The Organic Acids. Carboxylic Acids * *

Transcription

1 arboxylic Acids The rganic Acids Some Notation: Acids and their conjugate bases pka ~ 15 - weak acid arboxylic Acid pka ~ 4 moderate acid - arboxylate Anion pka ~ -7 very strong acid l - l arboxylic acids are MDEATE acids, somewhere between the weak acid water and "real" acids such as hydrochloric (l) The conjugate base anion of a carboxylic acid is the ESNANE STABILIZED carboxylate anion 1 Nomenclature IUPA priority: acid > aldehyde> ketone> alcohol > alkene > alkyne > halide priority increases with increasing oxidation state, acids are the most oxidized, always highest priority carbon carrying the - 2 is number 1 suffix "-oic acid" Examples ethanoic acid (acetic acid, non-iupa) ,2-dimethylpropanoic acid oxohexanoic acid 2 N p-nitrobenzoic acid 1.1 Some ommon Names for arboxylic Acids 3 formic acid acetic acid trifluoroacetic acid (TFA) (ant bite) (vinegar) * you need to know these, TFA is a common organic acid used in catalysis 2 Factors ontrolling Acidity comparing acidity - think about acidity as a "chemical reaction" * F 3 * * which is stronger acid? Z Y Z Y determined by stabilities of conjugate base anions arboxylic Acids : Page 1

2 Examples pf pkas compare the simplest carboxylic acids pka acid conjugate base 3.7 formic acid 4.8 Me acetic acid for formic versus acetic acid (above), higher solvation of the smaller formate anion is almost certainly an additional contributing factor pka acid conjugate base W.D. 4.8 Me Me acetic acid 3.9 l 2 chloroacetic acid 0.3 F 3 trifluoroacetic acid (TFA) 3.6 Me 2 methoxyacetic acid NTE: the methoxy substituent in the last example is not directly attached to the pi-system, there is an sp3 hybridized carbon atom in between, in this case it is NT a donating group because there is no resonance donation, only a weak inductive effect of the electronegative oxygen substituent effects for some aromatic carboxylic acids W.D. Me W.W. l 2 S.W. X F 3 sp3 Me 2 W.W. π-system pka acid conjugate base W.D. 4.8 Me Me acetic acid anion weakly destabilized by donating -Me anion weakly stabilized by l (inductive effect) anion strongly stabilized by F 3 anion weakly stabilized by Me (inductive only, no resonance here!) 4.2 benzoic acid N 2 N anion weakly stabilized by sp 2 carbon (no resonance here!) anion further stabilized by N 2 (inductive and resonance) 4.5 Me Me anion weakly destabilized by -Me (resonance) NTE: in the benzoate anion (conjugate base of benzoic acid), there is no possibility of delocalizing the nonbonding electrons into the benzene ring, the ring does NT stabilize the electrons by resonance, there is only a very small stabilization due to the slightly stronger bonds attached to the pi-system due to the sp2 hybridized carbon of the ring. arboxylic Acids : Page 2

3 3 Synthesis of arboxylic Acids 3.1 "ld" Methods (eview) Malonic ester is a specialized method of synthesis of carboxylic acids 1. NaEt Et 2 malonic ester 2 Et / heat oxidation of a primary alcohols works well when there are no other functional groups present that are sensitive to acid, forms a carboxylic acid to the original carbon chain when you don't need to add any carbon carbons Na 2 r 2 7 / 2 S 4 / carbons oxidation of any alkyl group that has a benzylic hydrogen on a benzene ring works if there are no other functional groups that are sensitive to acid 1. KMn 4 / - / 2 /boil New Methods 1. Using a Grignard reaction Mg.TF 2 Mg 3 1 carbon added Mg 6 carbons 7 carbons This reaction is simply a Grignard reaction with "one carbon", the Grignard adds to the carbon dioxide in the same way any Grignard adds to an aldehyde or ketone acid workup as usual hydrolyzes the -Mg bond to form the acid overall this reaction "adds" NE carbon atom to the original bromide (the carbon that was in the 2) 2. From a Nitrile S N 2 3 Na N N N2 sodium cyanide nitrile heat amide 3 carbons hydrolysis 3 heat hydrolysis 4 carbons 1 carbon added This reaction is simply SN2 on an alkyl bromide using the cyanide anion as the nucleophile to form a nitrile acid hydrolysis converts the nitrile into an amide, the amide can be further hydrolyzed into a carboxylic acid, the hydrolysis requires EAT! "adds" a carbon atom to the original bromide, the bromide must be capable of SN2 (methyl, primary, allylic etc) arboxylic Acids : Page 3

4 Mechanism of hydrolysis This is a standard acid catalyzed hydrolysis mechanism, but a LT longer! Because it is longer we will use the abbreviated /- notation Even though this is a LNG mechanism, it should be approached by analogy to previous hydrolysis mechanisms and using our knowledge of fundamental onsted/lewis acid/base reactions and understanding how we break bonds from nitrogen to carbon by protonating 3 N 3 heat N 2 heat amide acid N N - N N 2 N 2 - N 2 AMIDE same thing!! - N N 3 N 2 NTE: There are TW steps in this mechanism that look odd, the reprotonation step after the amide forms the same intermediate that deprotonated to form the amide, obviously formation of the amide could have been omitted from the mechanism and the mechanism would have been simpler The purpose of this step, however, is to show that an amide is a FMAL intermediate in the overall hydrolysis process, and also to remind us that an amide can be hydrolyzed to form an acid. Example benzylic, easy to do S N 2 NaN N 3 heat (hydrolysis) phenylacetic acid 3.3 arboxylic Acid Synthesis Strategies STATING with a bromide leaving group. use the Grignard method for tertiary (3 ) and aromatic halides (where the S N 2 reaction is not possible) use the nitrile method in presence of acidic protons (where no Grignard reaction is possible use the malonic ester method when you must add TW carbon atoms Examples 1. Mg. TF an't do nitrile hydrolysis here because can't add the nitrile (NaN) because can't do S N 2 at an sp2 hybridized carbon arboxylic Acids : Page 4 adds 1 carbon

