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Acetals as Protecting Groups The reversibility of acetal formation along with the relative inertness of theRO-C-OR linkage make acetals useful as protecting groups. Protecting groups are functional groups which may be introduced in a moleculeby converting another functional group in a reversible reaction. If the protecting group is more inert than the original functional group, thenother reactions may be carried out with this molecule without worrying aboutaltering or destroying the protecting group. When the other desired reactions are completed, the original group may berestored by carrying out the reverse of the reaction which introduced theprotecting group.OC ROHORORCCORORprotection(acetal formation)OH3 O Cdeprotectionfurtherreactions(reverse of acetal formation)25Cyclic Hemiacetals Cyclic hemiacetals containing five and six atoms in the ring can formspontaneously from hydroxyaldehydes:HOHHOHOOalcohol and carbonyl functions arecontained in the same moleculeCyclic hemiacetals are more stable than noncyclichemiacetals; they can be isolated. They arefavored under equilibrium (large Keq) conditions.This oxygen becomes an OH group.HC O Five and six-carbon sugarsare important biologicalexamples of cyclichemiacetals:HCHOOHHOH2 CHOCHHCOHHCOHHOOHOHOHCH2 OHthis oxygen ends up in the ring26

Cyclic Acetals Acetaldehyde forms a cyclic trimer when treated with acid:CH3H3acidH3 C OOH3 COOCH3Cyclic acetals are often used as protecting groups.OOHOH acidH2 COHOOHOO H2OOacidO H2 O27Reactions of Aldehydes and Ketones with Amines Aldehydes and ketones react with primary amines to form imines, orSchiff bases.OHNH2heatN H2OAn imine is a compound with aC N double bond ( a nitrogenanalog of an aldehyde or ketone The mechanism of imine formation involves the nucleophilic addition of theamine to the carbonyl carbon, forming a stable intermediate species called acarbinolamine.OCarbinolamines are compunds withan amine group and a hydroxygroup attached to the same carbon.CRHCarbinolamines areanalogous to hemiacetals.NH28

Mechanism of Carbinolamine Formation Carbinolamine formation begins with nucleophilic attack on the carbonyl carbon. The product of this attack is a neutral, charge-separated species. Water and its conjugate acid both play roles in the reaction.!OHNHOHO HOH H2 ORRHHRN HHN HHProtonated water as a Bronsted acid:nucleophilic attack of the negativelycharged oxygen of the intermediate onprotonated water.OHOH H3OCWater as a Bronsted base: nucleophilicattack of the oxygen of water on aproton of the positively charged amine.RNcarbinolamineH29Reaction of Aldehydes/Ketones with 2 Amines Aldehydes and ketones react with secondary amines to form enamines.OHNacidN O H2 OOEnamines have a nitrogen bound to acarbon which is part of a C C double bond. The mechanism involves nucleophilicaddition of the amine to the carbonylto form a carbinolamine.Enamines form only if the carbonylcompound has at least one hydrogen on acarbon adjacent to the carbonyl carbon.Formation of the alkene may be recognizedas an elimination reaction.carbinolamineOHNOHHOHNHHO30

Irreversible Addition of Aldehydes and Ketones Aldehydes and ketones also undergo addition reactions which are essentiallyirreversible. These reactions use organometallic reagents to add alkyl groups to thecarbonyl carbon atom. These reactions are nucleophilic additions; this means that the organic groupadded is acting as a nucleophile in the reaction.We’re accustomed to electrophilic behavior of alkyl groups (I.e., carbocations), buthow does an alkyl group act as a nucleophile?R-LiR:! Li think of as .R-MgXR:! MgX (Grignard Reagent)The alkyl groups act as if they were free carbanions31Organometallic Reagents The actual structure of Grignard reagents in solution is complex. These reagents are always prepared in ethereal solvents, and in fact two ethermolecules are associated with the Grignard reagent.OGrignard reagentprepared in diethyl etherR Mg XGrignard reagents are highlypolar compounds and are verystrong Lewis bases.O Mechanism of addition of a Grignard reagent to a carbonyl compound:OMgXCRLewis acid-base interaction between basiccarbonyl oxygen and Mg makes the carbonylcarbon more reactive toward the alkyl group. O!CRMgXThe product of thisreaction step is ahalomagnesium alkoxide32

