity • There is a limitation to the use of stereo-specificity of addition as a diagnostic test for singlet or triplet carbenes. • When carbenes are generated by photolytic methods, they are often in a highly excited singlet state. • When they add to the double bond, the addition is stereospecific; but the cyclopropane formed carries excess energy; that is, it is in an excited state. • It has been shown that under certain conditions (low pressures in the gas phase) the excited cyclopropane may undergo cis, trans isomerization after it is formed, so that triplet carbene may seem to be involved although in reality the singlet was present.

IR Spectroscopy • Studies of the IR spectrum of CCl2 trapped at low temp. in solid argon indicate that the ground state for this species is the singlet. • The geometrical structure of triplet methylene can be investigated by ESR measurements, since triplet species are diradicals. • Such measurements made on triplet :CH2 trapped in matrices at very low temperatures (4 K) show that triplet :CH2 is a bent molecule, with an angle of 136.342 • EPR measurements cannot be made on singlet species, but from electronic spectra of :CH2 formed in flash photolysis of diazomethane it was concluded that singlet :CH2 is also bent, with an angle of 103.

• Singlet :CCl2 and :CBr2 are also bent, with angles of 100 and 114, respectively. • It has long been known that triplet aryl carbenes are bent.

Nitrenes

• Nitrenes, RN, are the nitrogen analogues of carbenes, and most of the properties what we have discussed about carbenes also applicable here.

• Nitrenes are too reactive for isolation under ordinary conditions, although ab-initio calculations show that nitrenes are more stable than carbenes with an enthalpy difference of 25–26 kcal mol1 (104.7–108.8 kJ mol1).

• Alkyl nitrenes have been isolated by trapping in matrices at 4 K, while aryl nitrenes, which are less reactive, can be trapped at 77 K. • The ground state of NH, and probably of most nitrenes, is a triplet, although nitrenes can be generated in both triplet and singlet states. • In additions of EtOOCN to CC double bonds two species are involved, one of which adds in a stereospecific manner and the other not. • By analogy with Skell’s proposal involving carbenes these are taken to be the singlet and triplet species, respectively.

• The two principal means of generating nitrenes are analogous to those used to form carbenes.

Reference Books 1. Organic Chemistry Book by Jonathan Clayden, Nick Greeves, and Stuart Warren, Oxford Second Edition 2014

2. Organic Chemistry Book by Paula Yurkanis Bruice, Pearson 8th edition 2020

3. A guidebook to mechanism in organic chemistry Book by Peter Sykes, Pearson 8th edition, 2003. 4. Organic Chemistry: A Modern Approach Book by Nimai Tewari (Vol-I ), McGraw Hill Education, 2017.

AROMATICITY

Introduction •

Cont., ,,

Cont., ,, ❖ Cyclic, conjugated π bond, planar with uninterrupted cloud of π electrons above and below the plane of the ring. ❖ Each atom in the ring must have an unhybridized p orbital. (The ring atoms are usually sp2 hybridized or occasionally sp hybridized.) ❖

The Chemist Erich Huckel was the first one to recognize that an aromatic compound must have an odd number of pairs of π electrons in cyclic structure (1, 3, 5, 7), which can mathematically be written as 4n+2 (n = 0,1,2,3 etc.).

❖ Delocalization of the pi electrons over the ring must lower the electronic energy and increases the stability. ❖ Aromatic compounds will have all occupied bonding molecular orbitals completely filled and the relative energies of p molecular orbitals in planar cyclic conjugated systems can be determined by a simplified approach developed by A. A. frost in 1953 (FROST CIRCLE). ❖ Aromatic systems exhibit a diamagnetic ring current, which causes protons on the outside of the ring to be shifted downfield while any inner protons are shifted upfield (eg-18- annulene), in sharp contrast to a paramagnetic ring current, which causes shifts in the opposite directions. Compounds that sustain a diamagnetic ring current are called diatropic; and are prevalent in 2, 6, 10, 14, 18… electron system. ❖ Commonly it shows electrophilic substitution reaction which is a characteristic of saturated compounds and not electrophilic addition reaction which is characteristic of

Ring current effects

∙

Molecule in which outer protons are deshielded and inner protons are shielded is known as diatropic molecule. These type of molecules are always aromatic in nature.

