ORGANIC CHEMISTRY II for 2 nd year Pharmacy students

Transcription

1 Tishk International University Faculty of Pharmacy ORGANIC CHEMISTRY II for 2 nd year Pharmacy students By Prof. Dr. Faiq H.S. Hussain Academic Year

2 1.0 Alkenes and their derivatives

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4 1.1 Nomenclature of alkenes The systematic name of an alkene originates from the name of the alkane corresponding to the longest continuous chain of carbon atoms that contains the double bond. When the chain is longer than three carbons, the atoms are numbered starting from the end nearest to the double bond. The functional group suffix is -ene. For branches, each alkyl group is given a number, but the double bond still gets preference when numbering the chain.

5 A cyclic alkene is named by a prefix cyclo- to the name of the acyclic alkene. Double bonded carbons are considered to occupy positions 1 and 2. When a geometric isomer is present, a prefix cis (Z) or trans (E) is added. Because of the double bonds, alkenes cannot undergo free rotation. Thus, the rigidity of a π bond gives rise to geometric isomers. Simple 1,2-alkenes can be described as cis- or trans-alkenes. When similar groups are present on the same side of the double bond, the alkene is said to be cis. When similar groups are present on opposite sides of the double bond, it is said to be trans. More complex alkenes are best described as E- or Z- based on the Cahn Ingold Prelog priority rules.

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7 1.2 Physical properties of alkenes

8 1.3 Preparation of alkenes and Cycloalkenes Alkenes are obtained by the transformation of various functional groups, e.g. (1) dehydration of alcohols, (2) dehalogenation of alkyl halides and (3) dehalogenation or reduction of alkyl dihalides. These reactions are known as elimination reactions. An elimination reaction results when a proton and a leaving group are removed from adjacent carbon atoms, giving rise to a p bond between the two carbon atoms.

9 2-propanol propene 1,2-dibromopentane 1-pentene

10 2.0 Alkynes and their derivatives

11 2.1 Nomenclature of alkynes

12 2.2 Structure of alkynes The triple bond consists of one s bond and two p bonds. Each carbon is bonded to two other atoms, and there are no nonbonding electrons. Carbon requires two hybrid orbitals to bond to the atoms, thus sp hybrids are used.

13 2.3 Preparation of alkynes Alkynes are prepared from alkyl dihalides via elimination of atoms or groups from adjacent carbons. Dehydrohalogenation of vicinal- or geminal-dihalides is a particularly useful method for the preparation of alkynes Example

14 Metal acetylides or alkynides react with primary alkyl halides or tosylates to prepare alkynes. Chloroethane + CH 3 C C CH 2 CH 3 2-pentyne

15 3.0 Aromatic compounds and their derivatives All drugs are chemicals and many of them are aromatic compounds. Therefore, in order to understand the chemical nature, physical properties, stability, pharmacological actions and toxicities of a majority of drug molecules, the knowledge of aromatic chemistry is extremely important. Before we look into the specific examples of various drugs that belong to this aromatic class, let us try to understand what aromaticity really is. Generally, the term aromatic compounds means fragrant substances. Later, benzene and its structural relatives were termed as aromatic. However, there are a number of other nonbenezenoid compounds that can be classified as aromatic compounds.

16 3.1 Definition: Huckel`s rule

17 3.2 General properties of aromatic compounds Aromatic compounds have the following general properties. (a) They have a high degree of unsaturation, but are resistant to addition reactions. (b) They favor electrophilic substitution reactions. (c) These compounds are unusually stable. (d) They have a low heat of hydrogenation and low heat of combustion. (e) They are cyclic compounds. (f) These compounds are flat and planar.

18 3.3 Classification of aromatic compounds

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20 Macrocyclic These are monocyclic nonbenzene structures, and the ring sizes are quite big. There is an adequate number of double bonds and π electrons to conform to Huckel s rule; e.g., [14] annulene obeys Huckel s rule and is aromatic. Heterocyclic These are compounds having at least one hetero atom (any other atom but carbon, e.g. O, N and S) within the ring, and conforming to Huckel s rule. The aromaticity of heterocyclic compounds, e.g. pyridine and pyrrole, can be explained as follows.

21 3.4 Pharmaceutical importance of aromatic compounds: some examples

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23 3.5 Nomenclature of benzene derivatives Benzene derivatives are named by prefixing the name of the substituent group to the word benzene, e.g. chlorobenzene and nitrobenzene. Many benzene derivatives have trivial names, which may show no resemblance to the name of the attached substituent group, e.g. phenol, toluene and aniline. When two groups are attached to the benzene ring, their relative positions have to be identified. The three possible isomers of a disubstituted benzene are differentiated by the use of the names ortho, meta and para, abbreviated as o-, m- and p-, respectively.

24 If the two groups are different, and neither is a group that gives a trivial name to the molecule, the two groups are named successively, and the word benzene is added. If one of the two groups is the kind that gives a trivial name to the molecule, then the compound is named as a derivative of this compound. In both cases, relative position should also be designated. When more than two groups are attached to the benzene ring, numbers are used to indicate their relative positions. If the groups are the same, each is given a number, the sequence being the one that gives the lowest combination of numbers; if the groups are different, then the lastnamed group is understood to be in position 1, and the other numbers conform to this. If one of the groups that give a trivial name is present, then the compound is named as having the special group in position 1.