Addition Using Organometallic Reagents Formation of alcohols via addition of Grignard reagents to aldehydes andketones is carried out in two separate stepsStep 1: Addition of the nucleophilic alkyl group to the carbonyl carbon, aidedby Lewis acid interaction between MgX and the carbonyl oxygen. Theproduct of this step is a halomagnesium alkoxide (see previous slide).Step 2. Protonation of the alkoxide oxygen. The product of this step is analcohol.H This notation makes it clear that the overallreaction occurs in two separate steps:OH2H O!CMgXORCO2 !R Mg X H2 OH3 CCOH1. H3 CHH3 CCHCH3 2. H / H2 OCH3halomagnesiumalkoxideMgBrCH32 MgBr! H2OStep 2.33Addition Using Grignard Reagents Primary, secondary and tertiary alcohols may be formed in the reactions ofaldehydes or ketones with Grignard reagents.primary alcohols from formaldehydeOHCH3O MgClHstep 12 !CH2 OH Mg Cl H2Ostep 2secondary alcohols from aldehydesCHH3O MgBr step 1Ostep 2 Mg2 Br! H2OCOHtertiary alcohols from ketonesOOHCH3 H3 O CH3 MgIstep 1 Mg2 I! H2 Ostep 234

Additions Using Organometallic Reagents The net effect of the reaction of a Grignard reagent with an aldehyde or ketonein the addition of the components R and H across the C O double bond. Compare to nucleophilic addition of HCN:Nucleophilic addition of HCNGrignard:OC1. RMgBrOHOCRCHCNOHCCN 2. H / H2ONucleophile attacking thecarbonyl carbon:“ R ”Nucleophile attacking thecarbonyl carbon:CN A separate step is needed toproduce the alcohol from thehalomagnesium alkoxide“one-pot” reaction (multi-stepmechanism, but all components maybe added at once).irreversible reactionreversible reaction35Addition Reactions Using OrganometallicReagents Addition reactions to aldehydes and ketones using Grignard reagents areamong the most important reactions in organic synthesis. These reactions are carbon-carbon bond forming reactions. The net result of the reaction is the addition of the elements of R-H across theC O double bondOC1. R MgBrO HC RO EOcompared to.C EYCY2. H / H2 O Other metal-based reagents also add components across the C O bond in ananalogous way:– Metal hydrides add H- and H across the C O double bond.– When we add H-H to a double bond, we call the reaction a reduction.36

Metal Hydrides LiAlH4 and NaBH4 act in a fashion similar to Grignard reagents. The hydride ion H acts as the nucleophilic reagent adding to the carbonylcarbon atom of an aldehyde or a ketone.OCLi!H Li O!LiCAlH3 O!AlH3CAlH3HHCOH!AlH3O 44OHCH Li , Al3 salts The hydride ion in LiAlH4 is more basic than the hydride ion in NaBH4, andtherefore it is more reactive. Some functional groups which may be reduced by LiAlH4 are unreactive withNaBH4 (e.g., alkyl halides R-X, nitro groups -NO2)– Therefore NaBH4 may be used to reduce C O bonds in the presence ofsuch groups.37Carboxylic Acids Carboxylic acids represent the next higher “oxidation level” up fromaldehydes/ketones.ORcarboxy groupCOH Carboxylic acids occur widely in nature. Carboxylic acids serve important roles in organic synthesis.Lewis basicity(greater at this oxygen)chemistry at #-hydrogensLewis basicity(lesser at this oxygen)OHCCOHBronsted acidity reactions at thecarbonyl group reactions at thecarboxylate oxygen reactions involving#-hydrogensLewis acidity38