∙

Similarly, molecule in which inner protons are shielded and outer protons are deshielded are known as paratropic molecule. Paratropic molecule is aromatic in nature.

•

Antiaromatic compounds show paramagnetic ring current due to unpaired electron

• Types of aromatic compounds

(A) 2π- electron system. I. It follow (4n+2)π- electron system. II. If electron is delocalized then compound is aromatic. III. If electron not delocalized then compound is non-aromatic.

•

Compound will never be antiaromatic

Example s:

(A) 4π- electron system. I. Belongs to 4nπ- electron system doesn’t follow Huckels rule. II. If electron is delocalized then compound is Anti-aromatic. III. If electron does not delocalized then compound is never aromatic. IV. If electron does not delocalized then compound is non-aromatic.

(A) 6π- electron system. I. Belongs to (4n+2)π- electron system. II ) If electron is delocalized then compound is aromatic III) If electron does not delocalized then compound must be non-aromatic

• 8π- electron system •

I.

Belongs to (4n)π- electron system.

•

II.

If electron is delocalized then compound must be Anti-aromatic.

•

III.

If electron does not delocalized then compound is non-aromatic

Heterocyclic compounds • • •

Heterocycle: any cyclic compound that contains ring atom(s) other than carbon (N, O, S, P). Cyclic compounds that contain only carbon are called carbocycles. Pyridine: pi-electron structure resembles benzene (6 pi-electrons) The nitrogen lone pair electrons are not part of the aromatic system. Pyrrole is aromatic but when nitrogen atom of pyrrole is protonated, it becomes non-aromatic.

Fused Systems •

The criteria for the aromaticity in the fused rings also follows the same rule as applied to the monocyclic systems. If the above two conditions are followed, then only, the compound is aromatic. For example, the aromaticity of naphthalene and phenanthrene are shown below:

Anthracene •

Anthracene is another example of aromatic fused system which contain three ortho fused benzene rings. It is colorless solid which shows blue fluorescence in ultraviolet light. It is the component of coal tar. Anthracene contains 7 C=C bonds in the closed loop Anthracene contain 14 pi electrons. So, according to Hückel’s Rule (n=3) Anthracene obeys (4n+2)pi electron rule. Anthracene shows four canonical forms.

Phenanthrene •

Phenanthrene contain 7 C=C bonds in the closed loop. Phenanthrene also contain 14 pi electrons. So, according to Hückel’s Rule (n=3) phenanthrene obeys (4n+2)pi electrons rule. It shows that phenanthrene is aromatic. The resonance structures of phenanthrene are shown below:

Pyrenes

Coronene

Acenes and helicenes ❖ Acenes and helicenes are molecules comprised of fused benzene rings that differ only in their connectivity. However, this seemingly trivial difference imparts these two classes of molecules with very distinctive properties. Acenes are comprised of linearly fused benzene rings, such as naphthalene ([2]acene) and anthracene ([3]acene). Helicenes are ortho-fused aromatic rings that adopt a helical conformation to avoid the overlapping of the terminal rings. ❖ Interestingly, helicenes are more stable and persistent than acenes. Also, while acenes dimerize in solution and oxidize in the presence of dioxygen, helicenes do not undergo either reaction. ❖ The difference in thermodynamic stability and reactivity is believed to be due to their differences in aromaticity even though they are both fused benzene rings. ❖ Since helicenes are inherently chiral and their enantiomers can be resolved, they are promising as chiral catalysts and ligands in asymmetric syntheses because of their high stability and resistance to isomerization.

Azulenes •

•

•

Azulenes is an isomer of naphthalene and one of the few benzenoid structure which show significant aromatic stabilization. It is a deep blue compound with the structure as shown and the name is derived from the Spanish word ‘Qzul’ meaning Blue. It is a fused cyclo-heptatriene and cyclopentadiene system. The compound shows the dipole moment of 0.80. In contrast to the fact that cyclopentadiene and cycloheptatriene independently possess antiaromatic characteristics which are responsible for their instability. But, this fused compound is aromatic and is stable. Charged resonating structures shows the –ve charge on the five-membered ring, making it equivalent to cyclopentadienyl anion and seven membered ring bearing +ve charge is similar to tropylium cation.

