Electrophilic aromatic substitution or EAS is an organic reaction in which an atom, usually hydrogen, appended to an aromatic system is replaced by an electrophile. Organic reactions are Chemical reactions involving Organic compounds The basic Organic chemistry reaction types are Addition reactions Elimination Hydrogen (ˈhaɪdrədʒən is the Chemical element with Atomic number 1 In Chemistry, an electrophile (literally electron-lover) is a Reagent attracted to Electrons that participates in a chemical reaction by accepting The most important reactions of this type that take place are aromatic nitration, aromatic halogenation, aromatic sulfonation, and acylation and alkylating Friedel-Crafts reactions. Nitration is a general Chemical process for the introduction of a nitro group into a Chemical compound. In Organic chemistry, an electrophilic aromatic halogenation is a type of Electrophilic aromatic substitution. Aromatic sulfonation is an Organic reaction in which a hydrogen atom on an arene is replaced by a Sulfonic acid Functional group in an Electrophilic The Friedel-Crafts reactions are a set of reactions developed by Charles Friedel and James Crafts in 1877.
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Basic reactions
Aromatic nitrations to form nitro compounds take place by generating a nitronium ion from nitric acid and sulfuric acid. Nitration is a general Chemical process for the introduction of a nitro group into a Chemical compound. Nitro compounds are Organic compounds that contain one or more nitro Functional groups (-2 Nitric acid ( H[[nitrate NO3]] also known as Aqua fortis and spirit of nitre, is a highly corrosive and Sulfuric (or sulphuric acid, H 2 S[[oxygen O]]4 is a strong Mineral acid.
Aromatic sulfonation of benzene with fuming sulfuric acid gives benzenesulfonic acid. Aromatic sulfonation is an Organic reaction in which a hydrogen atom on an arene is replaced by a Sulfonic acid Functional group in an Electrophilic Benzene, or benzol, is an organic Chemical compound and a known Carcinogen with the molecular formula C 6 H 6 Sulfuric (or sulphuric acid, H 2 S[[oxygen O]]4 is a strong Mineral acid.
Aromatic halogenation of benzene with bromine, chlorine or iodine gives the corresponding aryl halogen compounds catalyzed by iron tribromide. In Organic chemistry, an electrophilic aromatic halogenation is a type of Electrophilic aromatic substitution. Chlorine (ˈklɔriːn from the Greek word 'χλωρóς' ( khlôros, meaning 'pale green' is the Chemical element with Atomic number 17 and Iodine (ˈaɪədaɪn ˈaɪədɪn or /ˈaɪədiːn/ from ιώδης iodes "violet" is a Chemical element that has the symbol I and Atomic Iron(III bromide is the Chemical compound with the formula FeBr3
The Friedel-Crafts reaction exists as an acylation and an alkylation with as reactants acyl halides or alkyl halides. The Friedel-Crafts reactions are a set of reactions developed by Charles Friedel and James Crafts in 1877. In Chemistry, acylation (rarely but more formally alkanoylation) is the process of adding an Acyl group to a compound Alkylation is the transfer of an Alkyl group from one Molecule to another The haloalkanes (also known as halogenoalkanes or alkyl halides) are a group of Chemical compounds consisting of Alkanes such as Methane
The catalyst is most typically aluminium trichloride, but almost any strong Lewis acid can be used. Aluminium chloride (AlCl3 is a compound of Aluminium and Chlorine. In Fridel-Crafts acylation, a full measure of aluminium trichloride must be used, as opposed to a catalytic amount.