Nomenclature of Carboxylic Acids Many carboxylic acids are known by their common names. These common names are often formed by adding the suffix “ic” acid to thecommon names for aldehydes and ketones.OOOOHHH3 COHformic acid OHacetic acidbenzoic acidCarboxylic acids may also contain two carboxy groups. These compounds arecalled dicarboxylic acids.OOHOOOOHOHOHHOOHOOmalonic acidsuccinic acidphthalic acid39Structure and Properties of Carboxylic Acids Compare bond lengths and angles to other C O and C-O containingcompounds:sp2-sp3 single bond is shorter than sp3-sp3 bondC O bond length is thesame in aldehydes,ketones, and carboxylicacidsHO Carboxylic acids have high boiling pointsdue to their ability to act as both donors andacceptors in hydrogen bonding.ROHOROCarboxylic acids can existas dimers in solution40

Acidity of Carboxylic Acids Carboxylic acids are much more acidicthan alcohols. Two main reasons explain this acidity:– Resonance stabilization of theconjugate base, RCOO .pKa 15-17ROHpKa 10OHO– Electrostatic stabilization of thenegative charge by the adjacentpolar carbonyl group.RpKa 3-5OHconjugate base:!ORO!R!OOR OO!!ORROHO OHSeparation of charge in the carbonyl C and Ois already partially developed in carboxylicacid41Basicity of Carboxylic Acids As in aldehydes and ketones, the carbonyl oxygen of carboxylic acids is weaklybasic. The carbonyl carbon of carboxylic acids reacts with protons to form aresonance-stabilized conjugate acid.O H3 OR OHO HOOHH H2 OROHR OHROH Why does protonation occur only at the carbonyl oxygen, and not at thecarboxylate oxygen?OR OH Protonation at the carboxylate oxygenwould result in a species like this This species is not resonance-stabilized, soits formation is much less favorableH42

Reactions at the Carbonyl Group The most typical reaction at thecarbonyl group of carboxylicacid is substitution at thecarbonyl carbon: RRER EOYOHROEROHRThe carboxylate oxygen anioncan act as a nucleophile:O RO! OHOR YRO OEE! H3 O O!Y!OOHROHO H2 OEY Reaction at the carboxylateoxygen results in ionization: YOHOAnother important reactionis the reaction of thecarbonyl oxygen with anelectrophile:OOOY!E43Conversion of Carboxylic Acids into Esters The acid-catalyzed preparation of esters from carboxylic acids is known asFischer esterification.– Esters are carboxylic acid derivatives with the carboxylate -OH groupreplaced by an alkoxy group.– Treating a carboxylic acid with an excess of an alcohol gives esters.OOCOH H3COHH2 SO4COCH3 H2Oexcess This is an example of substitution at the carbonyl carbon. The reaction is driven forward by using a large excess of alcohol (usually assolvent), an application of Le Chatelier’s priniciple. This esterification can’t be carried out with tertiary alcohols (why?) or withphenols.44

Mechanism of Acid-Catalyzed Esterification The first steps of the reaction are familiar to us from aldehyde/ketonenucleophilic addition:– Protonation of the carbonyl oxygen by CH3OH2 .– Nucleophilic attack of the alcohol on the carbonyl carbon by CH3OH.– Deprotonation of the tetrahedral intermediate by CH3OH. H3COH HOHOOH RROHH3COHROHCH3 Oadditionprotonation OHOHOHCH3 OH H3 CO RHThis reaction differs from addition toaldehydes and ketones in the nextstep -- in what happens to thetetrahedral intermediate.HH3 COHdeprotonation45Mechanism of Acid-Catalyzed Esterification In acid-catalyzed reactions of aldehydes and ketones, the tetrahedral alcoholspecies formed in these three steps (protonation, addition, deprotonation) is ahemiacetal. It may undergo further reactions, but the ultimate product will be atetrahedral addition product. In acid-catalyzed reactions of carboxylic acid, this tetrahedral species is notstable and undergoes further reaction, ultimately producing a substitutionproduct and not an addition product.OHRHOH OCH3RHCH3 OOH OH2RCH3 OOH OHRCH3 OCH3 O OHRCH3 O H2 O ORCH3 OHH3COOH ROCH3HH OCH3carbonyl C O double bond isretained in the substitutionproduct46

