review inprotecting and neighbouring groups and peal-knorr...

Nagham Mahmood Aljamali et al,SPJTS, 2014,2.(2),349-360 ISSN 2321-4597

South pacific Journal of Technology and Science 349

Review inProtecting and Neighbouring Groups

and Peal-Knorr Reaction

Dr. NaghamMahmoodAljamali

Assist. Professor in Organic Chemistry , Chemistry Department .,College of Education .,Kufa University .,IRAQ.

Abstract: In this review study, some of named reactions , like peal-knorr reaction , protecting groups , neighbouring groups , methods of compounds synthesis , reactions , properties , stability , reactivity, using as catalysis in various reactions in most of organic reactions , edition and elimination reaction , reduction and oxidation compounds , products of reactions. Keyword: peal –knorr , protecting group ,neighbouring group, pyrrol , furan.

INTRODUCTION: Peal–Knorr synthesis The Peal–Knorr Synthesis in organic chemistry is a reaction that generates either furans, pyrroles, or thiophenes from 1,4-diketones. It is a synthetically valuable method for obtaining substituted furans and pyrroles, common structural components of many natural products. It was initially reported independently by German chemists Carl Peal and Ludwig Knorr in 1884 as a method for the preparation of furans, and has been adapted for pyrroles and thiophenes.[1,2] Although the Paal–Knorr synthesis has seen widespread use, the mechanism wasn't fully understood until it was elucidated by V. Amarnathet al. The furan synthesis requires an acid catalyst:[5]

In the pyrrole synthesis a primary amine participates:

and in that of thiophene for instance the compound phosphorus pentasulfide:



MECHANISM: Furansynthesis mechanism: The acid catalyzed furan synthesis proceeds by protonation of one carbonyl which is attacked by the forming enol of the other carbonyl. Dehydration of the hemiacetal gives the resultant furan.

The mechanism of the Paal–Knorr furan synthesis was elucidated in 1995 by V. Amarnathet al.[3]Amarnath'swork showed that the d,l-racemic and meso versions of 3,4-diethyl-2,5-phenyl diones react at different rates. In the commonly accepted mechanism, these diones would go through a common enol intermediate, meaning that the meso and d,l-racemic isomers would cyclize at the same rate as they form from a common intermediate. The implication of different reaction is that cyclization needs to occur in a concerted step with enol formation. Thus the mechanism was proposed to occur via attack of the protonated carbonyl with the forming enol. Amarnath also found that the unreacted dione had not undergone conformational isomerization, which also indicated that an enol was not an intermediate. Pyrrole synthesis mechanism: The mechanism for the synthesis of the pyrrole was investigated by V. Amarnathet al. in 1991.[4] His work suggests that the protonated carbonyl is attacked by the amine to form the hemiaminal. The amine attacks the other carbonyl to form a 2,5-dihydroxytetrahydropyrrole derivative which undergoes dehydration to give the corresponding substituted pyrrole.

The reaction is typically run under protic or Lewis acidic conditions, with a primary amine. Use of ammonium hydroxide or ammonium acetate (as reported by Peal) gives the N-unsubstitutedpyrrole.



Thiophene synthesis mechanism: Thiophene synthesis is achieved via a mechanism very similar to the furan synthesis. The initial diketone is converted to a thioketone with a sulfurizing agent, which then undergoes the same mechanism as the furan synthesis.

Most sulfurization agents are strong dehydrators and drive completion of the reaction. Early postulates toward the mechanism of the Paal-Knorr furan synthesis suggested that the thiophene was achieved by sulfurization of the furan product. Campaigne and Foye showed that treatment of isolated furans from the Paal-Knorr Furan Synthesis with phosphorus pentoxide gave inconsistent results with the treatment of 1,4-dicarbonyls with phosphorus pentoxide, which ruled out the sulfurization of a furan mechanism and suggests that the reaction proceeds via sulfurization of a dicarbonyl .[9] The Peal–Knorr reaction is quite versatile. In all syntheses almost all dicarbonyls can be converted to their corresponding heterocycle. R2 and R5 can be H, aryl or alkyl. R3 and R4 can be H, aryl, alkyl, or an ester. In the pyrrole synthesis (X = N), R1 can be H, aryl, alkyl, amino, or hydroxyl.[10]A variety of conditions can be used to carry out these reactions, most of which are mild. The Peal–Knorr Furan synthesis is normally carried out under aqueous acidic conditions with protic acids such as aqueous sulfuric or hydrochloric acid, or anhydrous conditions with a Lewis acid or dehydrating agent. Common dehydrating agents include phosphorus pentoxide, anhydrides, or zinc chloride. VARIATIONS: Several 1,4-dicarbonyl surrogates can be used in place of a 1,4-dicarbonyl. While these substitutes have different structures from a 1,4-dicarbonyl, their reactions proceed via mechanisms very similar to that of the Paal-Knorr.

