Protection for carboxylic group & Protection for the Amino group

PROTECTING GROUPS (PROTECTION FOR THE CARBOXYLIC GROUP & PROTECTION FOR THE AMINO GROUP

1. PROTECTION FOR CARBOXYLIC GROUP & THE PROTECTION FOR THE AMINO GROUP PRESENTED BY, ANBU DINESH JAYAKUMAR M.PHARM (SEM-I) DEPT OF PHARM CHEMISTRY

2. CONTENTS INTRODUCTION QUALITIES OF GOOD PROTECTING GROUPS PROTECTING GROUPS IN ORGANIC SYNTHESIS PROTECTION FOR THE CARBOXYLIC GROUP PROTECTION FOR THE AMINO GROUP REFERENCE CONCLUSION 2

3. What are protecting groups ? A protecting group is introduced into a molecule by chemical modification of a functional group to obtain chemo selectivity in a chemical reaction. It plays an important role in multistep organic synthesis When a chemical reaction is to be carried out selectively at one reactive site in a multifunctional compound, other reactive sites must be temporarily blocked . 3

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5. Then we can reduce the ester to the primary alcohol. OVERALL SCHEME 5

6. Qualities of a Good Protecting Group in Organic Synthesis It must react selectively in good yield to give a protected substrate that is stable to the projected reactions. The protective group must be selectively removed in good yield by readily available, preferably nontoxic reagents that do not attack the regenerated functional group. The protective group should form a derivative (without the generation of new stereogenic centers ) that can easily be separated from side products associated with its formation or cleavage . The protective group should have a minimum of additional functionality to avoid further sites of reaction . 6

7. PROTECTING GROUPS IN ORGANIC SYNTHESIS 7

8. PROTECTION FOR CARBOXYLIC GROUP

9. The protecting groups typically used for carboxylic acids are ester-based with the methyl ester Regeneration of the carboxylic acid is usually achieved by saponification or other hydrolytic methods, although non-basic reagents, such as lithium halides, are used. Alternatively , more specialist esters may be used in cases where the methyl ester or its deprotection protocol is unsuitable . These includes tert-butylesters , deprotected by acid/heat , T rimethylsilylethyl esters , de-protected with tetra-n- butylammonium fluoride (TBAF), 3-propionitrile (2-cyanoethyl) esters, deprotected by mild base. PROTECTION FOR CARBOXYLIC GROUP 9

10. Why a Carboxylic Acid group be protected? To mask the acidic proton so that it does not interfere with base -catalysed reactions To prevent nucleophilic addition reactions To improve the handling of the molecule Example- To make the compound less water soluble , To improve its NMR characteristics To make it more volatile so that it can be analysed by gas chromatography . 10

11. Carboxylic acid protecting groups Methyl ester Benzyl ester tert -Butyl ester Oxazoline Silyl ester 11

12. For example, lithium aluminium hydride is a highly reactive but useful reagent capable of reducing esters to alcohols. The carbonyl is converted into an acetal which does not react with hydrides. The acetal is then called a protecting group for the carbonyl group 12

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16. PROTECTION FOR THE AMINO GROUP

17. PROTECTION FOR AMINO GROUP Amino groups easily undergoes reactions with oxidizing reagents, alkylating reagents, and many carbonyl compounds. In order to prevent the amino group from undergoing such reactions it must be suitably protected. Many methods are available for protecting amino groups . It is due to peptide synthesis has become very important . I t is not possible to build a peptide of specific structure from its component amino acids unless the amino groups can be suitably protected . 17

18. METHODS OF PROTECTING AMINO GROUP 18

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20. A) PROTONATION R eactivity of amines is due to the bond which is made with unshared electron pair on nitrogen. This reduces the reactivity of this electron pair & reduces the reactivity of the nitrogen atom. The simplest way is to convert the amine to an ammonium salt with an acid. Protonation amounts to protection of the amine function: Unless the acid concentration is very high, there will be a significant proportion of unprotected free base present. Also , many desirable reactions are not feasible in acid solution . 20