Substitution vs. Addition Aldehydes and ketones undergo addition reactions while carboxylic acidsundergo substitution reactions.Osubstitution O RERYEXYXOadditionREYX In both reactions, a tetrahedral product is initially formed. The choice between substitution and addition depends on how good theleaving group, X, is.ORFor aldehydes and ketones: X R, HCannot act as leaving groupEYFor carboxylic acids: X OH, protonated to OH2 Can act as leaving groupXtetrahedral (intermediate) product47Esterification by Alkylation Another route to esterification of carboxylic acids involves one of the othertypes of reactions we outlined at the beginning of the discussion of carboxylicacids.reactivity at the carboxylate oxygen Alkylation of the carboxylate oxygen may be carried out using diazomethane, atoxic, explosive, allergenic gas.O ROH!H2CO N N2NRdiazomethaneORmechanism:!H2 COROH NOONRO! H3 C NNRboth steps involve the carboxylate oxygen and not the carbonyl oxygenOCH3 N248

Synthesis of Acid Chlorides from Carboxylic Acids Acid chlorides are prepared from carboxylic acids using either thionyl chloride(SOCl2) or phosphorus pentachloride (PCl5).OOO ROH HCl SO2SClRClthionyl chlorideClacid chloride This reaction fits the pattern of substitution at the carbonyl group; however, themechanism proceeds slightly differently from that of Fischer esterification. The first step involves attack of the sulfur of thionyl chloride by the carbonyloxygen acting as a Lewis base.OOOROSClHOSClThe sulfur is very electrophilic; why?!ClClR OH49Preparation of Acid ChloridesCompare reaction of carboxylic acids with SOCl2 to reaction with alcohols. Carbonyl oxygen acts as a Lewis base to attack the electrophilic sulfur atominstead of attacking a proton. The protonated product of this first step is a very powerful electrophile.– The Cl- anion can abstract a hydrogen, giving an unstable intermediate – Or, the Cl- anion can undergo nucleophilic attack on the carbonyl carbon(because this species is so electrophilic, even a weak nucleophile like Clcan undergo this reaction).OOOR SOOClH!ClRSOHClOClOR SOOClH!ORClSClOHCl50

Preparation of Acid Chlorides The last step is the elimination of the thionyl chloride group as SO2 and HCl.This step is irreversible because SO2 is a gas.HORClOOOS HCl SO2RClClOORedraw two of the intermediates in this mechanism:ODrawn this way, it makes it look like a simplesubstitution at the carboxylate oxygen.RHowever, if we look back at themechanism, we can see that the thionylchloride adds to oxygen in a carbonylgroup, not to oxygen in a carboxylate group.SOClROClSClOHredrawOThe reaction occurs this way because thecarbonyl oxygen is more strongly Lewis basicthan is the carboxylate oxygen.ROHOOSRClClOOSClOROH51Attack via the Carbonyl Oxygen The oxygens in a carboxylic acid are indistinguishable. The proton movesrapidly back and forth from one to the other.OROOHRHO .however, when the reaction takes place, it does so via attack by the moreLewis basic carbonyl oxygen (whichever one that happens to be at that instantin time), and not via the less basic carboxylate oxygen.OROOSClThe oxygen that is a carbonyl in this intermediate was a carboxylate when thereaction started.52

