These same reaction schemes are available without the mechanistic details, so you can practice filling in those details.

Transcription

1 314/315 reactions and mechanisms through topic 11 and some of topic 12 1 These same reaction schemes are available without the mechanistic details, so you can practice filling in those details. Problems - In the following reactions each step has been written without the formal charge or lone pairs of electrons and curved arrows. Assume each atom follows the normal octet rule, except hydrogen (duet rule). upply the lone pairs, formal charge and the curved arrows to show how the electrons move for each step of the reaction mechanism. Identify any obvious nucleophiles and electrophiles in each of the steps of the reactions below (on the left side of each reaction arrow). Let me know when you find errors. Free radical substitution at sp 3 - (overall reaction) hν sp 3 - bonds The weakest bonds react the fastest. Mechanism - fill in all necessary details (lone pairs, formal charge, curved arrows, structures = best plus one other) step 1 = initiation - the halogen bond is the weakest bond and most reactive to cleavage by hν. hν step 2a = propagation - these steps happen 100's to 1000's of times per initiation 3 3 step 2b = propagation bromine atom attacks the weakest - bond the fastest the carbon free radical attacks the weakest bond, (repeat) step 3 = termination - two free radicals encounter on another, pure release of energy, this is a rare event These X compounds can be made using free radical substitution of alkanes. 3 1 o benzylic 2 o benzylic These X compounds cannot be made using free radical substitution of alkanes. Z:\classes\315\315 andouts\arrow pushing mechs probs key.doc

2 314/315 reactions and mechanisms through topic 11 and some of topic reactions with -X patterns (above): methyl, 1 o, 2 o (sometimes), allylic and benzylic are very good for 2, (-X = l,, I, Ts), E2 is the competition. You add all necessary mechanistic details (lone pairs, charge, curved arrows). If no reaction or a different reaction occurs, indicate this. hown below are syntheses of alcohols, esters, ethers, nitriles, alkynes, thiols, thioethers and amines. Alkenes and alkynes can be made using E2 reactions. That s 10 different functional groups from X compounds, and we left out using 2 chemistry using ketone and ester enolates, dithianes and cuprate chemistry. K a make terminal acetylides a 3 only 2 at methyl new alkyne 3 alkynes mainly 2 > E2 at methyl and 1 o X nitrile K a a E2 > 2 using potassium t-butoxide with most reactive X compounds (in our course) I same alkyne mainly E2 at 2 o & 3 o X I I mainly 2 > E2 at methyl, 1 o and 2 o X I I E2 at 3 o X I a I ester - can react mainly 2 > E2 at methyl, 1 o and 2 o X further to form I 2 o alcohol a E2 at 3 o X acyl substitution - further reaction with a at ester can be used to make secondary alcohols = base hydrolysis (see imides on next page) a a a 2 o, minor products using X + a a a a 2 > E2 at methyl and 1 o X E2 at 2 o & 3 o X alkoxides are similar to hydroxide, except the 2 products are ethers instead of alcohols (potassium t-butoxide is our big exception = E2) make alkoxides from alcohols and sodium hydride = acid/base (in our course) a 3 make mainly 2 > E2 at methyl and 1 o X 3 a 3 mainly E2 at 2 o & 3 o X Z:\classes\315\315 andouts\arrow pushing mechs probs key.doc

3 314/315 reactions and mechanisms through topic 11 and some of topic 12 3 make alkoxides from alcohols and sodium hydride 3 a 3 a a a Using 2 reaction to make primary (1 o ) amines a. Gabriel amine synthesis make imidate nucleophile - acid/base chemistry a 2 reaction of imidate anion at methyl, 1 o and 2 o X a pk a = 8 2 reactions with methyl, 1 o and 2 o X a alkyl imide a 2 acyl substitution mechanism shown, just below primary amine acyl substitution - further reaction with a at imide (2x), base hydrolysis (similar to esters above, but twice) 2 primary amine (target) a a 2 > E2 at methyl, 1 o and 2 o X thiol 3 2 > E2 at methyl, 1 o and 2 o X thioether Z:\classes\315\315 andouts\arrow pushing mechs probs key.doc

