Organic chemistry ii


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Organic chemistry ii

  1. 1. Organic Chemistry II arranged by Putri Nur Aulia 1 ORGANIC CHEMISTRY II CHAPTER I BIFUNCTIONAL COMPOUNDS
  2. 2. Organic Chemistry II arranged by Putri Nur Aulia 2 CHAPTER I BIFUNCTIONAL COMPOUNDS 1.1 Introduction In organic molecules, functional groups are atom or atoms which are responsible for the characteristic properties of that molecule with the exceptions of double and triple bonds which are also functional groups. Some common functional groups are -COOH (carboxylic acids), -CHO (aldehyde), - CONH2 (amide), -CN (nitrile), -OH (alcohol) etc. When two of such different functional groups are present in a single organic molecule then it is called bifunctional molecule, which has properties of two different types of functional groups. Many of bifunctional molecules are used to produce medicine, catalysts and also used in condensation polymerization like polyester, polyamide etc. 1.2 Nomenclature Nomenclature of multifunctional compounds: The longest chain containing the suffix is chosen, the priority for choosing the suffix being carboxylic acid, -CO2H, > carboxylic acid derivative, -COX > aldehyde, -CHO > ketone, -CO-, > alcohol, -OH > amine, -NH2. The second and other groups are labelled as substituents. e.g. CH3CH(OH)CH2CO2H is 3- hydroxybutanoic acid; HOCH2CH2CH2COCH3 is 5-hydroxypentan-2-one; CH3CH(OH)CH2C(CH3)(NH2)CH3 is 4-amino-4-methylpentan-2-ol; CH3COCO2H is 2- oxopropanoic acid, (the =O of an aldehyde or ketone is called oxo when it has to be named as a substituent).
  3. 3. Organic Chemistry II arranged by Putri Nur Aulia 3 The carbon-carbon double and triple bonds are always incorporated in the chain, with lower priority than the other groups. [e.g. CH2=CHCH(OH)CH3 is but-3-en-2-ol; CH3C≡CCH2CO2H is pent-3-yn-oic acid.] For compounds with larger carbon skeletons a further condensation of structural may be used. represents propylcyclohexane. Each line represents two carbon atoms joined by a single bond, and hydrogens which are present are not shown. The number of H's is such to satisfy the valency of carbon, 4. Benzene is C6H6 and is the parent of aromatic compounds. Each carbon in the benzene ring has one hydrogen attached. As a second resonance structure with the double bonds in the other three positions can be drawn, the resonance hybrid of benzene is often represented as a hexagon with a circle inside: 1.3 How Can A Pure Be A mixture of Two (or More) Molecules
  4. 4. Organic Chemistry II arranged by Putri Nur Aulia 4 1 H- NMR Spectroscopy Using D2O as Co-Solvent 1.3.1 Keto-enol Tautomerism
  5. 5. Organic Chemistry II arranged by Putri Nur Aulia 5 Carbonyl Group Tautomer Solvent Effect
  6. 6. Organic Chemistry II arranged by Putri Nur Aulia 6 Enols and Enolates Unsymmetrical Ketones
  7. 7. Organic Chemistry II arranged by Putri Nur Aulia 7 Implications of Enolisation
  8. 8. Organic Chemistry II arranged by Putri Nur Aulia 8 Acid Catalysed Halogenations of Enols The Hell-Volhard –Zelinsky Reaction
  9. 9. Organic Chemistry II arranged by Putri Nur Aulia 9 The Aldol Reaction
  10. 10. Organic Chemistry II arranged by Putri Nur Aulia 10 The Knoevenagel Condensation The Claisen Condensation
  11. 11. Organic Chemistry II arranged by Putri Nur Aulia 11 The Dieckman Reaction β- Dicarbonyl Compounds
  12. 12. Organic Chemistry II arranged by Putri Nur Aulia 12 Decarboxylation of β-Ketoacids Aklylation of Dymethil Malonates
  13. 13. Organic Chemistry II arranged by Putri Nur Aulia 13 ORGANIC CHEMISTRY II CHAPTER II HETEROCYCLIC COMPOUNDS
  14. 14. Organic Chemistry II arranged by Putri Nur Aulia 14 CHAPTER II HETEROCYCLIC COMPOUNDS 2.1 Introduction Compounds classified as heterocyclic probably constitute the largest and most varied family of organic compounds. After all, every carbocyclic compound, regardless of structure and functionality, may in principle be converted into a collection of heterocyclic analogs by replacing one or more of the ring carbon atoms with a different element. Even if we restrict our consideration to oxygen, nitrogen and sulfur (the most common heterocyclic elements), the permutations and combinations of such a replacement are numerous. 2.2 Nomenclature Devising a systematic nomenclature system for heterocyclic compounds presented a formidable challenge, which has not been uniformly concluded. Many heterocycles, especially amines, were identified early on, and received trivial names which are still preferred. Some monocyclic compounds of this kind are shown in the following chart, with the common (trivial) name in bold and a systematic name based on the Hantzsch-Widman system given beneath it in blue. The rules for using this system will be given later. For most students, learning these common names will provide an adequate nomenclature background. An easy to remember, but limited, nomenclature system makes use of an elemental prefix for the heteroatom followed by the appropriate carbocyclic name.
  15. 15. Organic Chemistry II arranged by Putri Nur Aulia 15 A short list of some common prefixes is given in the following table, priority order increasing from right to left. Examples of this nomenclature are: ethylene oxide = oxacyclopropane, furan = oxacyclopenta-2,4-diene, pyridine = azabenzene, and morpholine = 1-oxa-4-azacyclohexane. Element Oxygen sulfur selenium nitrogen phosphorous silicon boron As Valence II II II III III IV III III Prefix Oxa Thia Selena Aza Phospha Sila Bora Arsa The Hantzsch-Widman system provides a more systematic method of naming heterocyclic compounds that is not dependent on prior carbocyclic names. It makes use of the same hetero atom prefix defined above (dropping the final "a"), followed by a suffix designating ring size and saturation. As outlined in the following table, each suffix consists of a ring size root (blue) and an ending intended to designate the degree of unsaturation in the ring. In this respect, it is important to recognize that the saturated suffix applies only to completely saturated ring systems, and the unsaturated suffix applies to rings incorporating the maximum number of non-cumulated double bonds. Systems having a lesser degree of unsaturation require an appropriate prefix, such as "dihydro"or "tetrahydro". Ring Size 3 4 5 6 7 8 9 10 Suffix Unsaturated Without N Saturated irene irane ete etane ole olane ine inane epine epane ocine ocane onine onane ecine ecane Despite the general systematic structure of the Hantzsch-Widman system, several exceptions and modifications have been incorporated to accommodate conflicts with prior usage. Some examples are: • The terminal "e" in the suffix is optional though recommended.
  16. 16. Organic Chemistry II arranged by Putri Nur Aulia 16 • Saturated 3, 4 & 5-membered nitrogen heterocycles should use respectively the traditional "iridine", "etidine" & "olidine" suffix. • Unsaturated nitrogen 3-membered heterocycles may use the traditional "irine" suffix. • Consistent use of "etine" and "oline" as a suffix for 4 & 5-membered unsaturated heterocycles is prevented by their former use for similar sized nitrogen heterocycles. • Established use of oxine, azine and silane for other compounds or functions prohibits their use for pyran, pyridine and silacyclohexane respectively. Examples of these nomenclature rules are written in blue, both in the previous diagram and that shown below. Note that when a maximally unsaturated ring includes a saturated atom, its location may be designated by a "#H " prefix to avoid ambiguity, as in pyran and pyrrole above and several examples below. When numbering a ring with more than one heteroatom, the highest priority atom is #1 and continues in the direction that gives the next priority atom the lowest number. All the previous examples have been monocyclic compounds. Polycyclic compounds incorporating one or more heterocyclic rings are well known. A few of these are shown in the following diagram. As before, common names are in black and systematic names in blue. The two quinolines illustrate another nuance
  17. 17. Organic Chemistry II arranged by Putri Nur Aulia 17 of heterocyclic nomenclature. Thus, the location of a fused ring may be indicated by a lowercase letter which designates the edge of the heterocyclic ring involved in the fusion, as shown by the pyridine ring in the green shaded box. Heterocyclic rings are found in many naturally occurring compounds. Most notably, they compose the core structures of mono and polysaccharides, and the four DNA bases that establish the genetic code. 2.3 Preparation and Reactions 2.3.1 Three-Membered Rings Oxiranes (epoxides) are the most commonly encountered three- membered heterocycles. Epoxides are easily prepared by reaction of alkenes with peracids, usually with good stereospecificity. Because of the high angle strain of the three-membered ring, epoxides are more reactive that unstrained ethers. Addition reactions proceeding by electrophilic or nucleophilic opening of the ring constitute the most general reaction class. Example 1 in the following diagram shows one such transformation, which is interesting due to subsequent conversion of the addition intermediate into the corresponding thiirane. The initial ring opening is stereoelectronically directed in a trans-diaxial fashion, the intermediate relaxing to the diequatorial conformer before cyclizing to a 1,3- oxathiolane intermediate. Other examples show similar addition reactions to thiiranes and aziridines. The acid-catalyzed additions in examples 2 and 3, illustrate the
  18. 18. Organic Chemistry II arranged by Putri Nur Aulia 18 influence of substituents on the regioselectivity of addition. Example 2 reflects the SN2 character of nucleophile (chloride anion) attack on the protonated aziridine (the less substituted carbon is the site of addition). The phenyl substituent in example 3 serves to stabilize the developing carbocation to such a degree that SN1 selectivity is realized. The reduction of thiiranes to alkenes by reaction with phosphite esters (example 6) is highly stereospecific, and is believed to take place by an initial bonding of phosphorous to sulfur. Examples 7 and 8 are thermal reactions in which both the heteroatom and the strained ring are important factors. The α-lactone intermediate shown in the solvolysis of optically active 2-bromopropanoic acid (example 9) accounts both for the 1st-order kinetics of this reaction and the retention of configuration in the product. Note that two inversions of configuration at C-2 result in overall retention. Many examples of intramolecular interactions, such as example 10, have been documented. An interesting regioselectivity in the intramolecular ring-opening reactions of disubstituted epoxides having a pendant γ-hydroxy substituent has been noted. As illustrated below, acid and base-catalyzed reactions normally proceed by 5-exo-substitution (reaction 1), yielding a tetrahydrofuran product. However, if the oxirane has an unsaturated substituent (vinyl or phenyl), the acid-catalyzed opening occurs at the allylic (or benzylic) carbon (reaction 2) in a 6-endo fashion. The π-electron system of the
  19. 19. Organic Chemistry II arranged by Putri Nur Aulia 19 substituent assists development of positive charge at the adjacent oxirane carbon, directing nucleophilic attack to that site. 2.3.2 Four-Membered Rings Preparation Several methods of preparing four-membered heterocyclic compounds are shown in the following diagram. The simple procedure of treating a 3-halo alcohol, thiol or amine with base is generally effective, but the yields are often mediocre. Dimerization and elimination are common side reactions, and other functions may compete in the reaction. In the case of example 1, cyclization to an oxirane competes with thietane formation, but the greater nucleophilicity of sulfur dominates, especially if a weak base is used. In example 2 both aziridine and azetidine formation are possible, but only the former is observed. This is a good example of the kinetic advantage of three-membered ring formation. Example 4 demonstrates that this approach to azetidine formation works well in the absence of competition. Indeed, the exceptional yield of this product is attributed to the gem-dimethyl substitution, the Thorpe-Ingold effect, which is believed to favor coiled chain conformations. The relatively rigid configuration of the substrate in example 3, favors oxetane formation and prevents an oxirane cyclization from occurring. Finally, the Paterno-Buchi photocyclizations in examples 5 and 6 are particularly suited to oxetane formation. Reactions Reactions of four-membered heterocycles also show the influence of ring strain. Some examples are given in the following diagram. Acid-
  20. 20. Organic Chemistry II arranged by Putri Nur Aulia 20 catalysis is a common feature of many ring-opening reactions, as shown by examples 1, 2 & 3a. In the thietane reaction (2), the sulfur undergoes electrophilic chlorination to form a chlorosulfonium intermediate followed by a ring-opening chloride ion substitution. Strong nucleophiles will also open the strained ether, as shown by reaction 3b. Cleavage reactions of β- lactones may take place either by acid-catalyzed acyl exchange, as in 4a, or by alkyl-O rupture by nucleophiles, as in 4b. Example 5 is an interesting case of intramolecular rearrangement to an ortho-ester. Finally, the β-lactam cleavage of penicillin G (reaction 6) testifies to the enhanced acylating reactivity of this fused ring system. Most amides are extremely unreactive acylation reagents, thanks to stabilization by p-π resonance. Such electron pair delocalization is diminished in the penicillins, leaving the nitrogen with a pyramidal configuration and the carbonyl function more reactive toward nucleophiles. 2.3.3`Five-Membered Rings Preparation Commercial preparation of furan proceeds by way of the aldehyde, furfural, which in turn is generated from pentose containing raw materials like corncobs, as shown in the uppermost equation below. Similar preparations of pyrrole and thiophene are depicted in the second row equations. Equation 1 in the third row illustrates a general preparation of
  21. 21. Organic Chemistry II arranged by Putri Nur Aulia 21 substituted furans, pyrroles and thiophenes from 1,4-dicarbonyl compounds, known as the Paal-Knorr synthesis. Many other procedures leading to substituted heterocycles of this kind have been devised. Two of these are shown in reactions 2 and 3. Furan is reduced to tetrahydrofuran by palladium-catalyzed hydrogenation. This cyclic ether is not only a valuable solvent, but it is readily converted to 1,4-dihalobutanes or 4- haloalkylsulfonates, which may be used to prepare pyrrolidine and thiolane. Dipolar cycloaddition reactions often lead to more complex five- membered heterocycles. Indole is probably the most important fused ring heterocycle in this class. The first proceeds by an electrophilic substitution of a nitrogen- activated benzene ring. The second presumably takes place by formation of a dianionic species in which the ArCH2(–) unit bonds to the deactivated carbonyl group. Finally, the Fischer indole synthesis is a remarkable sequence of tautomerism, sigmatropic rearrangement, nucleophilic addition, and elimination reactions occurring subsequent to phenylhydrazone formation. This interesting transformation involves the oxidation of two carbon atoms and the reduction of one carbon and both nitrogen atoms.
