Organic Functional Groups Lecture 4 PDF

ORGANIC FUNCTIONAL GROUPS Dr Graeme Kay Academic Strategic Lead – Chemical Sciences 01224 262548 [email protected] Lecture 4  ALCOHOLS General formula: R-OH PHYSICAL PROPERTIES Alcohols are able to form H-bonds between molecules so even low molar...

ORGANIC FUNCTIONAL GROUPS Dr Graeme Kay Academic Strategic Lead – Chemical Sciences 01224 262548 [email protected] Lecture 4  ALCOHOLS General formula: R-OH PHYSICAL PROPERTIES Alcohols are able to form H-bonds between molecules so even low molar mass ones are liquids. O R H H O Solubility R Alcohols can form H-bonds with water so low mol. mass ones are very soluble in water: O R H H O Remember as R has a longer chain, the alcohol will get less water soluble H General Properties of Alcohols cohols are weakly basic and weakly acidic: cidity Constants of Some Alcohols and Phenols REACTIVITY/STABILITY Under normal conditions, alcohols are quite stable. However, they are quite reactive towards other types of compound. Always have to remember this when combining compounds in various formulations. One significant reaction is with mild oxidising agents. The type of oxidation depends on whether the alcohol is a 1°, 2° or 3° alcohol; If we have a 1º alcohol the initial product is an aldehyde: Aldehydes may further oxidise to carboxylic acids: If we have a 2º alcohol product is a ketone: Tertiary alcohols are resistant to oxidation. ESTER FORMATION Reaction of an alcohol with an acid yields an ester Biologically, phosphate esters are important: O R O P OH Also have di- and tri- phosphates OH Reaction with organic acids also gives esters (see O later): R OH R'-COOH R' C OR ester  R R O Ketones / Alkanones O R R Alkenes R R' R OH Carboxylic Acids / Alkanoic Acids O O Aldehydes / Alkanals Esters R H R OR' ROH Alkyl Halides RX ROR' ethers Alcohols are very important in organic synthesis STORAGE REQUIREMENTS Although 1º and 2º alcohols are susceptible to oxidation this is not usually a problem in air.  ETHERS General Formula: R-O-R PHYSICAL PROPERTIES Unlike alcohols, ethers cannot H-bond with each other so only form van der Waals bonds with each other. So the low RMM ethers are gases/liquids at room temperature. Solubility Ethers can form H-bonds with water so the low RMM ones are soluble in water. Again the solubility falls off with increasing C chain length. Reactivity / Stability Ethers are relatively unreactive and are widely used as solvents particularly diethyl ether or “ether”. However, like alkenes, they can form peroxides in air. With diethyl ether: Storage requirements Beware peroxide formation in air!  ALDEHYDES AND KETONES (Alkanals and Alkanones) Both contain the CARBONYL, C=O, group. So we have: Like alkenes we have a π bond between C and O but unlike alkenes the bond is polar due to the electronegative O atom PHYSICAL PROPERTIES Because of the polar C=O bond there are intermolecular attractions but no H-bonds between molecules. Most are liquids at room temperature. Solubility Aldehydes and ketones can H-bond with water so low mol. mass ones are soluble in water.   H bond C O H O H Higher mol mass compounds less soluble (more “alkane-like”) Reactivity and Stability Because of the polar bond in the C=O group aldehydes and ketones react with nucleophiles. Because of the π bond it is a nucleophilic addition reaction. They are of the general type Here the nucleophile Nu: donates its electron pair to the δ+ C of the C=O bond at the same time the electron pair of the π bond move to the O atom. We could add some acid (H+) first to make the C=O more reactive: In both cases the product is: Nu C OH When the nucleophile is an alcohol the reaction is: This reaction is of particular importance in the properties of sugars. Here, the OH group and carbonyl group within the same molecule react to produce the cyclic form of the sugar. Another important reaction of this type is when the nucleophile is an amine We can then lose water: Therefore, we have converted a C=O bond to a C=N bond. Reactions of this type are very important for the combination of drugs with receptors in the body. Also important in enzyme reactions. OXIDATION OF ALDEHYDES AND KETONES When we have a H atom attached to the C=O carbon atom, oxidation is possible. Therefore, aldehydes can be oxidised to carboxylic acids: R R [O] C O C O H HO aldehyde carboxylic acid No such reaction takes place with ketones since there is no H bonded to the C=O carbon: R [O] C O no oxidation, stable to oxidation R ketone REDUCTION REACTIONS OF ALDEHYDES AND KETONES We produce the corresponding alcohols Like the reduction of an alkene, (earlier): H C O + H2 C OH alcohol We could also use a metal hydride e.g. LiAlH4 H lithium aluminium hydride hydride anion, a very strong nucleophile In the usual way, the hydride ion attacks the δ+ carbon atom of the C=O bond: Metal hydrides SELECTIVELY reduce C=O groups. They do NOT reduce alkene C=C double bonds. Storage of aldehydes and ketones Under normal conditions ketones are stable but aldehydes are unstable and oxidise in air. This would give the corresponding carboxylic acid.  