1. β-Epoxy carbonyls:

β-Epoxy carbonyls have been known to cyclize to furans. This procedure can use the β-γ-unsaturated carbonyls as starting materials, which can be epoxidized. The resulting epoxycarbonyl can be cyclized to a furan under acidic or basic conditions.[11]



2. 1,4-Diol-2-ynes:

1,4-diol-2-yne systems have also been used to do Paal–Knorr chemistry. Using palladium, a 1,4-diol-2-yne can be isomerized to the corresponding 1,4-diketone in situ and then dehydrated to the corresponding furan using a dehydration agent.[12]

Related reactions: The Knorr pyrrole synthesis, reported by Knorr in 1884 is the synthesis of a substituted pyrrole from an amino-ketone and a ketone.[14] Also reported by Knorr is a syntheisis of pyrazoles from 1,3-dicarbonyls and hydrazines, hydrazides, or semibicarbazides. This synthesis occurs via a condensation mechanism similar to the Paal-Knorr, however if a substituted hydrazine is used, it results in a mixture of regioisomerswherethe substituted heteroatom is either next to the R1 substituent or the R3 substituent.[15]

PROTECTING GROUP A protecting group or protective group is introduced into a molecule by chemical modification of a functional group in order to obtain chemoselectivity in a subsequent chemical reaction. It plays an important role in multistep organic synthesis. Common protecting groups

- Alcohol protecting groups

- Amine protecting groups



- Carbonyl protecting groups

- Carboxylic acid protecting groups

Functional Group Synthesis



SOME COMMON PROTECTING GROUPS IN ORGANIC SYNTHESIS: Hydroxyl(OH) protecting groups in Organic Synthesis: Protection of alcohols:

Acetyl (Ac) – Removed by acid or base. Benzoyl (Bz) – Removed by acid or base, more stable than Ac group. Benzyl (Bn, Bnl) – Removed by hydrogenolysis. Bn group is widely used in sugar and nucleoside

chemistry. β-Methoxyethoxymethyl ether (MEM) – Removed by acid. Dimethoxytrityl, [bis-(4-methoxyphenyl)phenylmethyl] (DMT) – Removed by weak acid. DMT

group is widely used for protection of 5′-hydroxy group in nucleosides, particularly in oligonucleotide synthesis.

Methoxymethyl ether (MOM) – Removed by acid. Methoxytrityl [(4-methoxyphenyl)diphenylmethyl, MMT) – Removed by acid and hydrogenolysis. p-Methoxybenzyl ether (PMB) – Removed by acid, hydrogenolysis, or oxidation. Methylthiomethyl ether – Removed by acid. Pivaloyl (Piv) – Removed by acid, base or reductant agents. It is substantially more stable than other

acyl protecting groups. Tetrahydropyranyl (THP) – Removed by acid. Trityl (triphenylmethyl, Tr) – Removed by acid and hydrogenolysis. Silyl ether (most popular ones include trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), tri-

iso-propylsilyloxymethyl (TOM), and triisopropylsilyl (TIPS) ethers) – Removed by acid or fluoride ion. (such as NaF, TBAF (Tetra-n-butylammonium fluoride, HF-Py, or HF-NEt3)). TBDMS and TOM groups are used for protection of 2′-hydroxy function in nucleosides, particularly in oligonucleotide synthesis.