  22. 22. Organic Chemistry II arranged by Putri Nur Aulia 22 Reactions The chemical reactivity of the saturated members of this class of heterocycles: tetrahydrofuran, thiolane and pyrrolidine, resemble that of acyclic ethers, sulfides, and 2º-amines, and will not be described here. 1,3- Dioxolanes and dithiolanes are cyclic acetals and thioacetals. These units are commonly used as protective groups for aldehydes and ketones, and may be hydrolyzed by the action of aqueous acid. It is the "aromatic" unsaturated compounds, furan, thiophene and pyrrole that require our attention. In each case the heteroatom has at least one pair of non-bonding electrons that may combine with the four π-electrons of the double bonds to produce an annulene having an aromatic sextet of electrons. This is illustrated by the resonance description at the top of the following diagram. The heteroatom Y becomes sp2 -hybridized and acquires a positive charge as its electron pair is delocalized around the ring. An easily observed consequence of this delocalization is a change in dipole moment compared with the analogous saturated heterocycles, which all have strong dipoles with the heteroatom at the negative end. As expected, the aromatic heterocycles have much smaller dipole moments, or in the case of pyrrole a large dipole in the opposite direction. An important characteristic of aromaticity is enhanced thermodynamic stability, and this is usually demonstrated by relative heats of hydrogenation or heats of combustion measurements. By this standard, the three aromatic heterocycles under examination are stabilized, but to a lesser degree than benzene. Additional evidence for the aromatic character of pyrrole is found in its exceptionally weak basicity (pKa ca. 0) and strong acidity (pKa = 15) for a 2º-amine. The corresponding values for the saturated amine pyrrolidine are: basicity 11.2 and acidity 32.
  23. 23. Organic Chemistry II arranged by Putri Nur Aulia 23 Another characteristic of aromatic systems, of particular importance to chemists, is their pattern of reactivity with electrophilic reagents. Whereas simple cycloalkenes generally give addition reactions, aromatic compounds tend to react by substitution. As noted for benzene and its derivatives, these substitutions take place by an initial electrophile addition, followed by a proton loss from the "onium" intermediate to regenerate the aromatic ring. The aromatic five-membered heterocycles all undergo electrophilic substitution, with a general reactivity order: pyrrole >> furan > thiophene > benzene. Some examples are given in the following diagram. The reaction conditions show clearly the greater reactivity of furan compared with thiophene. All these aromatic heterocycles react vigorously with chlorine and bromine, often forming polyhalogenated products together with polymers. The exceptional reactivity of pyrrole is evidenced by its reaction with iodine (bottom left equation), and formation of 2-acetylpyrrole by simply warming it with acetic anhydride (no catalyst).
  24. 24. Organic Chemistry II arranged by Putri Nur Aulia 24 There is a clear preference for substitution at the 2-position (α) of the ring, especially for furan and thiophene. Reactions of pyrrole require careful evaluation, since N-protonation destroys its aromatic character. Indeed, N-substitution of this 2º-amine is often carried out prior to subsequent reactions. For example, pyrrole reacts with acetic anhydride or acetyl chloride and triethyl amine to give N-acetylpyrrole. Consequently, the regioselectivity of pyrrole substitution is variable, as noted by the bottom right equation. An explanation for the general α-selectivity of these substitution reactions is apparent from the mechanism outlined below. The intermediate formed by electrophile attack at C-2 is stabilized by charge delocalization to a greater degree than the intermediate from C-3 attack. From the Hammond postulatewe may then infer that the activation energy for substitution at the former position is less than the latter substitution. Functional substituents influence the substitution reactions of these heterocycles in much the same fashion as they do for benzene. Indeed, once one understands the ortho-para and meta-directing character of these substituents, their directing influence on heterocyclic ring substitution is not difficult to predict. The following diagram shows seven such reactions. Reactions 1 & 2 are 3-substituted thiophenes, the first by an electron donating substituent and the second by an electron withdrawing group. The third reaction has two substituents of different types in the 2 and 5- positions. Finally, examples 4 through 7 illustrate reactions of 1,2- and 1,3-oxazole, thiazole and diazole. Note that the basicity of the sp2 - hybridized nitrogen in the diazoles is over a million times greater than that
  25. 25. Organic Chemistry II arranged by Putri Nur Aulia 25 of the apparent sp3 -hybridized nitrogen, the electron pair of which is part of the aromatic electron sextet. Other possible reactions are suggested by the structural features of these heterocycles. For example, furan could be considered an enol ether and pyrrole an enamine. Such functions are known to undergo acid- catalyzed hydrolysis to carbonyl compounds and alcohols or amines. Since these compounds are also heteroatom substituted dienes, we might anticipate Diels-Alder cycloaddition reactions with appropriate dienophiles. As noted in the upper example, furans may indeed be hydrolyzed to 1,4-dicarbonyl compounds, but pyrroles and thiophenes behave differently. The second two examples, shown in the middle, demonstrate typical reactions of furan and pyrrole with the strong dienophile maleic anhydride. The former participates in a cycloaddition reaction; however, the pyrrole simply undergoes electrophilic substitution at C-2. Thiophene does not easily react with this dienophile. The bottom line of the new diagram illustrates the remarkable influence that additional nitrogen units have on the hydrolysis of a series of N- acetylazoles in water at 25 ºC and pH=7. The pyrrole compound on the left is essentially unreactive, as expected for an amide, but additional nitrogens markedly increase the rate of hydrolysis. This effect has been put to practical use in applications of the acylation reagent 1,1'- carbonyldiimidazole (Staab's reagent).
  26. 26. Organic Chemistry II arranged by Putri Nur Aulia 26 Another facet of heterocyclic chemistry was disclosed in the course of investigations concerning the action of thiamine (following diagram). As its pyrophosphate derivative, thiamine is a coenzyme for several biochemical reactions, notably decarboxylations of pyruvic acid to acetaldehyde and acetoin. Early workers speculated that an "active aldehyde" or acyl carbanion species was an intermediate in these reactions. Many proposals were made, some involving the aminopyrimidine moiety, and others, ring-opened hydrolysis derivatives of the thiazole ring, but none were satisfactory. This puzzle was solved when R. Breslow (Columbia) found that the C-2 hydrogen of thiazolium salts was unexpectedly acidic (pKa ca. 13), forming a relatively stable ylide conjugate base. As shown, this rationalizes the facile decarboxylation of thiazolium-2-carboxylic acids and deuterium exchange at C-2 in neutral heavy water. Appropriate thiazolium salts catalyze the conversion of aldehydes to acyloins in much the same way that cyanide ion catalyzes the formation of benzoin from benzaldehyde, the benzoin condensation. Note that in both cases an acyl anion equivalent is formed and then adds to a carbonyl function in the expected manner. The benzoin condensation is limited to aromatic aldehydes, but the use of thiazolium catalysts has proven broadly effective for aliphatic and aromatic aldehydes. This approach to acyloins employs milder conditions than the reduction of esters to enediol intermediates by the action of metallic sodium .