CARBOXYLIC ACIDS (alkanoic acids) Formula: O R C OH The R-C=O group is called the acyl group and is present in acid derivatives. PHYSICAL PROPERTIES Form Like other functional groups, this depends on the RMM. Generally up to 9 C atoms we have liquids and 10 or more C atoms we have solids. Extensive intermolecular H-bonding Solubilities As we have see with previous functional groups, water solubility depends on H-bonding. Low RMM acids are very R soluble in water due to H-bonding: C O H O H O H O H H bonds H ACIDIC NATURE OF CARBOXYLIC ACIDS They are acidic because they can donate a proton (H+) to a more basic substance e.g. water: H R R C O + H O C O + H O HO O H H As we saw earlier the carboxylate ion is stabilised by resonance (see ethanoic acid) O O R C R C O O This can be written O R O The relative strength of carboxylic acids depends on the nature of the R group. If we have electron withdrawing groups attached to R the this increases the acid strength. If we have electron donating groups then this decreases the strength So if we have 3 acids: The electron withdrawing Cl renders that acid the strongest The electron donating CH3 renders that acid the weakest SALT FORMATION We can neutralise an acid by forming a salt with base, e.g. NaOH. This is often done to make an insoluble carboxylic acid much more water soluble. This is very common in pharmaceutical formulation i.e. many acidic drugs are supplied as salts for increased water solubility. R R C O + NaOH C O + H2O HO Na O more water soluble sodium salt REACTIVITY OF CARBOXYLIC ACIDS Most reactions of acyl containing groups (including carboxylic acids) are of the type: R R C O + Nu: C O G Nu So we have nucleophilic substitution reactions. When the nucleophile is an alcohol the important product is an ESTER. R R C O + RO-H C O HO RO OXIDATION OF CARBOXYLIC ACIDS Under normal conditions, they are resistant to oxidation. STORAGE Much more stable than aldehydes, being less susceptible to oxidation.  ESTERS AND AMIDES General Structure: Amides are often referred to as 1º (i.e. –NH2) 2º (-NHR) or 3º (-NR2). We shall consider esters and amides together as they behave in a similar fashion PHYSICAL PROPERTIES Esters are unable to form H- bonds between ester molecules so they are low boiling liquids. Amides are able to H-bond with each other so have much higher boiling points than esters. SOLUBILITY Since both are able to form H-bonds with water, lower RMM ones are soluble in water. As with other functional groups, increasing C number decreases water solubility. REACTIVITY OF ESTERS AND AMIDES Similar but amides react much more slowly than esters. R main reaction type is nucleophilic substitution Generally, the R of the type: C O + Nu: C O G Nu Pharmaceutically, HYDROLYSIS (i.e. water is the nucleophile) is important. R R C O + H2O C O G HO Amides – lack of basic properties As we will see with amines, the presence of a N atom with its unbonded electrons normally makes such a group basic However, with the amides, the unbonded pair are delocalised and so cannot be donated: Unlike amines, then, amides are neutral. We also have cyclic forms of esters and amides: cyclic esters called lactones, cyclic amides are called lactams For example OXIDATION Both are resistant to oxidation under normal conditions. STORAGE Store in a dry place to avoid hydrolysis reactions  AMINES GENERAL STRUCTURE: R NH2 This is a primary (1) amine but remember that there are secondary (2) and tertiary (3) as well. PHYSICAL PROPERTIES FORM Low mol. mass amines (1, 2 and 3) are gases at room temperature due to weak intermolecular attractions Higher RMM amines tend to be liquids. SOLUBILITY Are able to form H-bonds with water so low RMM amines are soluble in water. Like other functional groups, increasing chain length lowers solubility in water (become more “alkane-like”).  Amines H3C NH 2 Primary Amino group H3C Secondary Amino group NH CH 3 H3C CH 3 N Tertiary Amino group CH 3 CH 3 Quaternary Amino group (salt – cationic) H3C N CH 3 CH 3 AMINES AS BASES Due to the pair of electrons on the N atom, amines can take up a proton (H) from acid: + + R NH2 + H R NH3 alkylammonium ion When we consider the relative base strength of 1, 2 and 3 amines we have a strange order! 2º > 3º > 1º This is because of the electron donating effect of alkyl groups attached to the N atom: With these amines: So the electron releasing R groups become δ+ and thus spread the + charge. With the 3º amine we have a hindered structure with little room to bond the H+ ion. A common conversion of an amine with low water solubility is to convert it to its hydrochloride salt by reaction with HCl: + R3N + HCl R3NH Cl hydrochloride salt: very soluble in water so of obvious importance in pharmacy REACTIVITY OF AMINES As we saw earlier, (e.g. with aldehydes and ketones) amines are good nucleophiles. Very important in drug and receptor combinations STORAGE OF AMINES Not particularly susceptible to oxidation in air. With amine salts (eg the hydrochloride salts), keep away from alkaline materials as the free amine will precipitate, since we may lose its water solubility: R+NH3 Cl +  OH RNH2 sol. in water may be insol. in water (precipitates out of soln.)