21. B) ALKYLATION An alkylation is suitable for primary and secondary amines: At first glance, you may not consider that such reactions achieve protection because there is an electron pair on nitrogen in the products. However , it a suitably bulky alkylating agent , RX , is used the reactivity of the resulting alkylated amine can be reduced considerably by a steric effect. The most useful group of this type is the triphenylmethyl group (C 6 H 5 ) 3 C− , which can be introduced on the amine nitrogen by the reaction of triphenyl methyl chloride (" trityl"chloride ) with the amine in the presence of a suitable base to remove the HCl that is formed: 21

22. The triphenyl methyl group can be removed from the amine nitrogen under very mild conditions, either by catalytic hydrogenation or by hydrolysis in the presence of a weak acid: 22

23. C) ACYLATION One useful way of reducing the basicity and nucleophilicity of an amine nitrogen is to convert it to an amide by treatment with an acid chloride or acid anhydride The reduced reactivity is associated with the stabilization produced by the attached carbonyl group because of its ability to accept electrons from the nitrogen atom. This can be seen clearly in valence-bond structures 9a and 9b, which show electron delocalization of the unshared pair of the amide function : 23

24. The stabilization energy (SE) of a simple amide grouping is about 18kcal mol −1 and if a reaction occurs in which the amide nitrogen acts as an electron-pair donor, almost all of the electron delocalization of the amide group is lost in the transition state This loss in stabilization energy at the transition state makes an amide far less nucleophilic than an amine. The most common acylating agents are the acyl chlorides and acid anhydrides of ethanoic acid and benzoic acid. The amine can be recovered from the amide by acid- or base-catalyzed hydrolysis: Another useful protecting group for amines has the structure R−O−CO−. It differs from the common acyl groups of the type R−CO− in that it has the  alkoxy carbonyl structure rather than an  alkyl carbonyl structure. 24

25. The most used examples are: The phenylmethoxycarbonyl ( benzyloxycarbonyl ) group can be introduced by way of the corresponding acyl chloride, which is prepared from phenylmethanol  (benzyl alcohol) and carbonyl dichloride: The  tert -butoxycarbonyl group cannot be introduced by way of the corresponding acyl chloride because (CH3)3COCOCl is unstable. One of several alternative derivatives is the azide , ROCON3: 25

26. Although these protecting groups may seem bizarre, their value lies in the fact that they can be removed easily by acid-catalyzed hydrolysis under very mild conditions. The sequence of steps is shown in Equation 23-10 and involves proton transfer to the carbonyl oxygen and cleavage of the carbon-oxygen bond by an S N1 process (R=  tert -butyl) or S N2 process (R= phenylmethyl ). The product of this step is a carbamic acid. Acids of this type are unstable and readily eliminate carbon dioxide, leaving only the free amine 26

27. D)SULFONYLATION A sulfonyl group, RSO2 −, like an acyl group, R−CO− or RO−CO−, will deactivate an attached nitrogen. Therefore amines can be protected by transformation to sulfonamides with sulfonyl chlorides However, sulfonamides are much more difficult to hydrolyze back to the amine than are carboxamides . In peptide synthesis the commonly used sulfonyl protecting groups are 4-methylbenzenesulfonyl or 4-bromobenzenesulfonyl groups. These groups can be removed as necessary from the sulfonamide by reduction with sodium metal in liquid ammonia . 27

28. REFERENCE John D. Robert and Marjorie C. Caserio (1977) Basic Principles of Organic Chemistry, second edition. W. A. Benjamin, Inc. , Menlo Park, CA. ISBN 0-8053-8329-8. Protection of Carboxyl Groups E . Haslam Department of Chemz"stry , University of Sheffield, Sheffield , England Protective groups in organic synthesis, third edition, theodora.W.Greene,Peter G.M. Wuts 28

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