  27. 27. Organic Chemistry II arranged by Putri Nur Aulia 27 The most important condensed ring system related to these heterocycles is indole. Some electrophilic substitution reactions of indole are shown in the following diagram. Whether the indole nitrogen is substituted or not, the favored site of attack is C-3 of the heterocyclic ring. Bonding of the electrophile at that position permits stabilization of the onium-intermediate by the nitrogen without disruption of the benzene aromaticity. 2.3.4 Six-Membered Rings Properties The chemical reactivity of the saturated members of this class of heterocycles: tetrahydropyran, thiane and piperidine, resemble that of acyclic ethers, sulfides, and 2º-amines, and will not be described here. 1,3- Dioxanes and dithianes are cyclic acetals and thioacetals. These units are
  28. 28. Organic Chemistry II arranged by Putri Nur Aulia 28 commonly used as protective groups for aldehydes and ketones, as well as synthetic intermediates, and may be hydrolyzed by the action of aqueous acid. The reactivity of partially unsaturated compounds depends on the relationship of the double bond and the heteroatom (e.g. 3,4-dihydro-2H- pyran is an enol ether). Fully unsaturated six-membered nitrogen heterocycles, such as pyridine, pyrazine, pyrimidine and pyridazine, have stable aromatic rings. Oxygen and sulfur analogs are necessarily positively charged, as in the case of 2,4,6-triphenylpyrylium tetrafluoroborate. From heat of combustion measurements, the aromatic stabilization energy of pyridine is 21 kcal/mole. The resonance description drawn at the top of the following diagram includes charge separated structures not normally considered for benzene. The greater electronegativity of nitrogen (relative to carbon) suggests that such canonical forms may contribute to a significant degree. Indeed, the larger dipole moment of pyridine compared with piperidine supports this view. Pyridine and its derivatives are weak bases, reflecting the sp2 hybridization of the nitrogen. From the polar canonical forms shown here, it should be apparent that electron donating substituents will increase the basicity of a pyridine, and that substituents on the 2 and 4-positions will influence this basicity more than an equivalent 3-substituent. The pKa values given in the table illustrate a few of these substituent effects. Methyl substituted derivatives have the common names picoline (methyl pyridines), lutidine (dimethyl pyridines) and collidine (trimethyl pyridines). The influence of 2-substituents is complex, consisting of steric hindrance and electrostatic components. 4- Dimethylaminopyridine is a useful catalyst for acylation reactions carried out in pyridine as a solvent. At first glance, the sp3 hybridized nitrogen might appear to be the stronger base, but it should be remembered that
  29. 29. Organic Chemistry II arranged by Putri Nur Aulia 29 N,N-dimethylaniline has a pKa slightly lower than that of pyridine itself. Consequently, the sp2 ring nitrogen is the site at which protonation occurs. The diazines pyrazine, pyrimidine and pyridazine are all weaker bases than pyridine due to the inductive effect of the second nitrogen. However, the order of base strength is unexpected. A consideration of the polar contributors helps to explain the difference between pyrazine and pyrimidine, but the basicity of pyridazine seems anomalous. It has been suggested that electron pair repulsion involving the vicinal nitrogens destabilizes the neutral base relative to its conjugate acid. 2.4 Electrophilic Substitution of Pyridine Pyridine is a modest base (pKa=5.2). Since the basic unshared electron pair is not part of the aromatic sextet, as in pyrrole, pyridinium species produced by N- substitution retain the aromaticity of pyridine. As shown below, N-alkylation and N-acylation products may be prepared as stable crystalline solids in the absence of water or other reactive nucleophiles. The N-acyl salts may serve as acyl transfer agents for the preparation of esters and amides. Because of the stability of the pyridinium cation, it has been used as a moderating component in complexes with a number of reactive inorganic compounds. Several examples of these stable and easily handled reagents are shown at the bottom of the diagram. The poly(hydrogen fluoride) salt is a convenient source of HF for addition to alkenes and conversion of alcohols to alkyl fluorides, pyridinium chlorochromate (PCC) and its related dichromate analog are versatile oxidation agents and the
  30. 30. Organic Chemistry II arranged by Putri Nur Aulia 30 tribromide salt is a convenient source of bromine. Similarly, the reactive compounds sulfur trioxide and diborane are conveniently and safely handled as pyridine complexes. Amine oxide derivatives of 3º-amines and pyridine are readily prepared by oxidation with peracids or peroxides, as shown by the upper right equation. Reduction back to the amine can usually be achieved by treatment with zinc (or other reactive metals) in dilute acid. From the previous resonance description of pyridine, we expect this aromatic amine to undergo electrophilic substitution reactions far less easily than does benzene. Three examples of the extreme conditions required for electrophilic substitution are shown on the left. Substituents that block electrophile coordination with nitrogen or reduce the basicity of the nitrogen facilitate substitution, as demonstrated by the examples in the blue-shaded box at the lower right, but substitution at C-3 remains dominant. Activating substituents at other locations also influence the ease and regioselectivity of substitution. The amine substituent in the upper case directs the substitution to C-2, but the weaker electron donating methyl substituent in the middle example cannot overcome the tendency for 3-substitution. Hydroxyl substituents at C-2 and C-4 tautomerize to pyridones, as shown for the 2-isomer at the bottom left. Pyridine N-oxide undergoes some electrophilic substitutions at C-4 and others at C-3. The coordinate covalent N–O bond may exert a push-pull influence, as illustrated by the two examples on the right. Although the positively charged nitrogen alone would have a strong deactivating influence, the negatively charged
  31. 31. Organic Chemistry II arranged by Putri Nur Aulia 31 oxygen can introduce electron density at C-2, C-4 & C-6 by π-bonding to the ring nitrogen. This is a controlling factor in the relatively facile nitration at C-4. However, if the oxygen is bonded to an electrophile such as SO3, the resulting pyridinium ion will react sluggishly and preferentially at C-3. The fused ring heterocycles quinoline and isoquinoline provide additional evidence for the stability of the pyridine ring. Vigorous permanganate oxidation of quinoline results in predominant attack on the benzene ring; isoquinoline yields products from cleavage of both rings. Note that naphthalene is oxidized to phthalic acid in a similar manner. By contrast, the heterocyclic ring in both compounds undergoes preferential catalytic hydrogenation to yield tetrahydroproducts. Electrophilic nitration, halogenation and sulfonation generally take place at C-5 and C-8 of the benzene ring, in agreement with the preceding description of similar pyridine reactions and the kinetically favored substitution of naphthalene at C-1 (α) rather than C-2 (β). 2.5 Other Reactions of Pyridine Thanks to the nitrogen in the ring, pyridine compounds undergo nucleophilic substitution reactions more easily than equivalent benzene derivatives. In the following diagram, reaction 1 illustrates displacement of a 2- chloro substituent by ethoxide anion. The addition-elimination mechanism shown for this reaction is helped by nitrogen's ability to support a negative charge. A similar intermediate may be written for substitution of a 4-halopyridine, but substitution at the 3-position is prohibited by the the failure to create an intermediate of this kind. The two Chichibabin aminations in reactions 2 and 3 are
  32. 32. Organic Chemistry II arranged by Putri Nur Aulia 32 remarkable in that the leaving anion is hydride (or an equivalent). Hydrogen is often evolved in the course of these reactions. In accord with this mechanism, quinoline is aminated at both C-2 and C-4. Addition of strong nucleophiles to N-oxide derivatives of pyridine proceed more rapidly than to pyridine itself, as demonstrated by reactions 4 and 5. The dihydro-pyridine intermediate easily loses water or its equivalent by elimination of the –OM substituent on nitrogen. Because the pyridine ring (and to a greater degree the N-oxide ring) can support a negative charge, alkyl substituents in the 2- and 4-locations are activated in the same fashion as by a carbonyl group. Reactions 6 and 7 show alkylation and condensation reactions resulting from this activation. Reaction 8 is an example of N-alkylpyridone formation by hydroxide addition to an N-alkyl pyridinium cation, followed by mild oxidation. Birch reduction converts pyridines to dihydropyridines that are bis-enamines and may be hydrolyzed to 1,5-dicarbonyl compounds. Pyridinium salts undergo a one electron transfer to generate remarkably stable free radicals. The example shown in reaction 9 is a stable (in the absence of oxygen), distillable green liquid. Although 3-halopyridines do not undergo addition-elimination substitution reactions as do their 2- and 4-isomers, the strong base sodium amide effects amination by way of a pyridyne intermediate. This is illustrated by reaction 10. It is interesting that 3-pyridyne is formed in preference to 2-pyridyne. The latter is formed if C-4 is occupied by an alkyl substituent. The pyridyne intermediate is similar to benzyne.
  33. 33. Organic Chemistry II arranged by Putri Nur Aulia 33 2.6 Some Polycyclic Heterocycles Heterocyclic structures are found in many natural products. Examples of some nitrogen compounds, known as alkaloids because of their basic properties, were given in the amine chapter. Some other examples are displayed in the following diagram. Camptothecin is a quinoline alkaloid which inhibits the DNA enzyme topoisomerase I. Reserpine is an indole alkaloid, which has been used for the control of high blood pressure and the treatment of psychotic behavior. Ajmaline and strychnine are also indole alkaloids, the former being an antiarrhythmic agent and latter an extremely toxic pesticide. The neurotoxins saxitoxin and tetrodotoxin both have marine origins and are characterized by guanidiniun moieties. Aflatoxin B1 is a non-nitrogenous carcinogenic compound produced by the Aspergillus fungus. Porphyrin is an important cyclic tertrapyrrole that is the core structure of heme and chlorophyll. Derivatives of the simple fused ring heterocycle purine constitute an especially important and abundant family of natural products. The amino compounds adenine and guanine are two of the complementary bases that
  34. 34. Organic Chemistry II arranged by Putri Nur Aulia 34 are essential components of DNA. Structures for these compounds are shown in the following diagram. Xanthine and uric acid are products of the metabolic oxidation of purines. Uric acid is normally excreted in the urine; an excess serum accumulation of uric acid may lead to an arthritic condition known as gout. Caffeine, the best known of these, is a bitter, crystalline alkaloid. It is found in varying quantities, along with additional alkaloids such as the cardiac stimulants theophylline and theobromine in the beans, leaves, and fruit of certain plants. Drinks containing caffeine, such as coffee, tea and some soft drinks are arguably the world's most widely consumed beverages. Caffeine is a central nervous system stimulant, serving to ward off drowsiness and restore alertness. Paraxantheine is the chief metabolite of caffeine in the body. Sulfur heterocycles are found in nature, but to a lesser degree than their nitrogen and oxygen analogs. Two members of the B-vitamin complex, biotin and thiamine, incorporate such heterocyclic moieties. These are shown together with other heterocyclic B-vitamins in the following diagram.
  35. 35. Organic Chemistry II arranged by Putri Nur Aulia 35 Terthienyl is an interesting thiophene trimer found in the roots of marigolds, where it provides nemicidal activity. Studies have shown that UV irradiation of terthienyl produces a general phototoxicity for many organisms. Polymers incorporating thiophene units and fused systems such as dithienothiophene have interesting electromagnetic properties, and show promise as organic metal-like conductors and photovoltaic materials. The charge transfer complex formed by tetrathiofulvalene and tetracyanoquinodimethane has one of the highest electrical conductivities reported for an organic solid.
  36. 36. Organic Chemistry II arranged by Putri Nur Aulia 36 ORGANIC CHEMISTRY II CHAPTER III CARBOHYDRATES
  37. 37. Organic Chemistry II arranged by Putri Nur Aulia 37 CHAPTER III CARBOHYDRATES 3.1 Introduction Carbohydrates, along with lipids, proteins, nucleic acids, and other compounds are known as biomolecules because they are closely associated with living organisms. Carbohydrates are compounds of tremendous biological importance: – they provide energy through oxidation – they supply carbon for the synthesis of cell components – they serve as a form of stored chemical energy – they form part of the structures of some cells and tissues Carbohydrates, or saccharides (saccharo is Greek for ―sugar) are polyhydroxy aldehydes or ketones, or substances that yield such compounds on hydrolysis. Carbohydrates include not only sugar, but also the starches that we find in foods, such as bread, pasta, and rice. The term carbohydrates comes from the observation that when you heat sugars, you get carbon and water (hence, hydrate of carbon).