Non aromaticity • • •

•

A cyclic compound that does not have a continuous, overlapping ring of p orbitals cannot be aromatic or antiaromatic. It is said to be nonaromatic, nonplanar or aliphatic. Its electronic energy is almost similar to its openchain counterpart. Eg - 1,3 Cyclohexadiene is as stable as cis, cis - 2,4 hexadiene. Cyclooctatetraene is [8] annulene, with eight pi electrons (four double bonds) in the classical structure. It is a 4N sy stem, with N = 2. If Huckel 's rule were applied to cyclooctatetraene, it would predict antiaromaticity. However, cyclooctatetraene is a stable hydrocarbon with a boiling point of 153 °C. It does not show the high reactivity associ ated with antiaromaticity, yet it is not aromatic either. Its reactions are typical of alkenes. Cyclooctatetraene would be antiaromatic if Huckel 's rule applied, so the conjugation of its double bonds is energetically unf avorable. Remember that Huckel's rule applies to a compound only if there is a continuous ring of overlapping p orbitals,usually in a planar system. Cyclooctatetraene is more flex ible then cyclobutadiene and it assumes a nonplanar ‘tub shaped’ conformation that avoids most of the overlap between pi bonds. Huckels rule simply not applicable for non planar structure.

Phenalene • •

Not all fused systems can be fully aromatic. This can be completely explained by taking some examples: In case of phenalene the double bond cannot be distributed in such a way so that each carbon has one single and one double bond so it is not aromatic. But it is acidic in nature so reacts rapidly with potassium methoxide to give the corresponding anion as shown. The anionic form of phenalene is completely aromatic.

Anti-Aromaticity •

•

Cyclic, containing some number of conjugated π bond, planar with uninterrupted cloud of π electrons above and below the plane of the ring. Each atom in the ring must have an unhybridized p orbital. (The ring atoms are usually sp2 hybridized or occasionally sp hybridized.) Delocalization of the pi electrons over the ring increases the electronic energy and decreases the stability. 4. According to Huckel Antiaromatic compound must have an even number of pairs of π electrons in cyclic structure ( 2, 4, 6, 8 ) which can mathematically be written as 4n (n = 1,2,3 etc.). Antiaromatic systems exhibit a paramagnetic ring current, which causes protons on the outside of the ring to be shifted upfield while any inner protons are shifted downfield (eg-12-annulene), in sharp contrast to a diamagnetic ring current, which causes shifts in the opposite directions. Compounds that sustain a paramagnetic ring current are called paratropic; and are prevalent in 4, 8, 12, 16, 20… electron system

Tropylium ion

Pentalene

Cyclopentadienyl anion

Annulene • •

Hydrocarbons containing a single ring with alternating double and single bonds are called annulene. To name an annulene, indicate the number of atoms in the ring in brackets and add the word annulene. Thus, benzene is [6]-annulene. Both [14]-annulene and [18]- annulene are cyclic, planar, completely conjugated molecules that follow Hückel’s rule, and so they are aromatic.[10] annulene fits the Huckel rule criteria but not planar so considered nonaromatic (already discussed above). [16] Annulene fits the criteria for antiaromatic but they are nonplanar so its nonaromatic.

Homoaromatic compound •

•

Compound that contain one or more sp3-hybridized C-atom in a conjugate cyclic ring but sp3-hybridized carbon atom are force to lie almost vertically above the plane (out of the plane) of the aromatic system for effective orbital overlapping in a closed loop known as homoaromatic compounds. Homoaromatic compound involves delocalization of Pi electron cloud bypassing sp3 hybridized atom. When cyclooctatetraene is dissolved in concentrated H2SO4, a proton adds to one of the double bonds to form the homotropylium ion. In this species, an aromatic sextet is spread over seven carbons, as in the tropylium ion. The eighth carbon is a sp3 carbon and so cannot take part in the aromaticity.

Quasi aromatic • •

Aromatic compounds in which +ve or -ve charge is part of Huckle's rule or aromaticity, i.e., the charge is present in the ring, are called quasi aromatic compounds or most preferably quasi aromatic ions. Thus, all quasi aromatic ions are aromatic compounds but the reverse is not true. Quasiaromatic compound are highly stable.