Other reactions
- Other reactions that follow an electrophilic aromatic substitution pattern are a group of aromatic formylation reactions including the Vilsmeier-Haack reaction, the Gattermann Koch reaction and the Reimer-Tiemann reaction. The Vilsmeier-Haack reaction (also called the Vilsmeier reaction) is the Chemical reaction of a substituted Amide ( 1) with Phosphorus oxychloride The Gattermann-Koch reaction, named for the German chemists Ludwig Gattermann and Julius Arnold Koch, in Organic chemistry refers to a Friedel-Crafts The Reimer-Tiemann reaction is a Chemical reaction used for the ortho- Formylation of Phenols The reaction was discoverd by Karl Ludwig Reimer
- Other electrophiles are aromatic diazonium salts in diazonium couplings, carbon dioxide in the Kolbe-Schmitt reaction and activated carbonyl groups in the Pechmann condensation. Diazonium compounds or diazonium salts are a group of Organic compounds sharing a common Functional group with the characteristic structure of R-N2+ An azo coupling is an Organic reaction between a Diazonium compound and an Aniline or a Phenol. Carbon dioxide ( Chemical formula:) is a Chemical compound composed of two Oxygen Atoms covalently bonded to a single The Kolbe-Schmitt reaction / Kolbe process (named after Adolph Wilhelm Hermann Kolbe and Rudolf Schmitt) is a Carboxylation Chemical reaction In Organic chemistry, a carbonyl group is a Functional group composed of a Carbon Atom double-bonded to an Oxygen The Pechmann condensation is a synthesis of Coumarins starting from a Phenol and a Carboxylic acid or Ester containing a &beta- Carbonyl
- In the multistep Lehmstedt-Tanasescu reaction, one of the electrophiles is a N-nitroso intermediate. The Lehmstedt-Tanasescu reaction is a method in Organic chemistry for the Organic synthesis of Acridone derivatives ( 3) from a 2-nitro Benzaldehyde
- In the Tscherniac-Einhorn reaction (named after Alfred Einhorn) the electrophile is a N-methanol derivative of an amide [1]
Basic reaction mechanism
In the first step of the reaction mechanism for this reaction, the electron-rich aromatic ring which in the simplest case is benzene is attacked by the electrophile A. Alfred Einhorn (1856 &ndash 1917 was a German Chemist most notable for first synthesizing Procaine in 1905 which he patented under the name Novocain In Chemistry, an amide is one of three kinds of Compounds (sometimes called acid amide the organic Functional group characterized Chemistry, a reaction mechanism is the step by step Sequence of Elementary reactions by which overall Chemical change occurs. Benzene, or benzol, is an organic Chemical compound and a known Carcinogen with the molecular formula C 6 H 6 This leads to the formation of a positively-charged cyclohexadienyl cation, also known as an arenium ion. An ion is an Atom or Molecule which has lost or gained one or more Valence electrons giving it a positive or negative electrical charge An arenium ion in Organic chemistry is the cyclohexadienyl Cation that appears as a reactive intermediate in Electrophilic aromatic substitution. This carbocation is unstable, owing both to the positive charge on the molecule and to the temporary loss of aromaticity. A carbocation (ˌkɑrboʊˈkætaɪɒn is an Ion with a positively-charged Carbon Atom. However, the cyclohexadienyl cation is partially stabilized by resonance, which allows the positive charge to be distributed over three carbon atoms. Resonance in Chemistry is a theory used to represent and model certain types of non-classical Molecular structures Resonance is a key component
In the second stage of the reaction, a Lewis base B donates electrons to the hydrogen atom at the point of electrophilic attack, and the electrons shared by the hydrogen return to the pi system, restoring aromaticity.
An electrophilic substitution reaction on benzene does not always result in monosubstitution. While electrophilic substituents usually withdraw electrons from the aromatic ring and thus deactivate it against further reaction, a sufficiently strong electrophile can perform a second or even a third substitution. This is especially the case with the use of catalysts. Catalysis is the process in which the rate of a Chemical reaction is increased by means of a Chemical substance known as a catalyst
Substituted aromatic rings
Electrophiles may attack aromatic rings with functional groups. In Organic chemistry, functional groups are specific groups of Atoms within Molecules that are responsible for the characteristic Chemical reactions Performing an electrophilic substitution on an already substituted benzene compound raises the problem of regioselectivity. In Chemistry, regioselectivity is the preference of one direction of Chemical bond making or breaking over all other possible directions. In case of a monosubstituted benzene, there are 4 different reactive positions. For a monosubstituted benzene, the ring carbon atom bearing the substituent is position 1 or ipso, the next ring atom is position 2 or ortho, position 3 is meta and position 4 is para. In Organic chemistry, a substituent is an atom or group of atoms substituted in place of a Hydrogen atom on the Parent chain of a Hydrocarbon Arene substitution patterns are part of Organic chemistry IUPAC nomenclature and pinpoint the position of Substituents other than Hydrogen in Arene substitution patterns are part of Organic chemistry IUPAC nomenclature and pinpoint the position of Substituents other than Hydrogen in Arene substitution patterns are part of Organic chemistry IUPAC nomenclature and pinpoint the position of Substituents other than Hydrogen in Arene substitution patterns are part of Organic chemistry IUPAC nomenclature and pinpoint the position of Substituents other than Hydrogen in Positions 5 and 6 are respectively equal to 3 and 2.