4 314/315 reactions and mechanisms through topic 11 and some of topic 12 4 ucleophilic hydride = sodium borohydride (a 4 ) and lithium aluminum hydride (Al 4 = LA), [deuterium is used below to show reaction site] 2 reaction at Me, 1 o and 2 o X. reacts 4x a a Al reacts 4x Alkyl carbanions (lithium and magnesium) are poor nucleophiles with X compounds, [but cuprates work well] poor reaction ther copper reactions are shown later. 2 n-butyl lithium (very strong base) u (twice) transmetallation poor yields, too many side reactions, later we will use cuprates to make this reaction work u dialkyl cuprate X compound I poor reaction Al poor yields, too many side reactions, I later we will use cuprates to make this reaction work via " 2-like" reaction, newly formed - bond becomes lost among others Z:\classes\315\315 andouts\arrow pushing mechs probs key.doc

5 314/315 reactions and mechanisms through topic 11 and some of topic 12 5 Acyl substitution, and similar to imide hydrolysis on page 3 base hydrolysis of ester to from alcohol, including acid neutralization of the carboxylate to recover the carboxylic acid (if desired) esters a a a carboxylic acids 2. workup (neutralize carboxylate) a carboxylate alcohols ometimes we want the acid, sometimes we want the alcohol and sometimes we want both of them. E2 reactions with -X patterns, usually with potassium t-butoxide (in our course) as the base (to make alkenes) and a 2 as the base (in our course) with dibromoalkanes (to make alkynes). 2 can be very weak competition (that we ignore). emember, β - and α -X should be anti. a. potassium t-butoxide with 1 o, 2 o and 3 o X compounds to make alkenes (in our course) make potassium t-butoxide using t-butyl alcohol and potassium hydride (in our course) K potassium hydride (always a base) K K K K K Z:\classes\315\315 andouts\arrow pushing mechs probs key.doc

6 314/315 reactions and mechanisms through topic 11 and some of topic 12 6 b. sodium amide with dialkyl X 2 compounds to make alkynes (in our course). make the alkyne (two E2 reactions and terminal sp - (pk a = 25) is lost to the amide anion (conj. acid, 3, pk a = 37) a further can't stop this reaction a possible a 2 pk 2 a = 25 pk a = 37 = phenyl 3 a 2 a Four workup reactions with terminal acetylides available in our course (tep 2) can't stop this further 3 a a 3 reaction possible 2 2 pk a = 25 pk a = 37 can't stop this 2 further reaction a a possible 2 2 pk a = 25 pk a = 37 tep 2 = eutralize with mild acid to get a terminal alkyne, or tep 2 = react with methyl or 1 o X ( 2), or tep 2 = react with epoxide (best 2 site reacts fastest) followed by mild acid to protonate the alkoxide, or tep 2 = react with aldehyde or ketone (carbonyl addition), followed by mild acid to protonate the alkoxide. make from above a 2. workup 2. workup a a react with X ( 2) mild acid neutralize only methyl & 1 o X 3. workup react with epoxide ( 2) a react with = 3. workup make 2. workup 2. workup from a a 3 above 3 react with X ( 2) 3 mild acid neutralize 3 only methyl & 1 o X Z:\classes\315\315 andouts\arrow pushing mechs probs key.doc

7 314/315 reactions and mechanisms through topic 11 and some of topic a make from above 3. workup react with epoxide ( 2) 3 3 a react with = 3. workup 2. workup 2. workup a a react with X ( mild acid neutralize 2) only methyl & 1 o X 3 a 3. workup react with epoxide ( 2) a react with = 3. workup Examples of useful 1 reactions 1 and E1 reactions require 2 o, 3 o, allylic or benzylic X so that an energetically stable carbocation can form. Useful reactions should not have rearrangement possibilities. We assume 1 > E1. ur only synthetically useful reaction is: / alkenes. 1 and E1 possibilities (make carbocation 1. rearrangement, 2. add nucleophile, 3. lose beta proton). This example shows all three possibilities and would not be synthetically useful. Three weak nucleophiles in our course are 2, and 2 a d rearrangement a b with water c b b without water c f d e d e E and Z E and Z add top and bottom and diastereomers add top and bottom (no difference in this example) f 2 achiral Z:\classes\315\315 andouts\arrow pushing mechs probs key.doc