• Stability Order. Aromatic > Homoaromatic > Nonaromatic > Antiaromatic.

• Energy Order. Antiaromatic > Nonaromatic > Homoaromatic > Aromatic

Questions ?

Definition:

Heterocyclic compounds

Heterocyclic compounds are organic compounds that contain a ring structure containing atoms in addition to carbon, such as sulfur, oxygen or nitrogen, as the heteroatom. The ring may be aromatic or non-aromatic

Significance – Two thirds of all organic compounds are aromatic heterocycles. Most pharmaceuticals are heterocycles. Examples

Pfizer: Viagra

Quinine Treatment of malaria for 400 years (Peru)

Erectile dysfunction

Treating stomach & intestinal ulcers

Camptothecin Analogues Pfizer - Irinotecan

GSK - Topotecan

Ovarian & lung cancer More soluble & less side-effects

• Heterocyclic compounds include many of the biochemical material essential to life. For example, nucleic acids, the chemical substances that carry the genetic information controlling inheritance, consist of long chains of heterocyclic units held together. Many naturally occurring pigments, vitamins, and antibiotics are heterocyclic compounds.

When Is A Molecule Aromatic? • For a molecule to be aromatic it must: • • • •

Be cyclic Have a p-orbital on every atom in ring Be planar Posses 4n+2 p electrons (n = any integer)

Erich Hückel

In general : heterocyclic is the largest and most varied family of organic compounds, heterocyclic system can be 3, 4, 5, 6, 7 membered rings

in addition to a fused rings (two rings joined at two adjacent atoms)

75

Heterocyclic derivatives and classification Heterocyclic derivatives as a group, can be divided into two broad areas: aromatic and non-aromatic. (note : aromatic system must have 4n+2 π-electron) 1) the 1, five-membered rings are shown below, the derivative furan 1 is aromatic, while tetrahydrofuran (2), dihydrofuran-2-one (3) are not aromatic, Why?.

2) The six-membered rings below, pyridine is aromatic (5), while piperidine (6), piperidin-2-one (7) are not aromatic, why? ⮚ Most heterocycles have the same chemistry as their open-chain counterparts particularly when the ring is unsaturated.

Dr. Dina Bakhotmah

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Six Membered Heterocycles: Pyridine

Pyridine replaces the CH of benzene by a N atom (and a pair of electrons) Hybridization = sp2 with similar resonance stabilization energy Lone pair of electrons not involved in aromaticity 1H

NMR: δ

Pyridinium ion: pKa = 5.5 Piperidine: pKa = 11.29 diethylamine : pKa = 10.28

Pyridine is a weak base Pyridine is π-electron deficient Electrophilic aromatic substitution is difficult Nucleophilic aromatic substitution is easy

Pyridine as a nucleophile

Use Pyridine as a solvent to make esters

E.g.

Acyl pyridinium ion Reactive intermediate

DMAP (DimethylAminoPyridine) Whereas acylations “catalyzed” by pyridine are normally carried out in pyridine as the reaction solvent. Only small amounts of DMAP are required to do acylations

Attempted Electrophilic Aromatic Substitution

Unreactive, Stable

How can we nitrate pyridine?

We now have an activating and protecting group

Mechanism

Nucleophilic Substitution at 2- and 4-positions of pyridine is most favoured

E.g.

Five Membered Heterocycles: Pyrrole

Aromatic: Thus, 6π electrons 1H

NMR: δ

Sp2 hybridised and planar Lone pair tied up in aromatic ring

Pyrrole is π-electron excessive Thus, Electrophilic Aromatic Substitution is Easy Nucleophilic Substitution is Difficult

Electrophilic Aromatic Substitution preferred at the 2-position

Normal acidic nitration causes polymerization

Vilsmeier Reaction

Electron-withdrawing group allows substitution at the 3-position

Organic Synthesis with Pyrrole should avoid strong acids

i

i; 1 X SO2Cl2, Et2O ii; 4 X SO2Cl2, Et2O

ii

Class exercise 1) In each of the following, encircle the stronger base:

2) If the proton was removed from Pyrrole to give the structure shown below, would it still be considered aromatic? Why or why not? Use pictures in your explanation.