  38. 38. Organic Chemistry II arranged by Putri Nur Aulia 38 3.2 Classes of carbohydrates  Monosaccharides contain a single polyhydroxy aldehyde or ketone unit (e.g., glucose, fructose).  Disaccharides consist of two monosaccharide units linked together by a covalent bond (e.g., sucrose).  Oligosaccharides contain from 3 to 10 monosaccharide units (e.g., raffinose).  Polysaccharides contain very long chains of hundreds or thousands of monosaccharide units, which may be either in straight or branched chains (e.g., cellulose, glycogen, starch). 3.3 The stereochemistry of carbohydrates Glyceraldehyde, the simplest carbohydrate, exists in two isomeric forms that are mirror images of each other:
  39. 39. Organic Chemistry II arranged by Putri Nur Aulia 39 3.3.1 Streoisemers  These forms are stereoisomers of each other.  Glyceraldehyde is a chiral molecule — it cannot be superimposed on its mirror image. The two mirror-image forms of glyceraldehyde are enantiomers of each other. 3.3.2 Chirality and handedness Chiral molecules have the same relationship to each other that your left and right hands have when reflected in a mirror. A. Chiral Carbon Chiral objects cannot be superimposed on their mirror images — e.g., hands, gloves, and shoes. Achiral objects can be superimposed on the mirror images — e.g., drinking glasses, spheres, and cubes. Any carbon atom which is connected to four different groups will be chiral, and will
  40. 40. Organic Chemistry II arranged by Putri Nur Aulia 40 have two nonsuperimposable mirror images; it is a chiral carbon or a center of chirality. – If any of the two groups on the carbon are the same, the carbon atom cannot be chiral. Many organic compounds, including carbohydrates, contain more than one chiral carbon. Examples : Chiral Carbon Atoms Identify the chiral carbon atoms (if any) in each of the following molecules: B. 2n Rule When a molecule has more than one chiral carbon, each carbon can possibly be arranged in either the right-hand or left-hand form, thus if there are n chiral carbons, there are 2n possible stereoisomers. Maximum number of possible stereoisomers = 2n
  41. 41. Organic Chemistry II arranged by Putri Nur Aulia 41 Examples : Number of Streoisomers What is the maximum number of possible stereo-isomers of the following compounds? C. Fischer Projections  Fischer projections are a convenient way to represent mirror images in two dimensions.  Place the carbonyl group at or near the top and the last achiral CH2OH at the bottom.
  42. 42. Organic Chemistry II arranged by Putri Nur Aulia 42 3.4 Naming Streoisomers When there is more than one chiral center in a carbohydrate, look at the chiral carbon farthest from the carbonyl group: if the hydroxy group points to right when the carbonyl is ―up‖ it is the D-isomer,and when the hydroxy group points to the left, it is the L-isomer. 3.4.1. Optical Activity A levorotatory (–) substance rotates polarized light to the left [e.g., l-glucose; (-)-glucose]. A dextrorotatory (+) substance rotates polarized light to the right [e.g., d-glucose; (+)-glucose]. Molecules which rotate the plane of polarized light are optically active. Many biologically important molecules are chiral and optically active. Often, living systems contain only one of the possible stereochemical forms of acompound, or they are found in separate systems. – D-lactic acid is found in living muscles; D-lactic acid is present in sour milk. – In some cases, one form of a molecule is beneficial, and the enantiomer is a poison (e.g., thalidomide). – Humans can metabolize D-monosaccharides but not L-isomers; only L-amino acids are used in protein synthesis 3.5 Monosaccharides 3.5.1 Classification of Monosaccharides  The monosaccharides are the simplest of the carbohydrates, since they contain only one polyhydroxy aldehyde or ketone unit.
  43. 43. Organic Chemistry II arranged by Putri Nur Aulia 43  Monosaccharides are classified according to the number of carbon atoms they contain: No. Of Carbon Class Of monosaccharides 3 4 5 6 triose tetrose pentose hexose  The presence of an aldehyde is indicated by the prefix aldo- and a ketone by the prefix keto-.  Thus, glucose is an aldohexose (aldehyde + 6 Cs) and ribulose is a ketopentose (ketone + 5 Cs)
  44. 44. Organic Chemistry II arranged by Putri Nur Aulia 44 3.5.2 The Family of D-aldoses
  45. 45. Organic Chemistry II arranged by Putri Nur Aulia 45 3.5.3 The family of D-ketoses 3.5.4 Phisical properties of Monosaccharides  Most monosaccharides have a sweet taste (fructose is sweetest; 73% sweeter than sucrose).  They are solids at room temperature.  They are extremely soluble in water: – Despite their high molecular weights, the presence of large numbers of OH groups make the monosaccharides much more water soluble than most molecules of similar MW. – Glucose can dissolve in minute amounts of water to make a syrup (1 g / 1 ml H2O).
  46. 46. Organic Chemistry II arranged by Putri Nur Aulia 46 Table The Relative sweetness of sugars (sucrose =1.00) Sugar Relative swetness type Lactose 0.16 Disaccharides Galactose 0.22 Monosaccharides Maltose 0.32 Disaccharides Xylose 0.40 Monosaccharides Glucose 0.74 Monosaccharides Sucrose 1.00 Disaccharides Invert Sugar 1.30 Mixture of glucose and fructose Fructose 1.73 monosaccharides 3.5.5 Chemical Properties of Monosaccharides Monosaccharides do not usually exist in solution in their ―open-chain‖ forms: an alcohol group can add into the carbonyl group in the same molecule to form a pyranose ring containing a stable cyclic hemiacetal or hemiketal.
  47. 47. Organic Chemistry II arranged by Putri Nur Aulia 47 A.Glucose Anomers In the pyranose form of glucose, carbon-1 is chiral, and thus two stereoisomers are possible: one in which the OH group points down ( α- hydroxy group) and one in which the OH group points up ( β-hydroxy group). These forms are anomers of each other, and carbon-1 is called the anomeric carbon. B. Fructose Anomers Fructose closes on itself to form a furanose ring:
  48. 48. Organic Chemistry II arranged by Putri Nur Aulia 48 3.5.6 Oxidation of Monosaccharides  Aldehydes and ketones that have an OH group on the carbon next to the carbonyl group react with a basic solution of Cu2+ (Benedict’s reagent) to form a red-orange precipitate of copper(I) oxide (Cu2O).  Sugars that undergo this reaction are called reducing sugars. (All of the monosaccharides are reducing sugars.) 3.5.7 Formation of phosphate Ester  Phosphate esters can form at the 6-carbon of aldohexoses and aldoketoses.  Phosphate esters of monosaccharides are found in the sugar- phosphate backbone of DNA and RNA, in ATP, and as intermediates in the metabolism of carbohydrates in the body. 3.5.8 Glycoside Formation The hemiacetal and hemiketal forms of monosaccharides can react with alcohols to form acetal and ketal structures called glycosides. The new carbon-oxygen bond is called the glycosidic linkage. Once the glycoside is formed, the ring can no longer open up to the open-chain form. Glycosides,therefore, are not reducing sugars.
  49. 49. Organic Chemistry II arranged by Putri Nur Aulia 49 3.5.9 Important Monosaccharides 3.6 Disaccharides and Oligosaccharides Two monosaccharides can be linked together through a glycosidic linkage to form a disaccharide
  50. 50. Organic Chemistry II arranged by Putri Nur Aulia 50 3.6.1 Dissacharides  Disaccharides can be hydrolyzed into their mono-saccharide building blocks by boiling them with dilute acids or reacting them with the appropriate enzymes.  Disaccharides that contain hemiacetal groups are reducing sugars. 3.6.2 Important Disaccharides
  51. 51. Organic Chemistry II arranged by Putri Nur Aulia 51 3.6.3 Oligosaccharides Oligosaccharides contain from 3 to 10 monosaccharide units. 3.7 Polysaccharides  Polysaccharides contain hundreds or thousands of carbohydrate units.  Polysaccharides are not reducing sugars, since the anomeric carbons are connected through glycosidic linkages.  We will consider three kinds of polysaccharides, all of which are polymers of glucose: starch, glycogen, and cellulose.
  52. 52. Organic Chemistry II arranged by Putri Nur Aulia 52 3.7.1 Starch Starch is a polymer consisting of D-glucose units. Starches (and other glucose polymers) are usually insoluble in water because of the high molecular weight. Because they contain large numbers of OH groups, some starches can form thick colloidal dispersions when heated in water (e.g., flour or starch used as a thickening agent in gravies or sauces). There are two forms of starch: amylose and amylopectin. A. Starch-Amylose Amylose consists of long, unbranched chains of glucose (from 1000 to 2000 molecules) connected by (1 4) glycosidic linkages. 10%-20% of the starch in plants is in this form. The amylose chain is flexible enough to allow the molecules to twist into the shape of a helix. Because it packs more tightly, it is slower to digest than other starches. Amylose helices can trap molecules of iodine, forming a characteristic deep blue-purple color. (Iodine is often used as a test for the presence of starch.) B. Starch – Amylopectin Amylopectin consists of long chains of glucose (up to 105 molecules) connected by (1 4) glycosidic linkages, with (1 6) branches every 24 to 30 glucose units along the chain. 80%-90% of the starch in plants is in this form.
  53. 53. Organic Chemistry II arranged by Putri Nur Aulia 53 3.7.2 Glycogen Glycogen, also known as animal starch, is structurally similar to amylopectin, containing both (1 4) glycosidic linkages and (1 6) branch points. Glycogen is even more highly branched,with branches occurring every 8 to 12 glucose units. Glycogen is abundant in the liver and muscles; on hydrolysis it forms D-glucose, which maintains normal blood sugar level and provides energy. 3.7.3 Cellulose Cellulose is a polymer consisting of long, unbranched chains of D- glucose connected by (1 4) glycosidic linkages; it may contain from 300 to 3000 glucose units in one molecule.