Methyl Ethers – Cleavage is by TMSI in DCM or MeCN or Chloroform. An alternative method to cleave methyl ethers is BBr3 in DCM

Ethoxyethyl ethers (EE) – Cleavage more trivial than simple ethers e.g. 1N Hydrochloric acid

Amine protecting groups in Organic Synthesis: Protection of amines:

Carbobenzyloxy (Cbz) group – Removed by hydrogenolysis p-Methoxybenzyl carbonyl (Moz or MeOZ) group – Removed by hydrogenolysis, more labile than

Cbz tert-Butyloxycarbonyl (BOC) group (Common in solid phase peptide synthesis) – Removed by

concentrated, strong acid. (such as HCl or CF3COOH) 9-Fluorenylmethyloxycarbonyl (FMOC) group (Common in solid phase peptide synthesis) –

Removed by base, such as piperidine



Acetyl (Ac) group is common in oligonucleotide synthesis for protection of N4 in cytosine and N6 in adenine nucleic bases and is removed by treatment with a base, most often, with aqueous or gaseous ammonia or methylamine. Ac is too stable to be readily removed from aliphatic amides.

Benzoyl (Bz) group is common in oligonucleotide synthesis for protection of N4 in cytosine and N6 in adenine nucleic bases and is removed by treatment with a base, most often with aqueous or gaseous ammonia or methylamine. Bz is too stable to be readily removed from aliphatic amides.

Benzyl (Bn) group – Removed by hydrogenolysis Carbamate group – Removed by acid and mild heating. p-Methoxybenzyl (PMB) – Removed by hydrogenolysis, more labile than Benzyl 3,4-Dimethoxybenzyl (DMPM) – Removed by hydrogenolysis, more labile than p-methoxybenzyl p-methoxyphenyl (PMP) group – Removed by Ammonium cerium(IV) nitrate (CAN) Tosyl (Ts) group – Removed by concentrated acid (HBr, H2SO4) & strong reducing agents (sodium

in liquid ammonia or sodium naphthalenide) Other Sulfonamides (Nosyl&Nps) groups – Removed by samarium iodide, tributyltin hydride.

Carbonyl protecting groups in Organic Synthesis: Protection of carbonyl groups:

Acetals and Ketals – Removed by acid. Normally, the cleavage of acyclic acetals is easier than of cyclic acetals.

Acylals – Removed by Lewis acids.

Dithianes – Removed by metal salts or oxidizing agents. Carboxylic acid protecting groups in Organic Synthesis Protection of carboxylic acids:

Methyl esters – Removed by acid or base. Benzyl esters – Removed by hydrogenolysis. tert-Butyl esters – Removed by acid, base and some reductants. Silyl esters – Removed by acid, base and organometallic reagents. Orthoesters – Removed by mild aqueous acid to form ester, which is removed according to ester

properties. Oxazoline – Removed by strong hot acid (pH < 1, T > 100 °C) or alkali (pH > 12, T > 100 °C), but not

e.g. LiAlH4, organolithium reagents or Grignard (organomagnesium) reagents

Phosphate protecting groups in Organic Synthesis 2-cyanoethyl – removed by mild base. The group is widely used in oligonucleotide synthesis. Methyl (Me) – removed by strong nucleophiles e.c. thiophenole/TEA.

Terminal alkyne protecting groups in Organic Synthesis

propargyl alcohols in the Favorskii reaction, silyl groups, especially in protection of the acetylene itself

Due to this effect the quantum yield for deprotection of the right-side ester group is reduced and it stays intact. Significantly by placing the deuterium atoms next to the left-side ester group or by changing the wavelength to



Neighbouring Group Participation Neighbouring Group Participation (NGP) is observed in nucleophilic substitution reactions, where a neighbouring group helps in the removal of the leaving group to form a reactive intermediate that leads to the formation of the product. Increase in the reaction rate and unexpected stereo chemical outcomes are associated in reactions involving NGP. An atom having an unshared pair of electrons and also present at least beta to the leaving group can act as a neighbouring group. Also, NGP is mostly observed on solvolysis reactions where the solvent acts as the nucleophile. A typical reaction involving NGP is shown below.

During NGP, the neighbouring group (G) attacks the electrophilic centre to eliminate the leaving group (L). This leads to the formation of a cyclic intermediate which is very reactive. This is called anchimeric assistance from the neighbouring group. The nucleophile (Nu-)then attacks this intermediate to form the product. If the attack happens of the carbon that was having the leaving group the configuration will be retained because the configuration at that carbon will be inverted twice. Groups like halides, hydroxides, ethers, thio ethers, amino groups, carboxylates, phenyl group, pi-bonds etc. have been indentified to act as neighbouring groups in many reactions. Some more examples of reaction involving NGP are shown below.