5 can't do Grignard 1. NaN adds 1 carbon Grignard not possible because of the - group, but formation of a nitrile followed by hydrolysis is possible here Multi-Step Synthesis Problem Example 1: Give a synthesis of the target carboxylic acid on the right from the starting structure on they left NBS/hν Na N 2. 3 /heat Mg.TF Mg no SN2 at 3 carbon need to add 1 carbon atom to a tertiary carbon, SN2 will not work, this has to be a Grignard reaction Example 2: Give a synthesis of the target carboxylic acid on the right from the starting structure on they left NBS/hν /heat K -t-bu Mg.TF Mg N / Na N need to add 1 carbon atom to a PIMAY carbon, either the Grignard the SN2 route with cyanide will work Example 3: Give a synthesis of the target carboxylic acid on the right from the starting structure on they left 2 adds zero carbons NBS/hν Na 2 r 2 7 / 2 S 4 / 2 K -t-bu 1. B 3.TF 2. Na/ 2 2 need to add zero carbon atoms, make the carboxylic acid by oxidation of a primary alcohol arboxylic Acids : Page 5

6 4 eactions of arboxylic Acids 4.1 Fischer Esterification only the mechanism is really important here since it introduces a NEW PINIPLE The reaction is acid catalyzed and is reversible TIS substitutes the reaction is SUBSTITUTIN at TIS sp2 carbon atom ' ' 2 can "push" towards ester by using excess alcohol as the solvent, or adding a dehydrating agent to remove the water (Le hatelier's principle) AN'T use 3 as the acid catalyst, this would push the reaction "back" towards the acid due to ester hydrolysis in the presence of water (remember, 3 is acid in water), use dry l gas that is bubbled into the alcohol solvent instead the reaction is formally SUBSTITUTIN at the sp2 hybridized carbon atom of the = carbonyl, WEVE AN'T D SN1 or SN2 even when the oxygen is protonated because the carbon is sp2 hybridized! need to break this bond can't do this on an sp2 carbon sp2 X FIST, need to make the carbon sp3 hybridized TIS works well! The sp2 hybridized = carbon MUST BE transformed into an sp3 hybridized carbon atom (tetrahedral intermediate), TEN, we can have the usual water leaving group. This is a NEW MEANISTI principle The Mechanism is similar to other mechanisms we have seen in aldehydes and ketones except that the substitution requires the transformation of the central carbon from sp2 to sp3 before the protonated leaving group can leave sp2 ' / ' 2 - ' ' ' ' tetrahedral intermediate sp3 ' 2 ' sp3 once the tetrahedral intermediate is formed, cleaving the - bond can occur in the usual way because the carbon is now sp3 hybridized, protonated the oxygen and have water as a good leaving group we will learn a MU better way of making esters in the next section arboxylic Acids : Page 6

7 4.2 Formation of Acid hlorides ecall - Sl 2 -l S 2 l Similarly - 2 Sl 2 S 2 l l the mechanism of this reaction is identical to that for formation of an alkyl chloride from an alcohol IMTANT EATIN, conversion to acid chloride allows synthesis of ALL arboxylic acid derivatives Example 2 important central position Sl 2 l ester amide anhydride 4.3 eduction With Lithium Aluminum ydride ecall: relative reducing ability: > LiAl 4 > NaB 4 Also relative reactivity: > > weakly donating to carbon stronger donation to carbon NaB 4 will not reduce an acid, but LiAl 4 will... mechanism Al Al you don't have to know!!! Al Al 2 Al Examples 2 NaB 4 Et LiAl arboxylic Acids : Page 7

8 note that the 3 that is used in the second step of the LiAl 4 reduction is in the form of an "acid workup", which means that enough acid is used to protonate any anions. ydration of a = bond in an alkene usually requires heating in the presence of high concentrations of acid fro extended periods, and so addition of water to the = bond in LiAl 4 reactions is unlikely to occur. 5 Summary of eactions Involving arboxylic Acids Do NT start studying by trying to memorize the reactions here! Work as many problems as you can, with this list of reactions in front of you if necessary, so that you can get through as many problems as you can without getting stuck on the reagents/conditions, and so that you can learn and practice solving reaction problems. Use this list AFTE you have worked all of the problems, and just before an exam. By then you will have learned a lot of the reagents/conditions just by using them and you will only have to memorize what you haven't learned yet. Then do the following: over the entire page of reagents/conditions with a long vertical strip of paper, see if you can write down the reagents/conditions for each reaction, check to see which you get correct, if MPLETELY correct, circle Y, if incorrect or even slightly incorrect, circle N. In this way you keep track of what you know and what you don't know. Keep coming back to this list and so the same thing only for those reactions you circled N, until all are circled Y. Knowing the reagents/conditions on this page is INSUFFIIENT to do well on an exam since you will ALS need to recognize how to use and solve reaction problems in different contexts, this page NLY helps you to learn the reagents/conditions that you have not YET learned by working problems. You have seen several of these reactions in earlier sections! Et 2 2 Et 2 malonic ester synthesis 1. NaEt 2. Me 3. NaEt 4. Et 5. 3 /heat seen previously Me 2 Et 2 Na 2 r S 4 / 2 seen previously 2 Bu 1. Boiling KMn 4 / seen previously Mgl seen previously 2 N 3, heat seen previously 2 2 Excess Sl 2 l 2 1. LiAl arboxylic Acids : Page 8