  54. 54. Organic Chemistry II arranged by Putri Nur Aulia 54 Because of the -linkages, cellulose has a different overall shape from amylose, forming extended straight chains which hydrogen bond to each other, resulting in a very rigid structure. Cellulose is the most important structural polysaccharide, and is the single most abundant organic compound on earth. It is the material in plant cell walls that provides strength and rigidity; wood is 50% cellulose. Most animals lack the enzymes needed to digest cellulose, but it does provide roughage (dietary fiber) to stimulate contraction of the intestines and help pass food through the digestive system. Some animals, such as cows, sheep, and horses (ruminants), can process cellulose through the use of colonies of bacteria in the digestive system which are capable of breaking cellulose down to glucose; ruminants use a series of stomachs to allow cellulose a longer time to digest. Some other animals such as rabbits reprocess digested food to allow more time for the breakdown of cellulose to occur. Cellulose is also important industrially, from its presence in wood, paper, cotton, cellophane, rayon, linen, nitrocellulose (guncotton), photographic films. 3.7.4 Nitrocellulose, Celluloid and Rayon Guncotton (German, schiessbaumwolle) is cotton which has been treated with a mixture of nitric and sulfuric acids. It was discovered by
  55. 55. Organic Chemistry II arranged by Putri Nur Aulia 55 Christian Friedrich Schönbein in 1845, when he used his wife‘s cotton apron to wipe up a mixture of nitric and sulfuric acids in his kitchen, which vanished in a flash of flame when it dried out over a fire. Schönbein attempted to market it as a smokeless powder, but it combusted so readily it was dangerous to handle. Eventually its use was replaced by cordite (James Dewar and Frederick Abel, 1891), a mixture of nitrocellulose, nitroglycerine, and petroleum jelly, which could be extruded into cords. Celluloid (John Hyatt, 1869) was the first synthetic plastic, made by combining partially nitrated cellulose with alcohol and ether and adding camphor to make it softer and more malleable. It was used in manufacturing synthetic billiard balls (as a replacement for ivory), photographic film, etc.; it was eventually replaced by less flammable plastics. Rayon (Louis Marie Chardonnet, 1884) consists of partially nitrated cellulose mixed with solvents and extruded through small holes, allowing the solvent to evaporate; rayon was a sensation when introduced since it was a good substitute for silk, but it was still highly flammable. 3.7.5 Dietary Fiber Dietary fiber consists of complex carbohydrates, such as cellulose, and other substances that make up the cell walls and structural parts of plants. Good sources of dietary fiber include cereal grans, oatmeal, fresh fruits and vegetables, and grain products. Soluble fiber, such as pectin, has a lower molecular weight, and is more water soluble. Soluble fiber traps carbohydrates and slows their digestion and absorption, thereby leveling out blood sugar levels during the day. Soluble fiber also helps to lower cholesterol levels by binding dietary cholesterol. Insoluble fiber, such as cellulose, provides bulk to the stool, which helps the body to eliminate solid wastes. 3.7.6 Chitin Chitin is a polymer of N-acetylglucosamine, an amide derivative
  56. 56. Organic Chemistry II arranged by Putri Nur Aulia 56 of the amino sugar glucosamine, in which one of the OH groups is converted to an amine (NH2) group. The polymer is extremely strong because of the increased hydrogen bonding provided by the amide groups. Chitin is the main component of the cell walls of fungi, the exoskeletons of arthropods such as crustaceans and insects, and the beaks of cephalopods. The chitin is often embedded in eithera protein matrix, or in calcium carbonate crystals. Since this matrix cannot expand easily, it must be shed by molting as the animal grows.
  57. 57. Organic Chemistry II arranged by Putri Nur Aulia 57 ORGANIC CHEMISTRY II CHAPTER IV AMINO ACIDS, PEPTIDES, AND PROTEINS
  58. 58. Organic Chemistry II arranged by Putri Nur Aulia 58 CHAPTER IV AMINO ACIDS, PEPTIDES, AND PROTEINS 4.1 Introduction Amino acids are molecules containing an amine group (-NH2) and a carboxylic acid group (-COOH). Naturally occurring amino acids have the following general formula: The amino acids are joined by amide linkages called peptide bonds. Chains with fewer than 50 units are called peptides and the large chains that have structural or catalytic functions in biology are called proteins. Here the example of a general protein and its constituent amino acids: 4.2 The Structures and Stereochemistry of -Amino Acids The term amino acid might mean any molecule containing both an amino group and any type of acid group; however, the term is almost always used to refer to an -amino carboxylic acid. The simplest -amino acid is aminoacetic acid, called glycine. Other common amino acids have side chains (symbolized by R) substituted on the carbon atom. For example, alanine is the amino acid with a methyl side chain.
  59. 59. Organic Chemistry II arranged by Putri Nur Aulia 59 Except for glycine, the -amino acids are all chiral. In all of the chiral amino acids, the chirality center is the asymmetric  carbon atom. Nearly all the naturally occurring amino acids are found to have the (S) configuration at the  carbon atom. The following pictures shows a Fischer projection of the (S) enantiomer of alanine, with the carbon chain along the vertical and the carbonyl carbon at the top. Notice that the configuration of (S)-alanine is similar to that of L-1-2-glyceraldehyde, with the amino group on the left in the Fischer projection. Because their stereochemistry is similar to that of L- -glyceraldehyde, the naturally occurring (S)-amino acids are classified as L-amino acids. Although D- amino acids are occasionally found in nature, we usually assume the amino acids under discussion are the common L-amino acids. Remember once again that the D and L nomenclature, like the R and S designation, gives the configuration of the asymmetric carbon atom. It does not imply the sign of the optical rotation, or which must be determined experimentally. 4.2.1 Standard Amino Acids of Proteins The standard amino acids are 20 common amino acids that are found in nearly all proteins. The standard amino acids differ from each other in the structure of the side chains bonded to their 
  60. 60. Organic Chemistry II arranged by Putri Nur Aulia 60 carbon atoms. For additional, all the standard amino acids are L- amino acids.
  61. 61. Organic Chemistry II arranged by Putri Nur Aulia 61 4.2.2 Essential Amino Acids Humans can synthesize about half of the amino acids needed to make proteins. Other amino acids, called the essential amino acids, must be provided in the diet. The ten essential amino acids are the following: arginine (Arg) valine (Val) methionine (Met) leucine (Leu) threonine (Thr) phenylalanine (Phe) histidine (His) isoleucine (Ile) tryptophan (Trp) lysine (Lys)
  62. 62. Organic Chemistry II arranged by Putri Nur Aulia 62 4.3 Acid-Base Properties of Amino Acids Carboxylic acids have acidic properties and react with bases but amines have basic properties and react with acids. It‘s the reason why amino acids have both acidic and basic properties. Amino acids react with strong bases such as sodium hydroxide: N H H C O C H R N H H C O OH C H R + NaOH O Na- + + H2O In high pH, therefore, amino acids exist in anionic form: -O N H H C O C H R Amino acids react with strong acids such as hydrochloric acid: OH N H H C O OH C H R + HCl N H H C O C H R H+Cl - In low pH, therefore, amino acids exist in cationic form: OH N H H C O C H R H+ Since amino acids have a proton donating group and a proton accepting group on the same molecule, it follows that each molecule can undergo an acid- base reaction with itself: N H H C O OH C H R N H H C O C H R O - H+
  63. 63. Organic Chemistry II arranged by Putri Nur Aulia 63 The double ion that is formed as a result of this reaction is called a Zwitterion. This reaction happens in the solid state. In the solid state, therefore, amino acids are ionic. This explains why they are solids with a high melting point. 4.4 Isoelectric Points and Electrophoresis An amino acid bears a positive charge in acidic solution (low pH) and a negative charge in basic solution (high pH). There must be an intermediate pH where the amino acid is evenly balanced between the two forms, as the dipolar zwitterion with a net charge of zero. This pH is called the isoelectric pH or the isoelectric point. This following table show the isoelectric points of standard amino acids. No Standard Amino Acid Isoelectric Points 1 glycine 6.0 2 alanine 6.0 3 valine 6.0 4 leucine 6.0 5 isoleucine 6.0 6 phenylalanine 5.5 7 proline 6.3 8 serine 5.7 9 threonine 5.6 10 tyrosine 5.7 11 cysteine 5.0 12 methionine 5.7 13 asparagine 5.4
  64. 64. Organic Chemistry II arranged by Putri Nur Aulia 64 14 glutamine 5.7 15 tyroptophan 5.9 16 aspartic acid 2.8 17 glutamic acid 3.2 18 lysine 9.7 19 arginine 10.8 20 histidine 7.6 Electrophoresis uses differences in isoelectric points to separate mixtures of amino acids. A streak of the amino acid mixture is placed in the center of a layer of acrylamide gel or a piece of filter paper wet with a buffer solution. Two electrodes are placed in contact with the edges of the gel or paper, and a potential of several thousand volts is applied across the electrodes. Positively charged (cationic) amino acids are attracted to the negative electrode (the cathode), and negatively charged (anionic) amino acids are attracted to the positive electrode (the anode). An amino acid at its isoelectric point has no net charge, so it does not move.
  65. 65. Organic Chemistry II arranged by Putri Nur Aulia 65 4.5 Synthesis of Amino Acids 4.5.1 Reductive Amination When an -ketoacid is treated with ammonia, the ketone reacts to form an imine. The imine is reduced to an amine by hydrogen and a palladium catalyst. Under these conditions, the carboxylic acid is not reduced. 4.5.2 Amination of -Halo Acid The reactions are: Bromination of a carboxylic acid by treatment with Br2 and PBr3 then use NH3 or phthalimide to displace Br 4.5.3 The Gabriel–Malonic Ester Synthesis One of the best methods of amino acid synthesis is a combination of the Gabriel synthesis of amines with the malonic ester synthesis of carboxylic acids. The conventional malonic ester synthesis involves alkylation of diethyl malonate, followed by hydrolysis and decarboxylation to give an alkylated acetic acid.
  66. 66. Organic Chemistry II arranged by Putri Nur Aulia 66 4.5.4 The Strecker Synthesis Step 1: Step 2:
  67. 67. Organic Chemistry II arranged by Putri Nur Aulia 67 In a separate step, hydrolysis of -amino nitrile gives an -amino acids. 4.6 Reaction of Amino Acids 4.6.1 Esterification of the Carboxyl Group Esters of amino acids are often used as protected derivatives to prevent the carboxyl group from reacting in some undesired manner. Methyl, ethyl, and benzyl esters are the most common protecting groups. Aqueous acid hydrolyzes the ester and regenerates the free amino acid. 4.6.2 Acylation of the Amino Group: Formation of Amides Just as an alcohol esterifies the carboxyl group of an amino acid, an acylating agent converts the amino group to an amide. Acylation of the amino group is often done to protect it from unwanted nucleophilic reactions. 4.6.3 Reaction with Nynhidrin Ninhydrin is a common reagent for visualizing spots or bands of amino acids that have been separated by chromatography or
  68. 68. Organic Chemistry II arranged by Putri Nur Aulia 68 electrophoresis. When ninhydrin reacts with an amino acid, one of the products is a deep violet, resonance-stabilized anion called Ruhemann’s purple. Ninhydrin produces this same purple dye regardless of the structure of the original amino acid. The side chain of the amino acid is lost as an aldehyde. 4.7 Structure and Nomenclature of Peptides 4.7.1 Peptides‘ Structure Having both an amino group and a carboxyl group, an amino acid is ideally suited to form an amide linkage. Under the proper conditions, the amino group of one molecule condenses with the carboxyl group of another. The product is an amide called a dipeptide because it consists of two amino acids. The amide linkage between the amino acids is called a peptide bond. Although it has a special name, a peptide bond is just like other amide bonds. A peptide is a compound containing two or more amino acids linked by amide bondsbetween the amino group of each amino acid and the carboxyl group of the neighboring amino acid. Each amino acid unit in the peptide is called a residue. A polypeptide is a peptide containing many amino acid residues but usually having a molecular weight of less than about 5000. Proteins contain more amino acid units, with molecular weights ranging from about 6000
  69. 69. Organic Chemistry II arranged by Putri Nur Aulia 69 to about 40,000,000. The term oligopeptide is occasionally used for peptides containing about four to ten amino acid residues. The end of the peptide with the free amino group is called the N- terminal end or the N terminus, and the end with the free carboxyl group is called the C-terminal end or the C terminus. Peptide structures are generally drawn with the N terminus at the left and the C terminus at the right, as bradykinin is drawn here: 4.7.2 Peptide Nomenclature The names of peptides reflect the names of the amino acid residues involved in the amide linkages, beginning at the N terminus. All except the last are given the -yl suffix of acyl groups. Example, for the peptide above (bradykinin), we can write it: arginyl prolyl prolyl glycyl phenylalanyl seryl prolyl phenylalanyl arginine Or to make it more simple, we can write the abbreviated name: Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg Or using single letters, we symbolize by: RPPGFSPFR 4.7.3 Disulfide Linkages Amide linkages (peptide bonds) form the backbone of the amino acid chains we call peptides and proteins. A second kind of covalent bond is possible between any cysteine residues present. Cysteine residues can form disulfide bridges (also called disulfide
  70. 70. Organic Chemistry II arranged by Putri Nur Aulia 70 linkages) which can join two chains or link a single chain into a ring. Two cysteine residues may form a disulfide bridge within a single peptide chain, making a ring. Figure above shows the structure of human oxytocin, a peptide hormone that causes contraction of uterine smooth muscle and induces labor. Oxytocin is a nonapeptide with two cysteine residues (at positions 1 and 6) linking part of the molecule in a large ring. In drawing the structure of a complicated peptide, arrows are often used to connect the amino acids, showing the direction from N terminus to C terminus. Notice that the C terminus of oxytocin is a primary amide (Gly. NH2) rather than a free carboxyl group.