Assistance by Other Neighboring Groups The ability of the pi-electrons in a suitably oriented, neighboring benzene ring to facilitate C-X ionization, where X is a halogen or a sulfonate ester, was described in the previous section. Other aromatic rings, such



as naphthalene, furan and thiophene, may function in a similar manner, as may the pi-electrons of double and triple bonds. The following diagram shows three examples of neighboring double bond interaction, the first being one of the most striking cases of anchimeric assistance on record. The use of dashed lines to show charge delocalization is a common practice. The text box below the diagram provides additional commentary concerning these examples.

Neighboring Group

Double Bonds Triple Bonds Sulfur Atoms Oxygen Atoms Nitrogen Atoms

Examples of other neighboring group perturbations, including non-bonding electron pair assistance by neighboring sulfur, oxygen and nitrogen atoms will be displayed above by clicking the appropriate button under the diagram. The text box commentary will change to suit the examples. In most of the cases involving heteroatom assistance, an "onium" intermediate is formed, in which the heteroatom is charged. Adjacent halogen atoms may also stabilize carbocations, as noted earlier with respect to trans-anti additions to cyclic alkenes. Functional rearrangement by way of halonium intermediates has also been reported. For example, a chloroform solution of the diaxial 2-bromo-3-chlorosteroid, shown on the left below, spontaneously rearranges to the more stable diequatorial 2-chloro-3-bromo isomer drawn on the right. The rearrangement is reversible and proceeds by way of the cyclic bromonium ion written in brackets.

The Nonclassical Carbocation Hypothesis The role of carbocation intermediates in many organic reactions is well established. Some, such as tert-butyl, are localized. Some,such as allyl and benzyl, are stabilized by conjugation to pi-electron systems. Some, as described above, are stabilized by bridging to neighboring nucleophiles. In all cases of anchimeric assistance described above, a charge delocalized or redistributed species is an intermediate on the reaction path. Such intermediates can be isolated in some cases, but they usually have only transitory existence. The



rate acceleration of ionization is attributed to structural and energetic similarities of the transition states to the intermediates they produce (the Hammond postulate). Anchimeric assistance is usually associated with one or more of the following observable characteristics.

• Rate acceleration compared with similar reactions lacking assistance. • Stereoelectroniccontrol that results in rate and product differences between stereoisomers. • Retention of configuration in substitution products. • Racemization of products (and often reactants) when a symmetrical bridged intermediate is involved.

Solvolysis of the exo and endo-2-norbornyl sulfonate esters disclosed differences that suggested anchimeric assistance for the exo-isomer. As shown in the following diagram, the rate of acetolysis of the exo-isomer is substantially faster than that of the endo-isomer, which reacts at a rate similar to the cyclohexyl derivative. The former substitution proceeds with complete retention of configuration and racemization; whereas the endo-isomer is substituted with inversion of configuration and retains a small degree of optical activity. The source of this assistance was proposed to be the electron pair of the C1 : C6 sigma bond, which is ideally oriented anti to the sulfonate leaving group. A sigma-delocalized ion (drawn in brackets), was proposed as an intermediate, displayed by clicking on the diagram. Since this bridged ion is symmetrical, formation of racemic acetate is expected. The term "nonclassical" was applied to this charge delocalized cation, inasmuch as it appeared to be unique.By comparison, the endo-isomer ionizes to a classical 2º-carbocation, which is rapidly converted to the more stable nonclassical ion. Some acetate anion may bond to the 2º-carbocation before it changes, accounting for the residual optical activity in this reaction.

Not everyone was convinced by this interpretation of the evidence. The chief protagonists favoring the nonclassical view were S. Winstein and J. D. Roberts. The primary opposition came from H. C. Brown, who espoused a more conventional rationalization. Brown pointed out that the norbornyl compounds are better compared with cyclopentyl than with cyclohexyl analogs (eclipsing strain), and in such a comparison the endo isomer is abnormally slow, the exo isomer being only 14 times faster than cyclopentyl. The racemic product was explained by assuming the interconversion of enantiomeric classical carbocations was very rapid on the reaction time scale. Brown also noted that attachment of a stabilizing aryl substituent at C2 did not reduce the rate enhancement of exo-ionization or the preference for exo-product formation. Since these latter solvolyses proceed by way of a benzyliccation, sigma-bond assistance was assumed to be minimal.



