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Topic 10b

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Chemistry 2223B
Felix Lee

Chemistry 2213a  Fall 2012  Western University Topic 10b. Derivatives of Carboxylic Acids A. Structure and Nomenclature O  We’re interested in O O O O four derivatives, each of which has aR OR' R X R O R' R NR2 group bonded to an acyl halide anhydride ester amide acyl carbon: O O  The names of the derivatives come from the carboxylic acid. For esters, chaCHe ic OH CH OCH CH acid to ate, preceded by the name of the 3 2 3 alkyl group on the ester alcohol group.etic acid ethyl acetate  Cyclic esters are lactones and are designate using Greek letters (, , , , , etc.), O O   depending on the number of carbon atoms that the ester oxygen is from the carbonyl. O  O  a –lactone a –lactone Acid Derivatives  2  For acid halides, change ic acid to yl halide. O O OH Cl propanoic acid propanoyl chloride  For symmetrical anhydrides, change acid to anhydride. Anhydrides are usually formed by coupling two carboxylic acids with the loss of water (hence the name anhydride). O O O O  H2O CH 3 OH HO CH3 CH 3 O CH 3 acetic acid acetic anhydride  Cyclic anhydrides are formed by heating dicarboxylic acids. O O O = OH  HO OH O H2O OH O O O Acid Derivatives  3  For amides change oic acid or ic acid to amide. If the amide N has groups other than H, their attachment to the nitrogen is designated by the prefix N. O O O OH NH 2 N N,N-dimethylbenzamide benzoic acid benzamide  Cyclic amides are called lactams. When two acyl groups form amide bonds to the same N atom (like an anhydride), we get an imide. Designate with Greek letters.  O H  O N O   NH a –lactam an imide Acid Derivatives  4 B. Spectroscopy −1  All acid derivatives contain a strong C=O stretch near the 1630 – 1800 cm region. Esters also have two peaks near 1050 and 1250 cm −1 due to the C–O.  Shown below are the carbon- and proton-NMR spectra for ethyl butanoate. Acid Derivatives  5 −1  Amides have a C=O stretch near 1650 cm and the usual N–H peaks near 3330. e.g. N-methylbenzamide  Carbon- and proton-NMR spectra for N-methylbenzamide: Acid Derivatives  6 C. Reactivity of Acid Derivatives  The characteristic reaction of all acid derivatives is nucleophilic acyl substitution. The nucleophile is added followed by the elimination of the leaving group. This is not the sameNas SN1 or S 2. O O Nu LG R LG R Nu  The reactivity of an acid derivative towards nucleophilic acyl substitution depends on two factors: o How electrophilic is the acyl carbon (how likely the carbon is to be attacked by the nucleophile), and o The ability of LG to act as a leaving group. 1. Electrophilicity of the acyl carbon  As previously seen, resonance structures O can be drawn for the carbonyl group. The carbon atom is electrophilic. R Z R Z Acid Derivatives  7  The magnitude of the positive charge on the carbon is affected by the nature of Z. The better the Z can act as an electron-donating group, the less-positive and less-electrophilic the carbon is. Think carbocation stability… O O O R Z R Z R Z  Less-electronegative Z = better electron-donating group. For example, nitrogen is a better EDG than is oxygen. O O R N R O less more electrophilic electrophilic  A negatively charged Z, such as an O , is an excellent EDG and can stabilize the carbocation extremely well. On the other hand, electron-withdrawing (EWG) groups destabilize the carbocation and increase its electrophilicity. Acid Derivatives  8 O O O O R O R N R O R Cl not at all less more extremely electrophilelectrophilicelectrophilielectrophilic  What if an electron-donating Z were in between two carbonyl groups? It must donate to two carbocations, so each carbocation receives a smaller share of electrons. O O O O O O R O R N R O R O R R Cl not at all less more even more extremely electrophilic electrophilic elecelectrophilic electrophilic Acid Derivatives  9  Based on the electrophilicity of the carbon, acid chlorides are most susceptible to nucleophilic attack, followed by the anhydride, the ester or the carboxylic acid, the amide, and finally the carboxylate anion.  Important in biochemistry: the thioester, which is the sulfur version of the ester, is involved in many biological pathways. O O O R SR R SR R SR  Even though S is less-electronegative than O, it is a poorer EDG because of inefficient 2p −3p overlap. Thioesters are more reactive than esters, but carbon sulfur in biochemistry, higher reactivity is sometimes desirable. Acid Derivatives  10  Therefore, by examining the magnitude of the + on the carbon atom, we have devised the following trend in susceptibility towards nucleophilic attack. carboxylate < amide < ester or acid < thioester < anhydride < acid halide 2. Stability of the leaving group  Acid derivatives that have better leaving groups are more likely to undergo nucleophilic acyl substitution. The leaving groups are: thioester O O O O O O R O R N R O R O R R Cl O O 2– N O O R Cl horrible very poor good very poor good SR fair Acid Derivatives  11  Notice that this trend is in the same order as the trend for the electrophilicity of the carbonyl group.  Acid chlorides are extremely reactive because they are highly electrophilic and they have a very good leaving group. Amides, for example, are not very reactive because they are poorly electrophilic and have bad leaving groups. D. Hydrolysis and Formation of Other Derivatives  All acid derivatives can undergo two kinds of reactions: hydrolysis to the carboxylic acid, and conversion to another acid derivative. In both cases, the reaction again proceeds by nucleophilic acyl substitution.  Under basic conditions, the nucleophile is negatively charged. Note that under basic conditions, there are no cations in the reaction mechanism. O O O Nu R LG LG R LG R Nu Nu Acid Derivatives  12  Acid derivatives that are very reactive can react even in the absence of acid or base. In this case, the nucleophile is usually uncharged, and a deprotonation step occurs after the leaving group is expelled. O O O HNu LG R LG R LG R NuH NuH –H+ O R Nu  In the presence of an acid catalyst, nucleophilic acyl substitution occurs just like the Fischer esterification. Realize that the only difference is what the nucleophile and what the leaving group are. For example, acid-catalyzed amide hydrolysis: Acid Derivatives  13 O H O + H2O R 2H 2 R' NR 2 R' OH Acid Derivatives  14 1. Hydrolysis to carboxylic acids  All acid derivatives react under proper conditions with water to form carboxylic acids, a reaction called hydrolysis. Acid chlorides (most reactive)  Acid chlorides are very reactive, so no catalyst is needed. O O H O HCl 2 R Cl R OH Anhydrides (2 most reactive)  Anhydrides also react rapidly with water, but slower than acid halides. No catalyst is needed, but one can be helpful. O O O 2 H 2 R O R R OH Acid Derivatives  15 Esters (third most reactive)  Esters ne
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