Preparation of Acid Chlorides Another interesting point about the mechanism of acid chloride formation is therole of the thionyl intermediate.protonated intermediate(not isolated)reactantsOROHClOOO isolable intermediateSOClR OOClHRSClOThis reaction is driven towardsthe isolable intermediate.This species is present in only avery small concentrationbecause it is so unstable.The isolable intermediate is not a“true” intermediate species, sinceit is not on a direct pathway tothe product.SORClproductThe isolable intermediate servesas a kind of “reservoir” to supplythe reaction pathway with theprotonated intermediate.Can you recall an analogous example?53Reactive Intermediates Have Low Concentrations If the minor species is too reactive, a high concentration might make it subjectto unwanted side reactions. The concentration of the minor species is kept low by virtue of its reversiblereaction to form the more stable major species. This “reservoir” meters the concentration of the minor species so that it reactsimmediately to products and can’t build up in concentration.Minor species(very reactive)Major species(more stable)Products54

Preparation of Acid Anhydrides Acid anhydrides may be thought of as the condensation product of twocarboxylic acids, with loss of water. Anhydrides are formed by treatment of carboxylic acids with strong dehydrating reagents.O2F3 C O P2 O5OO H2 O phosphatesHF3 COCF3Anhydrides may be formed by reaction between an acid chloride and the conjugate baseof a carboxylic acid.OOOH3 C H2 OH OHHO!OClOClHO!CH3Cyclic anhydrides may be formed by treating a dicarboxylic acid with another anhydride.OOOHOHOOO HO CH3 COOHCH3OO55Carboxylic Acid Derivatives Carboxylic acid derivatives have the general formula:ORO-OH is replaced by LRLcarboxylic acid derivativeOHcarboxylic acidOResters, L OR’OR'Oacid halides, L X halogen (usually Cl)RXOOacid anhydrides, L OCOR’ROR'ORNH2amides, L NH2, NHR’, NHR’R”56

Carboxylic Acid Derivatives (Acyl Compounds) Not only are the structures of these compounds related, but their chemistriesare related also. One of the most important types of reactions these compounds undergo arenucleophilic addition-elimination reactions resulting in the replacement of L withanother nucleophile.OO!ORRNuLRLL!NuNu!elimination of L: addition of Nu: The two most important factors governing the chemistry of thesetransformations are:– The stability of the starting carboxylic acid derivative – The characteristics of the leaving group L:57Structure and Stability of Acyl Compounds Compare the C-O bond lengths of acyl compounds with their related singlebonded compounds:OOROCH31.33 ÅH3 COCH31.41 ÅRONH21.35 ÅH3 CNH21.47 ÅRClThe C-Cl bond in an acyl chlorideis not shortened compared to thatof an alkyl chloride1.78 ÅH3 CCl1.78 Å Acyl compounds are resonance-stabilized. The C-O and C-N bonds in esters and amides are shortened compared toethers and amines because of their double bond character.58

Structure and Stability of Acyl CompoundsLook at the resonance-stabilized structures:AmidesRONH2ROEstersROR'RRNH2R ! NH2R!O OClO OOAcidchlorides!OR'! ORR!OClR! Clweaker Lewis base - better leaving groupOincreased resonance stabilization higher energy resonance forms Acyl chlorides are the least resonance-stabilized of the acyl compounds Halides are the best leaving groups of the acyl compound “L” groups59Structure and Stability of Acyl Compounds Let’s take a look at one of the high energy resonance forms and compare themfor the different acyl compounds.OR!O NH2N is less electronegativethan O or Cl, so amidescan bear the positivecharge better than other Lgroups. The result is amore polar C O group anda more basic carbonyloxygen.R!O ORR!OO O& R'Oxygen is more electronegativethan nitrogen and likes bearingthe positive charge less.Anhydrides exhibit chargerepulsion between the carbon inthe leaving

The sp2 hybridization of the carbonyl compound means that attack of the nucleophile on the carbonyl carbon may occur from either face. The resulting addition product is sp 3-hybridized. Nu: Nu We used the example of hydration (formation of gem-diols) to illustrate nucleophilic additi