Dr. Dina Bakhotmah

85

Indole Aromatic due to 10 π-electrons Benzene part is non-reactive Electrophilic aromatic substitution occurs at the 3position

Indole Alkaloids

Lysergic acid (LSD)

Strychnine

Mitomycin C

Other Five Membered Heterocycles

Least reactive

More aromatic than Furan

The least aromatic: The O atom is too electronegative

Less reactive than pyrrole, but substitution always at 2-position

Electrophilic Substitution, not addition Can give addition, as well as substitution products when reacted with E+

Thiophene has similar reactivity to benzene

Electrophilic Aromatic Substitution of Thiophene Avoid concentrated mineral acids or strong Lewis acids, e.g. AlCl3

Some Reactions of Furan

Furan is more reactive than thiophene

Addition product Wittig reaction

Hydrolysis of acetal Furan is easily cleaved to dicarbonyls

Furan is a source of 1,4-dicarbonyls in Organic Synthesis

The Diels-Alder Reaction

Diene 4π system

dienophile 2π system

4+2π cycloaddition

Otto Diels

Electron rich Electron poor

Kurt Alder Noble Prize in 1950

The configuration of the dienophile is retained

Always reacts via the cis-diene

Under kinetic control

Furan readily undergoes the Diels-Alder reaction with maleic anhydride

endo-product

Thermodynamic exo-product forms as the temperature is raised More stable due to less steric reasons

Aromaticity prevents thiophene from taking part in the Diels-Alder reaction

- SO2

This sulfone is not aromatic & very reactive

Five-membered Rings with Two or More Nitrogens pKa = 14.5 (imidazole) pKa = 16.5 (pyrrole)

Diazoles

Pyrazole

Imidazole

Imidazole is more basic than pyridine, but more acidic than pyrrole

Imidazole + H+

Imidazole - H+

NaOH

- H2O Properties: Very stable cation and anion of imidazole is formed

Some Natural Imidazole Compounds Histidine Important ligand to many metalloproteins

Is one of the essential amino acids. A relatively small change in cellular pH can result in a change in its charge Body neurotransmitter & local immune response

histamine histidine carboxylase

Dipeptide in high concentrations in the brain & muscles - Improves social interactions & treatment of autism

Carnosine

Tetrazoles are used in drugs as replacements for CO2H

Indomethacin

Indomethacin Tetrazole derivative Anti-arthritis drug - Non steroidal anti-inflammatory drug – reduces fever, pain, stiffness, delays premature labour & other uses

Aspirin STRUCTU RE

PROPERT IES ⮚ Acetylsalicylic Acid is colourless to white crystalline solid ⮚ It has a smell similar to that of vinegar, because of the hydrolysis yielding salicylic and acetic acid of Acetylsalicylic Acid ⮚ It is bitter in taste, and density is 1.4 g/cc ⮚ The melting point of aspirin is 135 deg C, & decomposes at higher temperature

Acetyl Salicylic Acid

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⮚ soluble in water, ethyl ether, ethanol, and chloroform.

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Synthetic route of Aspirin The synthesis of aspirin is an esterification reaction. Salicylic acid is treated with acetic anhydride, an acid derivative, causing a chemical reaction that turns OH group of salicylic acid into anester group (R-OH → ROCOCH3). This process yields aspirin and acetic acid. The catalyst used in this reaction is sulphuric acid or phosphoric acid.

Mechanism of Aspirin Synthesis

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Application of Aspirin In the year of 1897, Bayer laboratory gave Acetylsalicylic Acid the name of Aspirin. It is a very popular medicine and is available all over the world in large quantities. Ever since the naming, the commercialization of it began.

This medicine is most commonly used as an anti-inflammatory and antipyretic. However, considering its use in recent decades, it has also gained a reputation for treating cardiovascular diseases. The other uses also include rheumatic fever and Kawasaki disease.