25 3.6 Electrophilic substitution of benzene Benzene is susceptible to electrophilic attack, and unlike any alkene it undergoes substitution reactions rather than addition reactions. Before we go into any details of such reactions, let us try to understand the following terms. Arenes. Aromatic hydrocarbons, as a class, are called arenes. Aryl group. An aromatic hydrocarbon with a hydrogen atom removed is called an aryl group,. designated by Ar Phenyl group. The benzene ring with one hydrogen atom removed (C 6 H 5 ( is called the phenyl. group, designated by Ph Electrophile. Electron loving. Cations, E +, or electron-deficient species. For example, Cl + or Br + (halonium ion) and + NO 2 (nitronium ion).

26 An electrophile (E + ) reacts with the benzene ring and substitutes for one of its six hydrogen atoms. A cloud of π electrons exists above and below the plane of the benzene ring. These π electrons are available to electrophiles. Benzene s closed shell of six p electrons gives it a special stability. Substitution reactions allow the aromatic sextet of π electrons to be regenerated after attack by the electrophile has occurred. Electrophiles attack the π system of benzene to form a delocalized nonaromatic carbocation (arenium ion or σ complex). Some specific examples of electrophilic substitution reactions of benzene are summarized here.

27 3.7 Phenols Phenols are compounds of the general formula ArOH, where Ar is a phenyl, a substituted phenyl, or one of the other aryl groups, e.g. naphthyl. Phenols differ from alcohols in having the OH group attached directly to an aromatic ring. Hydroxybenzene, the simplest member of the phenols, is generally referred to as phenol. Many pharmaceutically and pharmacologically important compounds, either of natural or synthetic origin, belong to this class of compounds, e.g. salicylic acid and quercetin.

28 3.7.1 Nomenclature of phenols Phenols are generally named as derivatives of the simplest member of the family, phenol, e.g. o-chlorophenol. Sometimes trivial or special names are also used, e.g. m-cresol. Occasionally, phenols are named as hydroxyl compounds, e.g. para-hydroxybenzoic acid. Numbering is often used to denote the position(s) of the substituent(s) on a phenol skeleton, e.g. 2,4-dinitrophenol.

29 3.7.2 Physical properties of phenols

30 3.7.3 Preparation of phenols

31 3.8.0 Aromatic amines: aniline

32 3.8.1 Physical properties of aniline

33 3.8.2 Preparation of aniline 1.Reduction of nitrobenzene: Aniline can be prepared from nitrobenzene by either chemical reduction using acid and metal or catalytic hydrogenation using molecular hydrogen. 2. From chlorobenzene: Treatment of chlorobenzene with ammonia (NH 3 ) at high temperature and high pressure in the presence of a catalyst yields aniline.

34 3. Hofmann degradation of benzamide: This reaction produces aniline, which contains one less carbon than the starting material (benzamide). The group (phenyl) attached to the carbonyl carbon in the amide (benzamide)is found joined to nitrogen in the product (aniline). This is an example of molecular rearrangement.

35 3.8.3 Sulpha drugs Sulfa drug is One of the sulfonamides, the sulfa-related antibiotics which are used to treat bacterial and some fungal infections. The first sulfa drug was prontosil. It was discovered by the German physician and chemist Gerhard Domagk in Sulfa drugs kill bacteria and fungi by interfering with their metabolism. They were the "wonder drugs" before penicillin and are still used today. Because sulfa drugs concentrate in the urine before being excreted, treating urinary tract infections is one of their most common uses. Sulfa drugs work by binding and inhibiting a specific enzyme called dihydropteroate synthase (DHPS). This enzyme is critical for the synthesis of folate, an essential nutrient. Mammals get folate from their diet, but bacteria must synthesize this vitamin. Folate synthesis requires a chemical reaction between 2 molecules, DHPP and PABA, that is catalyzed by DHPS.

36 Some examples about sulfa drugs Sulfamethoxazole-Trimethoprim Suspension Erythromycin-sulfisoxazole This medication is a combination of two antibiotics: sulfamethoxazole and trimethoprim. It is used to treat a wide variety of bacterial infections (such as middle ear, urine, respiratory, and intestinal infections). It is also used to prevent and treat a certain type of pneumonia(pneumocystis-type). Erythromycin/sulfisoxazole is a combination antibiotic used to treat middle ear infections in children. This product contains a macrolide (erythromycin) and a sulfa-type (sulfisoxazole) antibiotic. It works by stopping the growth of bacteria.

37 3.8.4 Synthesis of sulpha drugs from aniline Antimicrobial sulpha drugs, e.g. sulphanilamide, are the amide of sulphanilic acid, and certain related substituted amides. Sulphanilamide, the first of the sulpha drugs, acts by inhibiting the bacterial enzyme that incorporates para-aminobenzoic acid into folic acid. Sulphanilamide is a bacteriostatic drug, i.e. inhibits the further growth of the bacteria. Multistep synthesis, starting from aniline, as depicted in the following scheme, can achieve the product, sulpha drug.

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39 3.9 Polycyclic benzenoids