effect was noted for such substituents at C1 (1R). This influence is best explained by the nonclassical Interpretations of the considerable body of evidence amassed at this point may be summarized in the diagram on the right. In the first display, the nonclassical bridged cation is shown as a transition state for the interconversion of the classical carbocations. A relationship of this kind corresponds to the rearrangement of neopentyl chloride. A second possibility, presented by clicking on the diagram, has the nonclassical ion as a higher energy intermediate, linking the classical ions. Finally, by clicking on the diagram a second time, the possibility that the nonclassical ion represents the more stable intermediate is drawn. By the mid 1960's chemical and nmr techniques had improved to a stage that allowed direct observation of carbocations in low nucleophilic, acidic solutions, often referred to as "super acids". Much of this work was conducted by George Olah (Nobel Prize, 1994), using mixed solvents composed of SbF5, SO2, SO2F2& SO2FCl. At low temperatures, 1H and 13C nmr spectra of (CH3)3C(+) and (CH3)2CH(+) were obtained and interpreted. As anticipated, the charged tricoordinate carbon atom exhibited a 13C signal over 300ppm downfield from TMS. When similar nmr measurements were applied to the 2-norbornyl cation, a number of fast proton shifts were disclosed. These could be "frozen out" by working at low temperature, the 3,2-shift at -70º C and a faster 6,2-shift at -130º C. The resulting spectrum, which remained unchanged at temperatures as low as -160º C, had no low field signals near that expected for a classical 2º-carbocation, and was supportive of the nonclassical structure. Recently, a solid state 13C nmr spectra at 5º K proved consistent with the nonclassical ion. From these and other spectroscopic studies, the sigma-bridged nonclassicalcation has been firmly identified as the more stable carbocation species having the 2-norbornyl structure. Further confirmation was provided in 2013 by researchers in Germany, employing careful X-ray crystallographic measurements of an annealed [C7H11]

+[Al2Br7]– salt at 40º K.

Are there other relatively stable nonclassicalcarbocations? Several that seem to fit this classification have been identified, but few have been as exhaustively studied as the 2-norbornyl. One of the best criteria for evaluating candidate ions is to establish whether one or more of the participating carbon atoms is hypervalent (has more than four coordinating groups). In the following diagram, the simplest hypervalent carbocation, methanonium, is drawn on the left in the gray shaded box. This ion is commonly seen in the mass spectrum of methane (gas phase), but decomposes in solution as a consequence of its extreme acidity. To its right are two larger non-classical ions, 2-norbornyl and 7-norbornenyl. A pentacoordinate carbon



atom is identified in each case. Resonance contributors to these ions are shown to the right of the dashed bond representation, and in all the drawings the delocalized electron pair is colored blue. Finally, a broad overview of this classification, offered by Olah in his Nobel lecture, will be displayed by clicking on the diagram.

To see a model of the 2-norbornyl cation

References: 3. S .George . , ''Organic Chemistry" Mosby-Year Book .1995 , Chp.14 , p. 589-649 (1995). 4. P. Sykes ; "Agide Book to Mechanism in Oaganic Chemistry'' , 5th Ed ., Longman, (1974) . 5. R .E .Brewster , W. E. McEwen ; ''Organic Chemistry" , Ch . 30ed Ed ., p.638 , (1971) .

6. B.A. Marry ; "Organic Reaction Mechanism" , Ch . 1, Jon Willey sons , (2005) . 7. L.F. Fieser and K.L. Eilliamson ,''Organic Experiment" 5th Ed ., DC . Heath and company Toronto ,

Canada , p. 270 . (1983) . 8. F. A. Carey and R. J. Sundberg "Advanced Organic Chemistry" part A:strures and Mechanisms, 2nded

., Plenum Press. New York, p. 243, (1983). 9. Nagham MAljamali ., As. J. Rech., 2014 , 7 ,9 , 810-838. 10. C. O. Wilson and O. Givold, "Text book of Organic Medicinal and pharmaceutical Chemistry", 5thEd

., Pitman Medical Publishing Co. LTD, London coppy right. Cby. J. B. LippinCott Company (1966) . 11. Nagham MAljamali ., As. J. Rech., 2014 , 7 ,11. 12. Nagham MAljamali., Int. J. Curr.Res.Chem.Pharma.Sci. 1(9): (2014):121–151. 13. Nagham MAljamali., Int. J. Curr.Res.Chem.Pharma.Sci. 1(9): (2014):88- 120.

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