Similarly, we also use it as an intermediate and raw material in producing other medicines or chemical compounds like 4hydroxycoumarin. Safety Hazards

When kept at room temperature. Aspirin will remain stable. However, try to keep it dry so as to avoid its hydrolysis. If you continue using it for a long period of time, it can result in causing gastritis and ulceration. Similarly, it is also incompatible with tough oxidizing agents and strong acids and bases. 7/28/2021

99

PARACETA MOL

PROPERT IES Density

1.263 g/cm3

Melting point

169 °C (336 °F)

Solubility in water

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12.78 g/kg (20 °C) ~14 mg/ml (20 °C)

100

Synthetic route of Paracetamol

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Application of Paracetamol Paracetamol is a common painkiller (analgesic) used to treat aches and pain. It can also be used to reduce a high temperature (antipyretic). but it has no useful anti-inflammatory properties. It's available combined with other painkillers and anti-sickness medicines.

It's also an ingredient in a wide range of cold and flu remedies. Paracetamol's effects are thought to be related to inhibition of prostaglandin synthesis. Paracetamol is readily absorbed from the gastrointestinal tract.

Safety Hazards Adverse effects of Paracetamol are rare but hypersensitivity including skin rash may occur. There have been reports of blood dyscrasias including thrombocytopenia, neutropenia, pancytopenia, leukopenia and agranulocytosis but these were not necessarily causality related to Paracetamol Very rare cases of serious skin reactions have been reported.

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NAPROX EN

Properties Naproxen is a propionic acid derivative and a non-steroidal antiinflammatory drug (NSAID) Naproxen inhibits the activity of the enzymes cyclo-oxygenase I and II, resulting in a decreased formation of precursors of prostaglandins and thromboxanes.

White crystal or crystalline powder. Melting point 155.3 ℃. Soluble in acetone, soluble in methanol, ethanol, acetic acid, Practically insoluble in water. Soluble in acetone, soluble in methanol, ethanol, acetic acid, insoluble in benzene, practically insoluble in water. In case of light,it is color-graded, odorless, tasteless.

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Synthetic route of Naproxen

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Application of Naproxen It is a non-steroidal anti-inflammatory drug for the relief of fever and inflammation and pain associated with arthritis or other symptoms , It has anti-inflammatory, antipyretic and analgesic effects. Naproxen plays a role by inhibiting the cyclooxygenase, which generates prostaglandin and is one kind of enzymes related to inflammatory mediators .

It is recommended to take the drug during meals to reduce stomach irritation.

SIDE EFFECT

The most common side effects of naproxen are confusion, headache, ringing in the ears, changes in vision, tiredness, drowsiness, dizziness and rashes. For strains and sprains, some doctors and pharmacists recommend waiting 48 hours before taking naproxen as it may slow down healing

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Indomethacin STRUCTU RE

PROPERT IES ⮚ White to yellow crystalline powder ⮚ Practically insoluble in water and sparingly soluble in alcohol. ⮚ pKa of 4.5 and is stable in neutral or slightly acidic media ⮚ It decomposes in strong alkali. ⮚ The suspension has a pH of 4.0-5.0.

Synthetic route of Indomethacin

Application of ⮚Indomethacin Indomethacin is a nonsteroidal anti-inflammatory drug (NSAID) with broad medicinal applications ⮚ Widely used to relieve pain, swelling, joint stiffness caused by arthritis, gout, bursitis, and tendonitis ⮚ It works by blocking production of natural substances (prostaglandins) that cause inflammation in a human body ⮚ Prostaglandins are critical mediators of inflammation, fever, and pain ⮚ Indomethacin blocks the enzymes that make prostaglandins (cyclooxygenase 1 and 2) and thereby reduces the levels of prostaglandins ⮚ It is available in an extended release (long-acting) capsules and a suspension to take by mouth, but this extended release form (Indocin SR) should not treat gouty arthritis ⮚ Based on a recent investigation from india, low dosage of this medicine shows effective for mild COVID19 cases

⮚ In 2006, this drug reported as a potent inhibitor of coronavirus (SARS-CoV) replication and suggested that having both anti-inflammatory and antiviral activity, it could be beneficial in SARS therapy. ⮚ Apart from this, indomethacin has been widely used for other diseases and FDA was approved this drug in 1965.

⮚ common side effects – Nausea, Vomiting, Diarrhea, Rash, Headache, etc.,

⮚ some dangerous adverse effect, – Blood clots, Fluid retention, Heart attacks, Hypertension, and Heart failure.