  71. 71. Organic Chemistry II arranged by Putri Nur Aulia 71 4.8 Peptide Structure Determination 4.8.1 Cleavage of Disulfide Linkages The first step in structure determination is to break all the disulfide bonds, opening any disulfide-linked rings and separating the individual peptide chains. The individual peptide chains are then purified and analyzed separately. Cystine bridges are easily cleaved by reducing them to the thiol (cysteine) form. These reduced cysteine residues have a tendency to reoxidize and re-form disulfide bridges, however. The following figure shows a more permanent cleavage involves oxidizing the disulfide linkages with peroxyformic acid. This oxidation converts the disulfide bridges to sulfonic acid groups. The oxidized cysteine units are called cysteic acid residues. 4.8.2 Determination of the Amino Acid Composition Once the disulfide bridges have been broken and the individual peptide chains have been separated and purified, the structure of each chain must be determined. The first step is to determine which amino acids are present and in what proportions. To analyze the
  72. 72. Organic Chemistry II arranged by Putri Nur Aulia 72 amino acid composition, the peptide chain is completely hydrolyzed by boiling it for 24 hours in 6 M HCl. The resulting mixture of amino acids (the hydrolysate) is placed on the column of an amino acid analyzer, diagrammed in this figure: 4.8.3 Sequencing from the N Terminus: The Edman Degradation The most efficient method for sequencing peptides is the Edman degradation. A peptide is treated with phenyl isothiocyanate, followed by acid hydrolysis. The products are the shortened peptide chain and a heterocyclic derivative of the N-terminal amino acid called a phenylthiohydantoin. 1) Step One Nucleophilic attack by the free amino group on phenyl isothiocyanate, followed by a proton transfer, gives a phenylthiourea.
  73. 73. Organic Chemistry II arranged by Putri Nur Aulia 73 2) Step Two 3) Step Three The phenylthiohydantoin derivative is identified by chromatography, by comparing it with phenylthiohydantoin derivatives of the standard amino acids. This gives the identity of the original N-terminal amino acid. The rest of the peptide is cleaved intact, and further Edman degradations are used to identify additional amino acids in the chain. This process is well suited to automation, and several types of automatic sequencers have been developed. In theory, Edman degradations could sequence a peptide of any length. In practice, however, the repeated cycles of degradation cause some internal hydrolysis of the peptide, with loss of sample and accumulation of by-products. After about 30 cycles of degradation, further accurate analysis becomes impossible. A small peptide such as bradykinin can be completely determined by Edman degradation, but larger proteins must be broken into smaller fragments before they can be completely sequenced.
  74. 74. Organic Chemistry II arranged by Putri Nur Aulia 74 ORGANIC CHEMISTRY II CHAPTER V LIPIDS AND FAT
  75. 75. Organic Chemistry II arranged by Putri Nur Aulia 75 CHAPTER V LIPIDS AND FAT 5.1 Introduction Lipids are naturally occurring organic molecules that have limited solubility in water and can be isolated from organisms by extraction with nonpolar organic solvents. Fats, oils, waxes, many vitamins and hormones, and most nonprotein cell-membrane components are examples. Note that this definition differs from the sort used for carbohydrates and proteins in that lipids are defined by a physical property (solubility) rather than by structure. Of the many kinds of lipids, we‘ll be concerned in this chapter only with a few: triacylglycerols, eicosanoids, terpenoids, and steroids. Lipids are classified into two broad types: those like fats and waxes, whichcontain ester linkages and can be hydrolyzed, and those like cholesterol and other steroids, which don‘t have ester linkages and can‘t be hydrolyzed. 5.2 Waxes, Fats, and Oils Waxes are mixtures of esters of long-chain carboxylic acids with long- chainalcohols. The carboxylic acid usually has an even number of carbons from16 through 36, while the alcohol has an even number of carbons from24 through 36. One of the major components of beeswax, for instance, is triacontylhexadecanoate, the ester of the C30 alcohol 1-triacontanol and theC16 acid hexadecanoic acid. The waxy protective coatings on most fruits, berries, leaves, and animal furs have similar structures.
  76. 76. Organic Chemistry II arranged by Putri Nur Aulia 76 Animal fats and vegetable oils are the most widely occurring lipids. Althoughthey appear different—animal fats like butter and lard are solids, whereas vegetable oils like corn and peanut oil are liquid—their structures are closely related. Chemically, fats and oils are triglycerides, or triacylglycerols— triesters of glycerol with three long-chain carboxylic acids called fatty acids. Animals use fats for long-term energy storage because they are much less highly oxidized than carbohydrates and provide about six times as much energy as an equal weight of stored, hydrated glycogen. Hydrolysis of a fat or oil with aqueous NaOH yields glycerol and three fatty acids. The fatty acids are generally unbranched and contain an even number ofcarbon atoms between 12 and 20. If double bonds are present, they have largely, although not entirely, Z, or cis, geometry. The three fatty acids of a specific triacylglycerol molecule need not be the same, and the fat or oil from a given source is likely to be a complex mixture of many different triacylglycerols. Table 27.1 lists some of the commonly occurring fatty acids, and Table 27.2 lists the approximate composition of fats and oils from different sources. More than 100 different fatty acids are known, and about 40 occur widely.Palmitic acid (C16) and stearic acid (C18) are the most abundant saturated
  77. 77. Organic Chemistry II arranged by Putri Nur Aulia 77 fatty acids; oleic and linoleic acids (both C18) are the most abundant unsaturated ones. Oleic acid is monounsaturated because it has only one double bond, whereas linoleic, linolenic, and arachidonic acids are polyunsaturated fatty acids because they have more than one double bond. Linoleic and linolenic acids occur in cream and are essential in the human diet; infants grow poorly and develop skin lesions if fed a diet of nonfat milk for prolonged periods. Linolenic acid, in particular, is an example of an omega-3 fatty acid, which has been found to lower blood triglyceride levels and reduce the risk of heart attack. The data in the following table show that unsaturated fatty acids generally have lower melting points than their saturated counterparts, a trend that is also true for triacylglycerols. Since vegetable oils generally have a higher proportion of unsaturated to saturated fatty acids than animal fats, they have lower melting points. The difference is a consequence of structure. Saturated fats have a uniform shape that allows them to pack together efficiently in a crystal lattice. In unsaturated vegetable oils, however, the C5C bonds introduce bends and kinks into the hydrocarbon chains, making crystal formation more difficult. The more double bonds there are, the harder it is for the molecules to crystallize and the lower the melting point of the oil. The C5C bonds in vegetable oils can be reduced by catalytic hydrogenation, typically carried out at high temperature using a nickel catalyst, to produce saturated solid or semisolid fats. Margarine and shortening are produced by hydrogenating soybean, peanut, or cottonseed oil until the proper consistency is obtained. Unfortunately, the hydrogenation reaction is accompanied by some cis–trans isomerization of the double bonds that remain, producing fats with about 10% to 15% trans unsaturated fatty acids. Dietary intake of trans fatty acids increases cholesterol levels in the blood, thereby increasing the risk of heart problems. The conversion of linoleic acid into elaidic acid is an example.
  78. 78. Organic Chemistry II arranged by Putri Nur Aulia 78
  79. 79. Organic Chemistry II arranged by Putri Nur Aulia 79 5.3 Soap Soap has been known since at least 600 bc, when the Phoenicians prepared a curdy material by boiling goat fat with extracts of wood ash. The cleansing properties of soap weren‘t generally recognized, however, and the use of soap did not become widespread until the 18th century. Chemically, soap is a mixture of the sodium or potassium salts of the long-chain fatty acids produced by hydrolysis (saponification) of animal fat with alkali. Wood ash was used as a source of alkali until the early 1800s, when the development of the LeBlanc process for making Na2CO3 by heating sodium sulfate with limestone became available. Crude soap curds contain glycerol and excess alkali as well as soap but can bepurified by boiling with water and adding NaCl or KCl to precipitate the pure carboxylate salts. The smooth soap that precipitates is dried, perfumed, and pressed into bars for household use. Dyes are added to make colored soaps,
  80. 80. Organic Chemistry II arranged by Putri Nur Aulia 80 antiseptics are added for medicated soaps, pumice is added for scouring soaps, and air is blown in for soaps that float. Regardless of these extra treatments and regardless of price, though, all soaps are basically the same. Soaps act as cleansers because the two ends of a soap molecule are so different.The carboxylate end of the long-chain molecule is ionic and therefore hydrophilic (Section 2.12), or attracted to water. The long hydrocarbon portion of the molecule, however, is nonpolar and hydrophobic, avoiding water and therefore more soluble in oils. The net effect of these two opposing tendencies is that soaps are attracted to both oils and water and are therefore useful as cleansers. When soaps are dispersed in water, the long hydrocarbon tails clustertogether on the inside of a tangled, hydrophobic ball, while the ionic heads on the surface of the cluster stick out into the water layer. These spherical clusters, called micelles, are shown schematically in the figure below. Grease and oil droplets are solubilized in water when they are coated by the nonpolar, hydrophobic tails of soap molecules in the center of micelles. Once solubilized, the grease and dirt can be rinsed away. As useful as they are, soaps also have some drawbacks. In hard water, whichcontains metal ions, soluble sodium carboxylates are converted into insoluble magnesium and calcium salts, leaving the familiar ring of scum around bathtubs and the gray tinge on white clothes. Chemists have circumvented these problems by synthesizing a class of synthetic detergents based on salts of longchain alkylbenzenesulfonic acids. The principle of synthetic detergents is the
  81. 81. Organic Chemistry II arranged by Putri Nur Aulia 81 same as that of soaps: the alkylbenzene end of the molecule is attracted to grease, while the anionic sulfonate end is attracted to water. Unlike soaps, though, sulfonate detergents don‘t form insoluble metal salts in hard water and don‘t leave an unpleasant scum. 5.4 Phospholipids Just as waxes, fats, and oils are esters of carboxylic acids, phospholipids areesters of phosphoric acid, H3PO4. Phospholipids are of two general kinds: glycerophospholipids and sphingomyelins.Glycerophospholipids are based on phosphatidic acid, which contains aglycerolbackbone linked by ester bonds to two fatty acids and one phosphoric acid. Although the fatty-acid residues can be any of the C12–C20 units typicallypresentin fats, the acyl group at C1 is usually saturated and the one at C2 is usuallyunsaturated. The phosphate group at C3 is also bonded to an amino alcohol suchas choline [HOCH2CH2N(CH3)3]1, ethanolamine (HOCH2CH2NH2), or serine[HOCH2CH(NH2)CO2H]. The compounds are chiral and have an l, or R, configurationat C2.