Substituents can generally be divided into two classes regarding electrophilic substitution: activating and deactivating towards the aromatic ring. Activating substituents or activating groups stabilize the cationic intermediate formed during the substitution by donating electrons into the ring system, by either inductive effect or resonance effects. In Organic chemistry, a Functional group is called an activating group if a Benzene Molecule to which it is attached more readily participates The inductive effect in Chemistry is an experimentally observable effect of the transmission of charge through a chain of Atoms in a Molecule Resonance in Chemistry is a theory used to represent and model certain types of non-classical Molecular structures Resonance is a key component Examples of activated aromatic rings are toluene, aniline and phenol. Toluene, also known as methylbenzene or phenylmethane, is a clear water -insoluble liquid with the typical smell of Paint thinners redolent of Aniline, phenylamine or aminobenzene is an Organic compound with the formula C6H7N Phenol, is a toxic colourless Crystalline Solid with a sweet tarry odor commonly referred to as a "hospital smell"
The extra electron density delivered into the ring by the substituent is not equally divided over the entire ring, but is concentrated on atoms 2, 4 and 6 (the ortho and para positions). These positions are thus the most reactive towards an electron-poor electrophile. The highest electron density is located on both ortho positions, though this increased reactivity might be offset by steric hindrance between substituent and electrophile. See also Intramolecular forces ' Steric effects arise from the fact that each Atom within a Molecule occupies a certain The final result of the elecrophilic aromatic substitution might thus be hard to predict, and it is usually only established by doing the reaction and determining the ratio of ortho versus para substitution.
On the other hand, deactivating substituents destabilize the intermediate cation and thus decrease the reaction rate. In Organic chemistry, a deactivating group is a Functional group attached to a Benzene Molecule that removes Electron density from The reaction rate or rate of reaction for a Reactant or product in a particular reaction is intuitively defined as how fast a reaction takes They do so by withdrawing electron density from the aromatic ring, though the positions most affected are again the ortho and para ones. This means that the most reactive positions (or, least unreactive) are the meta ones (atoms 3 and 5). Examples of deactivated aromatic rings are nitrobenzene, benzaldehyde and trifluoromethylbenzene. Nitrobenzene, also known as nitrobenzol or oil of mirbane, is an Organic compound with the Chemical formula C 6 Benzaldehyde (C6H5CHO is a chemical compound consisting of a Benzene ring with an Aldehyde substituent The deactivation of the aromatic system also means that generally harsher conditions are required to drive the reaction to completion. An example of this is the nitration of toluene during the production of trinitrotoluene (TNT). Nitration is a general Chemical process for the introduction of a nitro group into a Chemical compound. Trinitrotoluene ( TNT) is a Chemical compound with the formula C6H2(NO23CH3 While the first nitration, on the activated toluene ring, can be done at room temperature and with dilute acid, the second one, on the deactivated nitrotoluene ring, already needs prolonged heating and more concentrated acid, and the third one, on very strongly deactivated dinitrotoluene, has to be done in boiling concentrated sulfuric acid. Sulfuric (or sulphuric acid, H 2 S[[oxygen O]]4 is a strong Mineral acid.
Functional groups thus usually tend to favor one or two of these positions above the others; that is, they direct the electrophile to specific positions. A functional group that tends to direct attacking electrophiles to the meta position, for example, is said to be meta-directing.
Ortho/para directors
Groups with unshared pairs of electrons, such as the amino group of aniline, are strongly activating and ortho/para-directing. lone pair is a (valence electron pair without bonding or sharing with other Atoms They are found in the outermost Electron shell of an atom so lone pairs Amines are Organic compounds and Functional groups that contain a basic Nitrogen Atom with a Lone pair. Aniline, phenylamine or aminobenzene is an Organic compound with the formula C6H7N Such activating groups donate those unshared electrons to the pi system. In Organic chemistry, a Functional group is called an activating group if a Benzene Molecule to which it is attached more readily participates
When the electrophile attacks the ortho and para positions of aniline, the nitrogen atom can donate electron density to the pi system, giving four resonance structures (as opposed to three in the basic reaction). Nitrogen (ˈnaɪtɹəʤɪn is a Chemical element that has the symbol N and Atomic number 7 and Atomic weight 14 Resonance in Chemistry is a theory used to represent and model certain types of non-classical Molecular structures Resonance is a key component This substantially enhances the stability of the cationic intermediate.
Compare this with the case when the electrophile attacks the meta position. In that case, the nitrogen atom cannot donate electron density to the pi system, giving only three resonance contributors. For this reason, the meta-substituted product is produced in much smaller proportion to the ortho and para products.
Other substituents, such as the alkyl and aryl substituents, may also donate electron density to the pi system; however, since they lack an available unshared pair of electrons, their ability to do this is rather limited. An alkyl is a Univalent radical consisting of Carbon and Hydrogen atoms arranged in a chain In the context of organic molecules aryl refers to any Functional group or Substituent derived from a Simple aromatic ring, may it be Phenyl In Organic chemistry, a substituent is an atom or group of atoms substituted in place of a Hydrogen atom on the Parent chain of a Hydrocarbon Thus they only weakly activate the ring and do not strongly disfavor the meta position.