Remdesivir PROPERT IES

STRUCTU RE

❑ Liquide (injection) and lyophilized powder for reconstitution ❑ Remdesivir is a nucleoside analog used to treat RNA virus infections including COVID-19

❑ Indicated for adults and pediatric patients aged ≥12 years who weigh ≥40 kg for treatment of COVID-19 requiring hospitalization

Synthetic route of Remdesivir

Application of Remdesivir ⮚ Remdesivir, a nucleotide analogue prodrug that inhibits viral RNA polymerases, has shown potential activity against SARS-CoV-2. ⮚ It binds to the viral RNA-dependent RNA polymerase and inhibits viral replication through premature termination of RNA transcription ⮚ In a rhesus macaque model of SARS-CoV-2 infection, remdesivir treatment was initiated soon after inoculation; ⮚ remdesivir-treated animals had lower virus levels in the lungs and less lung damage than the control animals ⮚ Remdesivir is approved by the FDA for the treatment of COVID-19 in hospitalized adult and pediatric patients

(aged ≥12 years and weighing ≥40 kg) ⮚ It is also available through an FDA Emergency Use Authorization (EUA) for the treatment of COVID-19 in hospitalized pediatric patients weighing 3.5 kg to <40 kg or aged <12 years and weighing ≥3.5 kg ⮚ Patients were administered 200mg of remdesivir intravenously on the first day, followed by 100mg daily thereafter

for 5 or 10 days.

⮚ Results from these studies showed a faster time to recovery in patients treated with remdesivir compared with placebo. ⮚ Moreover, the studies demonstrated similar clinical improvement with the 5-day and 10-day treatment regimens. ⮚ As for safety, remdesivir was found to be well tolerated with no new safety signals identified.

⮚ Remdesivir can cause – Gastrointestinal symptoms (e.g., nausea), – Elevated transaminase levels, an increase in prothrombin time – Hypersensitivity reactions.

Pantoprazole PROPERT IES

STRUCTU RE

⮚ White to off-white crystalline powder and is racemic ⮚ Pantoprazole has weakly basic and acidic properties. ⮚ Pantoprazole sodium is freely soluble in water, very slightly soluble in phosphate buffer at pH 7.4, and practically insoluble in n-hexane.

⮚ The stability of the compound in aqueous solution is pH-dependent. ⮚ The rate of degradation increases with decreasing pH. ⮚ Injection is in the pH range 9.0 to 10.5.

Synthetic route of Pantoprazole

Application of Pantoprazole

⮚ Proton pump inhibitors (PPIs), which block the production of acid by the stomach. ⮚ Pantoprazole inhibitor, blocks the enzyme in the wall of the stomach that produces acid.

⮚ By blocking the enzyme, the production of acid is decreased, and this allows the stomach and esophagus to heal ⮚ Pantoprazole is a proton pump inhibitor that decreases the amount of acid produced in the stomach.

⮚ pantoprazole exerts its pharmacodynamic actions by binding to the proton pump (H+,K+-adenosine triphosphatase) in the parietal cells, but, compared with other PPIs, its binding may be more specific for the proton pump. ⮚ pantoprazole using an adriamycin-resistant gastric cancer cell model (SGC7901/ADR). ⮚ It is used to treat erosive esophagitis (damage to the esophagus from stomach acid caused by gastroesophageal reflux disease) ⮚ Esophagitis can cause painful, difficult swallowing and chest pain.

⮚ Causes of esophagitis include stomach acids backing up into the esophagus, infection, oral medications

⮚ High doses and long-term use (1 year or longer) of pantoprazole may increase the risk of osteoporosisrelated fractures of the hip, wrist, or spine.

Common Side effect ✔severe stomach pain, diarrhea that is watery or bloody; sudden pain or trouble moving your hip, wrist, or back; ✔bruising or swelling where intravenous pantoprazole was injected;

✔kidney problems - fever, rash, nausea, loss of appetite, joint pain, urinating less than usual, blood in your urine, weight gain; ✔low magnesium - dizziness, fast or irregular heart rate, tremors (shaking) or jerking muscle movements, feeling jittery, muscle cramps, muscle spasms in your hands and feet, cough or choking feeling; ✔new or worsening symptoms of lupus - joint pain, and a skin rash on your cheeks or arms that worsens in sunlight.