  82. 82. Organic Chemistry II arranged by Putri Nur Aulia 82 Sphingomyelins are the second major group of phospholipids. These compoundshave sphingosine or a related dihydroxyamine as their backbone andare particularly abundant in brain and nerve tissue, where they are a major constituent of the coating around nerve fibers. Phospholipids are found widely in both plant and animal tissues and makeup approximately 50% to 60% of cell membranes. Because they are like soaps in having a long, nonpolar hydrocarbon tail bound to a polar ionic head, phospholipids in the cell membrane organize into a lipid bilayer about 5.0 nm (50 Å) thick.
  83. 83. Organic Chemistry II arranged by Putri Nur Aulia 83 As shown in the following figure, the nonpolar tails aggregate in the center of the bilayer in much the same way that soap tails aggregate in the center of a micelle. This bilayer serves as an effective barrier to the passage of water, ions, and other components into and out of cells. 5.5 Fatty Acid Fatty acids, both free and as part of complex lipids, play anumber of key roles in metabolism – major metabolic fuel (storage and transport of energy), as essential components of all membranes, and as gene regulators (Table 1). In addition, dietary lipids provide polyunsaturated fatty acids (PUFAs) that are precursors of powerful locally acting metabolites, i.e. the eicosanoids. As part of complex lipids, fatty acids are also important for thermal and electrical insulation, and for mechanical protection. Moreover, free fatty acids and their salts may function as detergents and soaps owing to their amphipathic properties and the formation of micelles. 5.6 Overview of Fatty Acid Structure Fatty acids are carbon chains with a methyl group at oneend of the molecule (designated omega, o) and a carboxyl group at the other end (Figure 1). The carbon atom next to the carboxyl group is called the a carbon, and thesubsequent one the b carbon. The letter n is also often usedinstead of the Greekoto indicate the position of the double bond closest to the methyl end. The systematic nomenclature for fatty acids may also indicate the location of double
  84. 84. Organic Chemistry II arranged by Putri Nur Aulia 84 bonds with reference to the carboxyl group (D). Figure 2 outlines the structures of different types of naturally occurring fatty acids. Figure 1 Nomenclature for fatty acids. Fatty acids may be namedaccording to systematic or trivial nomenclature. One systematic way to describe fatty acids is related to the methyl (o) end. This is used to describe the position of double bonds from the end of the fatty acid. The letter n is also often used to describe the o position of double bonds. 5.7 Saturated fatty acids Saturated fatty acids are ‗filled‘ (saturated) with hydrogen.Most saturated fatty acids are straight hydrocarbon chains with an even number of carbon atoms. The most common fatty acids contain 12–22 carbon atoms. 5.8 Unsaturated fatty acids Monounsaturated fatty acids have one carbon–carbondouble bond, which can occur in different positions. The most common monoenes have a chain length of 16–22 and a double bond with the cis configuration. This means that the hydrogen atoms on either side of the double bond are oriented in the same direction. Trans isomers may be produced
  85. 85. Organic Chemistry II arranged by Putri Nur Aulia 85 during industrial processing (hydrogenation) of unsaturated oils and in the gastrointestinal tract of ruminants. The presence of a double bond causes restriction in the mobility of the acyl chain at that point. The cis configuration gives a kink in the molecular shape and cis fatty acids are thermodynamically less stable than the trans forms. The cis fatty acids have lower melting points than the trans fatty acids or their saturated counterparts. In polyunsaturated fatty acids (PUFAs) the first double bond may be found between the third and the fourth carbon atom from the o carbon; these are called ω-3 fatty acids. If the first double bond is between the sixth and seventh carbon atom, then they are called o-6 fatty acids. The double bonds in PUFAs are separated from each other by a methylene grouping. Figure 2 Structure of different unbranched fatty acids with a methyl end and a carboxyl (acidic) end. Stearic acid is a trivial name for a saturated fatty acidwith 18 carbon atoms and no double bonds (18:0). Oleic acid has 18 carbon atoms and one double bond in the o-9 position (18:1 o-9), whereaseicosapentaenoic acid (EPA), with multiple double bonds, is represented as 20:5 ω-3. This numerical scheme is the systematic nomenclature most commonly used. It is also possible to describe fatty acids systematically in relation to the acidic end of the fatty acids; symbolized D (Greek
  86. 86. Organic Chemistry II arranged by Putri Nur Aulia 86 delta) and numbered 1. All unsaturated fatty acids are shown with cis configuration of the double bonds. DHA, docosahexaenoic acid. PUFAs, which are produced only by plants and phytoplankton,are essential to all higher organisms, including mammals and fish. ω-3 and o-6 fatty acids cannot be interconverted, and both are essential nutrients. PUFAs are further metabolized in the body by the addition of carbon atoms and by desaturation (extraction of hydrogen). Mammals have desaturases that are capable of removing hydrogens only from carbon atoms between an existing double bond and the carboxyl group (Figure 3). b-oxidation of fatty acids may take place in either mitochondria or peroxisomes. Figure 3 Synthesis of ω-3 and o-6 polyunsaturated fatty acids (PUFAs). There are two families of essential fatty acids that are metabolized in the body as shown in this figure. Retroconversion, e.g. DHA!EPA also takes place.
  87. 87. Organic Chemistry II arranged by Putri Nur Aulia 87 5.9 Major Fatty Acids Fatty acids represent 30–35% of total energy intake inmany industrial countries and the most important dietary sources of fatty acids are vegetable oils, dairy products, meat products, grain and fatty fish or fish oils. The most common saturated fatty acid in animals, plants and microorganisms is palmitic acid (16:0). Stearic acid (18:0) is a major fatty acid in animals and some fungi, and a minor component in most plants. Myristic acid (14:0) has a widespread occurrence, occasionally as a major component. Shorter- chain saturated acids with 8–10 carbonatoms are found in milk and coconut triacylglycerols. Oleic acid (18:1 o-9) is the most common monoenoic fatty acid in plants and animals. It is also found in microorganisms. Palmitoleic acid (16:1o-7) also occurs widely inanimals, plants and microorganisms, and is a major component in some seed oils. Linoleic acid (18:2 o-6) is a major fatty acid in plantlipids. In animals it is derived mainly from dietary plant oils. Arachidonic acid (20:4 o-6) is a major component ofmembrane phospholipids throughout the animal kingdom,but very little is found in the diet. a-Linolenic acid (18:3 ω-3) is found in higher plants (soyabean oil and rape seed oils) and algae. Eicosapentaenoic acid (EPA; 20:5ω- 3) and docosahexaenoic acid (DHA; 22:6ω-3) are major fatty acids of marine algae, fatty fish and fish oils; for example, DHA is found in high concentrations, especially in phospholipids in the brain, retina and testes. 5.10 Metabolism of Fatty Acids An adult consumes approximately 85 g of fat daily, most ofit as triacylglycerols. During digestion, free fatty acids(FFA) and monoacylglycerols are released and absorbed in the small intestine. In the intestinal mucosa cells, FFA are re-esterified to triacylglycerols, which are transported via lymphatic vessels to the circulation as part of chylomicrons. In the circulation, fatty acids are transported bound to albumin or as part of lipoproteins.
  88. 88. Organic Chemistry II arranged by Putri Nur Aulia 88 FFA are taken up into cells mainly by protein transportersin the plasma membrane and are transported intracellularly via fatty acid-binding proteins (FABP) (Figure 4). FFA are then activated (acyl-CoA) before they are shuttled via acyl-CoA-binding protein (ACBP) to mitochondria or peroxisomes for b- oxidation (and formation of energy asATPand heat) or to endoplasmic reticulum for esterification to different classes of lipid. Acyl-CoA or certain FFA may bind to transcription factors that regulate gene expression or may be converted to signal molecules (eicosanoids). Glucose may be transformed to fatty acids (lipogenesis) if there is a surplus of glucose/energy in the cells. 5.11 Physical Properties of Fatty Acids Fatty acids are poorly soluble in water in their undissociated(acidic) form, whereas they are relatively hydrophilicas potassium or sodium salts. Thus, the actual water solubility, particularly of longer-chain acids, is often very difficult to determine since it is markedly influenced by pH, and also because fatty acids have a tendency to associate, leading to the formation of monolayers or micelles. The formation of micelles in aqueous solutions of lipids is associated with very rapid changes in physical properties over a limited range of concentration. The point of change is known as the critical micellar concentration (CMC), and exemplifies the tendency of lipids to associate rather than remain as single molecules. The CMC is not a fixed value but represents a small concentration range that is markedly affected by the presence of other ions and by temperature. Fatty acids are easily extracted with nonpolar solventsfrom solutions or suspensions by lowering the pH to form the uncharged carboxyl group. In contrast, raising the pH increases water solubility through the formation of alkali metal salts, which are familiar as soaps. Soaps have important properties as association colloids and are surfaceactive agents. The influence of a fatty acid‘s structure on its meltingpoint is such that branched chains and cis double bonds will lower the melting point compared with that of equivalent saturated chains. In addition, the melting point of a fatty acid
  89. 89. Organic Chemistry II arranged by Putri Nur Aulia 89 depends on whether the chain is even- or oddnumbered; the latter have higher melting points. Saturated fatty acids are very stable, whereas unsaturatedacids are susceptible to oxidation: the more doublebonds, the greater the susceptibility. Thus, unsaturatedfatty acids should be handled under an atmosphere of inert gas and kept away from oxidants and compounds giving rise to formation of free radicals. Antioxidants may be very important in the prevention of potentially harmful attacks on acyl chains in vivo (see later). 5.12 Mechanisms of action The different mechanisms by which fatty acids can influencebiological systems are outlined in Figure 5. Figure 5 Mechanisms of action for fatty acids. Thromboxanes formed inblood platelets promote aggregation (clumping) of blood platelets. Leukotrienes in white blood cells act as chemotactic agents (attracting other white blood cells).