Halogens are ortho/para directors, since they possess an unshared pair of electrons just as nitrogen does. Abundance Owing to their high Reactivity, the halogens are found in the environment only in compounds or as Ions Halide ions and oxoanions However, the stability this provides is offset by the fact that halogens are substantially more electronegative than carbon, and thus draw electron density away from the pi system. " Electronegativity " is the opposite of " Electropositivity," which describes an element's ability to donate electrons This destabilizes the cationic intermediate, and EAS occurs less readily. Halogens are therefore deactivating groups. In Organic chemistry, a deactivating group is a Functional group attached to a Benzene Molecule that removes Electron density from
Directed ortho metalation is a special type of EAS with special ortho directors. Directed ortho metalation ( DoM) is an adaptation of Electrophilic aromatic substitution in which Electrophiles attach themselves exclusively to the
Meta directors
Non-halogen groups with atoms that are more electronegative than carbon, such as the nitro group (NO2) draw substantial electron density from the pi system. These groups are strongly deactivating groups. In Organic chemistry, a deactivating group is a Functional group attached to a Benzene Molecule that removes Electron density from Additionally, since the substituted carbon is already electron-poor, the resonance contributor with a positive charge on this carbon (produced by ortho/para attack) is less stable than the others. Therefore, these electron-withdrawing groups are meta directors.
Ipso substitution
Ipso substitution is a special case of electrophilic aromatic substitution where the leaving group is not hydrogen.
A classic example is the reaction of salicylic acid with a mixture of nitric and sulfuric acid to form picric acid. Salicylic acid (from the Latin word for the willow tree Salix, from whose bark it can be obtained is a Beta hydroxy acid (BHA with the formula Nitric acid ( H[[nitrate NO3]] also known as Aqua fortis and spirit of nitre, is a highly corrosive and Sulfuric (or sulphuric acid, H 2 S[[oxygen O]]4 is a strong Mineral acid. "TNP" redirects here For the airport with the IATA airport code TNP see Twentynine Palms Airport. The nitration of the 2 position involves the loss of CO2 as the leaving group.
Desulfonation in which a sulfonyl group is substituted by a proton is a common example. See also Hayashi rearrangement. The Hayashi rearrangement is the Chemical reaction of ortho-benzoylbenzoic acids catalyzed by Sulfuric acid or Phosphorus pentoxide.
In aromatics substituted by silicon, the silicon reacts by ipso substitution.
Five membered heterocyclic compounds
Furan, Thiophene, Pyrrole and their derivatives are all highly activated compared to benzene. Furan, also known as furane and furfuran, is a heterocyclic Organic compound. Thiophene is the Heterocyclic compound with the formula C4H4S Pyrrole, or pyrrol, is a Heterocyclic Aromatic Organic compound, a five-membered ring with the formula C 4 These compounds all contain an atom with an unshared pair of electrons (oxygen, sulfur, or nitrogen) as a member of the aromatic ring, which substantially increases the stability of the cationic intermediate. Oxygen (from the Greek roots ὀξύς (oxys (acid literally "sharp" from the taste of acids and -γενής (-genēs (producer literally begetteris the Sulfur or sulphur (ˈsʌlfɚ see spelling below) is the Chemical element that has the Atomic number 16 Nitrogen (ˈnaɪtɹəʤɪn is a Chemical element that has the symbol N and Atomic number 7 and Atomic weight 14 Examples of electrophilic substitutions to pyrrole are the Pictet-Spengler reaction and the Bischler-Napieralski reaction. Pyrrole, or pyrrol, is a Heterocyclic Aromatic Organic compound, a five-membered ring with the formula C 4 The Pictet-Spengler reaction is a Chemical reaction in which a &beta-arylethylamine such as Tryptamine undergoes ringclosure after condensation with an The Bischler-Napieralski reaction is a Chemical reaction that dehydrates an N-acyl β-arylethyl amines into the corresponding Heterocycle.