Other reported side effects include: ✔Pancreatitis and Reduced levels of blood cells

Aspirin STRUCTU RE

PROPERT IES ⮚ Acetylsalicylic Acid is colourless to white crystalline solid ⮚ It has a smell similar to that of vinegar, because of the hydrolysis yielding salicylic and acetic acid of Acetylsalicylic Acid ⮚ It is bitter in taste, and density is 1.4 g/cc ⮚ The melting point of aspirin is 135 deg C, & decomposes at higher temperature

Acetyl Salicylic Acid

7/28/2021

⮚ soluble in water, ethyl ether, ethanol, and chloroform.

157

Synthetic route of Aspirin The synthesis of aspirin is an esterification reaction. Salicylic acid is treated with acetic anhydride, an acid derivative, causing a chemical reaction that turns OH group of salicylic acid into anester group (R-OH → ROCOCH3). This process yields aspirin and acetic acid. The catalyst used in this reaction is sulphuric acid or phosphoric acid.

Mechanism of Aspirin Synthesis

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158

Application of Aspirin In the year of 1897, Bayer laboratory gave Acetylsalicylic Acid the name of Aspirin. It is a very popular medicine and is available all over the world in large quantities. Ever since the naming, the commercialization of it began.

This medicine is most commonly used as an anti-inflammatory and antipyretic. However, considering its use in recent decades, it has also gained a reputation for treating cardiovascular diseases. The other uses also include rheumatic fever and Kawasaki disease.

Similarly, we also use it as an intermediate and raw material in producing other medicines or chemical compounds like 4hydroxycoumarin. Safety Hazards

When kept at room temperature. Aspirin will remain stable. However, try to keep it dry so as to avoid its hydrolysis. If you continue using it for a long period of time, it can result in causing gastritis and ulceration. Similarly, it is also incompatible with tough oxidizing agents and strong acids and bases. 7/28/2021

159

PARACETA MOL

PROPERT IES Density

1.263 g/cm3

Melting point

169 °C (336 °F)

Solubility in water

7/28/2021

12.78 g/kg (20 °C) ~14 mg/ml (20 °C)

160

Synthetic route of Paracetamol

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161

Application of Paracetamol Paracetamol is a common painkiller (analgesic) used to treat aches and pain. It can also be used to reduce a high temperature (antipyretic). but it has no useful anti-inflammatory properties. It's available combined with other painkillers and anti-sickness medicines.

It's also an ingredient in a wide range of cold and flu remedies. Paracetamol's effects are thought to be related to inhibition of prostaglandin synthesis. Paracetamol is readily absorbed from the gastrointestinal tract.

Safety Hazards Adverse effects of Paracetamol are rare but hypersensitivity including skin rash may occur. There have been reports of blood dyscrasias including thrombocytopenia, neutropenia, pancytopenia, leukopenia and agranulocytosis but these were not necessarily causality related to Paracetamol Very rare cases of serious skin reactions have been reported.

7/28/2021

162

NAPROX EN

Properties Naproxen is a propionic acid derivative and a non-steroidal antiinflammatory drug (NSAID) Naproxen inhibits the activity of the enzymes cyclo-oxygenase I and II, resulting in a decreased formation of precursors of prostaglandins and thromboxanes.

White crystal or crystalline powder. Melting point 155.3 ℃. Soluble in acetone, soluble in methanol, ethanol, acetic acid, Practically insoluble in water. Soluble in acetone, soluble in methanol, ethanol, acetic acid, insoluble in benzene, practically insoluble in water. In case of light,it is color-graded, odorless, tasteless.

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163

Synthetic route of Naproxen

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164

Application of Naproxen It is a non-steroidal anti-inflammatory drug for the relief of fever and inflammation and pain associated with arthritis or other symptoms , It has anti-inflammatory, antipyretic and analgesic effects. Naproxen plays a role by inhibiting the cyclooxygenase, which generates prostaglandin and is one kind of enzymes related to inflammatory mediators .

It is recommended to take the drug during meals to reduce stomach irritation.

SIDE EFFECT

The most common side effects of naproxen are confusion, headache, ringing in the ears, changes in vision, tiredness, drowsiness, dizziness and rashes. For strains and sprains, some doctors and pharmacists recommend waiting 48 hours before taking naproxen as it may slow down healing

7/28/2021

165