  90. 90. Organic Chemistry II arranged by Putri Nur Aulia 90 5.13 Eicosanoids Eikosa means ‗twenty‘ in Greek, and denotes the number ofcarbon atoms in the PUFAs that act as precursors of eicosanoids (Figure 6). These signalling molecules are called leukotrienes, prostaglandins, thromboxanes, prostacyclins, lipoxins and hydroperoxy fatty acids. Eicosanoids are important for several cellular functions such as platelet aggregability (ability to clump and fuse), chemotaxis (movement of blood cells) and cell growth. Eicosanoids are rapidly produced and degraded in cells where they execute their effects. Different cell types produce various types of eicosanoids with different biological effects. For example, platelets mostly make thromboxanes, whereas endothelial cells mainly produce prostacyclins. Eicosanoids from the ω-3 PUFAs are usually less potent than eicosanoids derived from the o-6 fatty acids (Figure 7). 5.14 Substrate specificity Fatty acids have different abilities to interact with enzymesor receptors, depending on their structure. For example,EPA is a poorer substrate than all other fatty acids for esterification to cholesterol and diacylglycerol. Some ω-3fatty acids are preferred substrates for certain desaturases. The preferential incorporation of ω-3 fatty acids into some phospholipids occurs because ω-3 fatty acids are preferred substrates for the enzymes responsible for phospholipid synthesis. These examples of altered substrate specificity of ω-3 PUFA for certain enzymes illustrate why EPA and DHA are mostly found in certain phospholipids. 5.15 Membrane fluidity When large amounts of vhery long-chain ω-3 fatty acidsare ingested, there is a high incorporation of EPA and DHA into membrane phospholipids.Anincreased amountof ω-3 PUFA may change the physical characteristics of the membranes. Altered fluidity may lead to changes of membrane protein functions. The very large amount of DHA in phosphatidylethanolamine and phosphatidylserine in certain areas of the retinal
  91. 91. Organic Chemistry II arranged by Putri Nur Aulia 91 rod outer segments is probably crucial for the function of membrane phospholipids in light transduction, because these lipids are located close to the rhodopsin molecules. It has been shown that the flexibility of membranes from blood cells is increased in animals fed fish oil, and this might be important for themicrocirculation. Increased incorporation of very longchain ω-3 PUFAs into plasma lipoproteins changes the physical properties of low-density lipoproteins (LDL), lowering the melting point of core cholesteryl esters.
  92. 92. Organic Chemistry II arranged by Putri Nur Aulia 92 5.16 Requirements for and Uses of Fatty 5.16.1 Acids in Human Nutrition Although data on the required intake of essential fatty acidsare relatively few, the adequate intakes of linoleic acid(18:2o-6) and a-linolenic acid (18:3o-3) should be2% and 1% of total energy, respectively. Present evidence suggests that 0.2–0.3% of the energy should be derived from preformed very long-chain o-3 PUFAs (EPA and DHA) to avoid signs or symptoms of deficiency. This corresponds to approximately 0.5 g of these o-3 fatty acids per day. It should be stressed that this is the minimum intake to avoid clinical symptoms of deficiency (Table 4). It has been suggested that the ratio between o-3 and o-6 fatty acids should be 1:4 as compared to 1:10 in modern dietary habits, but the experimental basis for this suggestion is rather weak. From many epidemiological and experimental studiesthere is relatively strong evidence that there are significant beneficial effects of additional intake of PUFA in general and very long-chain o-3 fatty acids (EPA and DHA) in particular. It is possible that the beneficial effects may be obtained at intakes as low as one or two fish meals weekly, but many of the measurable effects on risk factors are observed at intakes of 1–2 g day21 of very long-chain o-3 PUFA. If 1–2 g day21 of EPA and DHA is consumed in combination with proper amounts of fruits and vegetables, and limited amounts of saturated and trans fatty acids, most people will benefit with better health for a longer time 5.16.2 Uses of Fatty Acids in the Pharmaceutical/Personal Hygiene Fatty acids are widely used as inactive ingredients (excipients)in drug preparations, and the use of lipid formulations as the carriers for active substances is growing rapidly. The largest amount of lipids used in pharmaceuticals is in the production of fat emulsions, mainly for clinical nutrition but also as drug vehicles. Another lipid formulation is the liposome, which is a lipid carrier particle for other active ingredients. In addition, there has been an increase in the use of lipids as formulation ingredients owing to their functional effects (fatty acids have several biological effects) and their biocompatible nature. For instance, very long-
  93. 93. Organic Chemistry II arranged by Putri Nur Aulia 93 chaino-3PUFAmay be used as a drug to reduce plasma triacylglycerol concentration and to reduce inflammation among patients with rheumatoid arthritis. Moreover, fatty acids themselves or as part of complexlipids, are frequently used in cosmetics such as soaps, fat emulsions and liposomes.
  94. 94. Organic Chemistry II arranged by Putri Nur Aulia 94 ORGANIC CHEMISTRY II CHAPTER VI TERPENES
  95. 95. Organic Chemistry II arranged by Putri Nur Aulia 95 CHAPTER VI TERPENE 6.1 Introduction There are many different classes of naturally occurring compounds. Terpenoids also form a group of naturally occurring compounds majority of which occur in plants, a few of them have also been obtained from other sources. The term terpenes originates from turpentine (lat. balsamum terebinthinae). Turpentine, the so-called "resin of pine trees", is the viscous pleasantly smelling balsam which flows upon cutting or carving the bark and the new wood of several pine tree species (Pinaceae). Turpentine contains the "resin acids" and some hydrocarbons, which were originally referred to as terpenes. Traditionally, all natural compounds built up from isoprene subunits and for the most part originating from plants are denoted as terpenes. Conifer wood, balm trees, citrus fruits, coriander, eucalyptus, lavender, lemon grass, lilies, carnation, caraway, peppermint species, roses, rosemary, sage, thyme violet and many other plants or parts of those (roots, rhizomes, stems, leaves, blossoms, fruits, seed) are well known to smell pleasantly, to taste spicy, or to exhibit specific pharmacological activities. Terpenes predominantly shape these properties. In order to enrich terpenes, the plants are carved, e.g. for the production of incense or myrrh from balm trees; usually, however, terpenes are extracted or steam distilled, e.g. for the recovery of the precious oil of the blossoms of specific fragrant roses. These extracts and steam distillates, known as ethereal or essential oils ("essence absolue") are used to create fine perfumes, to refine the flavor and the aroma of food and drinks and to produce medicines of plant origin (phytopharmaca). The biological and ecochemical functions of terpenes have not yet been fully investigated. Many plants produce volatile terpenes in order to attract specific insects for pollination or otherwise to expel certain animals using these plants as food. Less volatile but strongly bitter-tasting or toxic terpenes also protect some plants from being eaten by animals (antifeedants). Last, but not least,
  96. 96. Organic Chemistry II arranged by Putri Nur Aulia 96 terpenes play an important role as signal compounds and growth regulators (phytohormones) of plants, as shown by preliminary investigations. Many insects metabolize terpenes they have received with their plant food to growth hormones and pheromones. Pheromones are luring and signal compounds (sociohormones) that insects and other organisms excrete in order to communicate with others like them, e.g. to warn (alarm pheromones), to mark food resources and their location (trace pheromones), as well of assembly places (aggregation pheromones) and to attract sexual partners for copulation (sexual pheromones). Harmless to the environment, pheromones may replace conventional insecticides to trap harmful and damaging insects such as bark beetles. The term ‗terpene‘ was originally employed to describe a mixture of isomeric hydrocarbons of the molecular formula C10H16 occurring in the essential oils obtained from sap and tissue of plants, and trees. But there is a tendency to use more general term ‗terpenoids‘ which include hydrocarbons and their oxygenated derivatives. However the term terpene is being used these days by some authors to represent terpenoids. By the modern definition: ―Terpenoids are the hydrocarbons of plant origin of the general formula (C5H8)n as well as their oxygenated, hydrogenated and dehydrogenated derivatives.‖ 6.2 General Structure 6.2.1 The Isoprene Rule About 30 000 terpenes are known at present in the literature. Their basic structure follows a general principle: 2-Methylbutane residues, less precisely but usually also referred to as isoprene units, (C5)n , build up the carbon skeleton of terpenes; this is the isoprene rule found by RUZICKA and WALLACH (Table 1). Therefore, terpenes are also denoted as isoprenoids. In nature, terpenes occur predominantly as hydrocarbons, alcohols and their glycosides, ethers, aldehydes, ketones, carboxylic acids and esters.
  97. 97. Organic Chemistry II arranged by Putri Nur Aulia 97 Depending on the number of 2-methylbutane (isoprene) subunits one differentiates between hemi- (C5), mono- (C10), sesqui- (C15), di- (C20), sester- (C25), tri- (C30), tetraterpenes (C40) and polyterpenes (C5)n with n > 8 according to Table 1. The isopropyl part of 2-methylbutane is defined as the head, and the ethyl residue as the tail (Table 1). In mono-, sesqui-, di- and sesterterpenes the isoprene units are linked to each other from head-to-tail; tri- and tetraterpenes contain one tail-to-tail connection in the center. 6.2.2 Spescial Isoprene Rule Ingold suggested that isoprene units are joined in the terpenoid via ‗head to tail‘ fashion. Special isoprene rule states that the terpenoid
  98. 98. Organic Chemistry II arranged by Putri Nur Aulia 98 molecule are constructed of two or more isoprene units joined in a ‗head to tail‘ fashion. Head Tail But this rule can only be used as guiding principle and not as a fixed rule. For example carotenoids are joined tail to tail at their central and there are also some terpenoids whose carbon content is not a multiple of five. In applying isoprene rule we look only for the skeletal unit of carbon. The carbon skeletons of open chain monotrpenoids and sesqui terpenoids are, Head head tail Tail head Tail Tail tail Head head Example: 6.3 Biosynthesis Acetyl-coenzyme A, also known as activated acetic acid, is the biogenetic precursor of terpenes (Figure 1). Similar to the CLAISEN condensation, two equivalents of acetyl-CoA couple to acetoacetyl-CoA, which represents a biological analogue of acetoacetate. Following the pattern of an aldol reaction,
  99. 99. Organic Chemistry II arranged by Putri Nur Aulia 99 acetoacetyl-CoA reacts with another equivalent of acetyl-CoA as a carbon nucleophile to give β-hydroxy-β- methylglutaryl-CoA, followed by an enzymatic reduction with dihydronicotinamide adenine dinucleotide (NADPH + H+ ) in the presence of water, affording (R)- mevalonic acid. Phosphorylation of mevalonic acid by adenosine triphosphate (ATP) via the monophosphate provides the diphosphate of mevalonic acid which is decarboxylated and dehydrated to isopentenylpyrophosphate (isopentenyldiphosphate, IPP). The latter isomerizes in the presence of an isomerase containing SH groups to γ, γ- dimethylallylpyrophosphate. The electrophilic allylic CH2 group of γ,γ- dimethylallylpyrophosphate and the nucleophilic methylene group of isopentenylpyrophosphate connect to geranylpyrophosphate as monoterpene. Subsequent reaction of geranyldiphosphate with one equivalent of isopentenyldiphosphate yields farnesyldiphosphate as a sesquiterpene (Fig.1).
  100. 100. Organic Chemistry II arranged by Putri Nur Aulia 100 However, failing incoporations of 13 C-labeled acetate and successful ones of 13 Clabeled glycerol as well as pyruvate in hopanes and ubiquinones showed isopentenyldiphosphate (IPP) to originate not only from the acetate mevalonate pathway, but also from activated acetaldehyde (C2, by reaction of pyruvate and thiamine diphosphate) and glyceraldehyde-3-phosphate (C3). In this way, 1- deoxypentulose-5-phosphate is generated as the first unbranched C5 precursor of IPP.
  101. 101. Organic Chemistry II arranged by Putri Nur Aulia 101 Geranylgeranylpyrophosphate as a diterpene (C20) emerges from the attachment of isopentenylpyrophosphate with its nucleophilic head to farnesylpyrophosphate with its electrophilic tail (Fig. 2). The formation of sesterterpenes (C25) involves an additional head-to-tail linkage of isopentenylpyrophosphate (C5) with geranylgeranylpyrophosphate (C20). A tail-to- tail connection of two equivalents of farnesylpyrophosphate leads to squalene as a triterpene (C30, Fig. 2). Similarly, tetraterpenes such as the carotenoid 16-trans-