Asymmetric electrophilic aromatic substitution
Electrophilic aromatic substitutions with prochiral carbon electrophiles have been adapted for asymmetric synthesis by switching to chiral lewis acid catalysts especially in friedel-Crafts type reactions. In Chemistry, prochiral molecules can be converted from achiral to chiral in a single step Asymmetric synthesis, also called chiral synthesis, enantioselective synthesis or stereoselective synthesis, is Organic synthesis which The Friedel-Crafts reactions are a set of reactions developed by Charles Friedel and James Crafts in 1877. An early example concerns the addition of chloral to phenols catalyzed by aluminium chloride modified with (-)-menthol [2]. Chloral, also known as trichloroacetaldehyde is the Organic compound with the formula Cl3CCHO In Organic chemistry, phenols, sometimes called phenolics, are a class of Chemical compounds consisting of a Hydroxyl group (- Aluminium chloride (AlCl3 is a compound of Aluminium and Chlorine. Menthol is an Organic compound made synthetically or obtained from Peppermint or other mint oils A glyoxylate compound has been added to N,N-dimethylaniline with a chiral bisoxazoline ligand - copper(II) triflate catalyst system also in a Friedel-Crafts hydroxyalkylation [3]:
In another alkylation N-methylpryrrole reacts with crotonaldehyde catalyzed by trifluoroacetic acid modified with a chiral imidazolidinone [4]:
Indole reacts with an enamide catalyzed by a chiral BINOL derived phosphoric acid [5]:
In all these reactions the chiral catalyst load is between 10 to 20% and a new chiral carbon center is formed with 80-90 ee. Glyoxylic acid or oxoacetic acid is an Organic compound with the Chemical formula C2H2O3 N, N -Dimethylaniline (DMA is an organic chemical compound which is a substituted derivative of Aniline. In Chemistry, bisoxazoline ligands ( BOX ligands for short are Chiral ligands based on a bis Oxazoline skeleton and used in combination with a Copper (II triflate, Cu(OSO2CF32 is the copper (II salt of Trifluoromethanesulfonic acid (triflic acid a Superacid. The Friedel-Crafts reactions are a set of reactions developed by Charles Friedel and James Crafts in 1877. Pyrrole, or pyrrol, is a Heterocyclic Aromatic Organic compound, a five-membered ring with the formula C 4 Crotonaldehyde is a Chemical compound with the formula CH3CH=CHCHO Trifluoroacetic acid (TFA is the Chemical compound with the formula CF3CO2H Imidazole is a Organic compound with the formula HC3H3N2 This Aromatic Heterocyclic is classified as an Alkaloid Indole is an Aromatic heterocyclic Organic compound. It has a bicyclic structure consisting of a six-membered Benzene ring fused to a five-membered Phosphoric acid, also known as orthophosphoric acid or phosphoric(V acid, is a mineral (inorganic acid having the Chemical formula Enantiomeric excess exists where one Enantiomer is present more than the other in a Chemical substance, and is defined as the absolute difference between the mole
External links
References
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- ^ Asymmetric electrophilic substitution on phenols in a Friedel-Crafts hydroxyalkylation. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. Enantioselective ortho-hydroxyalkylation mediated by chiral alkoxyaluminum chlorides Franca Bigi, Giovanni Casiraghi, Giuseppe Casnati, Giovanni Sartori, Giovanna Gasparri Fava, and Marisa Ferrari Belicchi J. Org. Chem.; 1985; 50(25) pp 5018 - 5022; DOI: 10. The Journal of Organic Chemistry (abbreviated as J Org Chem or JOC) is a Scientific journal for original contributions of fundamental 1021/jo00225a003
- ^ Catalytic Enantioselective Friedel-Crafts Reactions of Aromatic Compounds with Glyoxylate: A Simple Procedure for the Synthesis of Optically Active Aromatic Mandelic Acid Esters Nicholas Gathergood, Wei Zhuang, and Karl Anker Jrgensen J. Am. Chem. Soc.; 2000; 122(50) pp 12517 - 12522; (Article) doi:10.1021/ja002593j
- ^ New Strategies in Organic Catalysis: The First Enantioselective Organocatalytic Friedel-Crafts Alkylation Nick A. The Journal of the American Chemical Society (usually abbreviated as J A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. Paras and David W. C. MacMillan J. Am. Chem. Soc.; 2001; 123(18) pp 4370 - 4371; (Communication) doi:10.1021/ja015717g
- ^ Chiral Brønsted Acid Catalyzed Enantioselective Friedel–Crafts Reaction of Indoles and a-Aryl Enamides: Construction of Quaternary Carbon Atoms Yi-Xia Jia, Jun Zhong, Shou-Fei Zhu, Can-Ming Zhang, and Qi-Lin Zhou Angew. Chem. Int. Ed. 2007, 46, 5565 –5567 doi:10.1002/anie.200701067
The Journal of the American Chemical Society (usually abbreviated as J A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. Angewandte Chemie is a weekly Peer-reviewed Chemistry journal that covers all disciplines of chemistry A digital object identifier ( DOI) is a permanent identifier given to an Electronic document.
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