8 314/315 reactions and mechanisms through topic 11 and some of topic 12 8 water 2 alcohols 1. L.G. leaves 2. -u: adds 3. lose + alcohols ethers 3 and 3 1. L.G. leaves 2. -u: adds 3. lose + carboxylic acid ester and 1. L.G. leaves 2. -u: adds 3. lose + Examples of useful E1 reactions The only example in our course is 2 4 / conditions with alcohols. We propose that 1 o, 2 o and 3 o alcohols all work. The less stable the carbocation, the higher the temperature required. This E1 reaction works because the alkene is distilled away from the reaction mixture, continually shifting the equilibrium in the E1 direction until the starting material is used up. A diabolical trick on the 1 reaction, the usual winner. earrangements are possible, with the most stable carbocation usually leading to the major alkene product (most substituted alkene). 3 no rearrangement problems 3 1. protonate 2. water leaves 3. lose + in E1 reaction carbocation possibilities 1. rearrange 2. add nucleophile 3. lose beta 3 no rearrangement problems carbocation possibilities 1. rearrange 2. add nucleophile 3. lose beta rearrangement most substituted alkene Z:\classes\315\315 andouts\arrow pushing mechs probs key.doc

9 314/315 reactions and mechanisms through topic 11 and some of topic 12 9 Alcohol eactions ( and E reactions) (Acid/base with X acids 2 & 1 reactions) (1. tosylate synthesis 2. 2 with a ) (l 2,/ 2, Pl 3 /P 3 X compounds from alcohols, can also make acid halides) (formation of alkoxides with a which can form ethers and esters 2 above and acyl substitution with acid chlorides), (oxidation reactions using r 3 + water acids and ketones and without water aldehydes and ketones) Examples of important patterns to know in our course (plus a few others). methyl and primary secondary tertiary 3 special examples allylic 1 o, 2 o and 3 o vinyl enol is unstable, keto tautomer preferred benzylic 1 o, 2 o and 3 o phenyl There are many variations. 1 o neopentyl a. X + ( 2 at methyl and primary and 1 at secondary, tertiary, allylic and benzylic in our course, X = l,, I) I I 1 > E1 I 3 +, I 1 > E1 1 and E1 are possible here, but not shown. rearrangement E no / Z:\classes\315\315 andouts\arrow pushing mechs probs key.doc

10 314/315 reactions and mechanisms through topic 11 and some of topic b. Formation of tosylates from + Tsl (toluenesulfonyl chloride = tosyl chloride), /E chemistry is possible l l l l 1 l rearrangement and, (racemic) compare 1. Tsl/pyridine 2. al (prevents + formation and any rearrangement) l separate step l a 2 l alkyl tosylate = X compound c. Thionyl chloride with methyl, 1 o = acyl-like substitution at l 2, then 2 at methyl and primary X. 2 is also available. synthesis of an alkyl chloride from an alcohol + thionyl chloride (l 2 ) [can also make from 2 ] l l acyl-like substitution o rearrangement because no +. 2 l l l 2 l 2 product l 2 at methyl and primary alcohols Thionyl chloride with 2 o and 3 o = acyl substitution, then 1 (there are various ways you can write this mechanism) l l l synthesis of an alkyl chloride from an alcohol + thionyl chloride (l 2 ) [can also make from 2 ] l / l l acyl-like substitution l l l 1 at secondary and tertiary alcohols l l l l Z:\classes\315\315 andouts\arrow pushing mechs probs key.doc

11 314/315 reactions and mechanisms through topic 11 and some of topic ynthesis of acid chlorides from acids + thionyl chloride (l 2 ), use the carbonyl oxygen over the. l acid chlorides made from carboxylic acids l l l acylium ion l l l l d. Formation of esters from + acid chlorides and amides from 2 or 2 + acid chlorides l l l l ase ase l l ester synthesis from acid chloride and alcohols l l l acyl substitution There are many variations of and l joined together by oxygen. esters amide synthesis from acid chloride and amines l acyl substitution l l 2 There are many variations of 2 or 2 and l joined together by nitrogen. amides e. osphorous tribromide (P 3 ) = 2 at P 3, then 2 (at methyl and primary ) 3 P P 2 2 P reacts twice more Z:\classes\315\315 andouts\arrow pushing mechs probs key.doc

12 314/315 reactions and mechanisms through topic 11 and some of topic osphorous tribromide (P 3 ) = 2, then 1 (at secondary, tertiary, allylic and benzylic ) P 2 P 2 at 1 o X P reacts twice more P 2 P 1 at 2 o, 3 o X P reacts twice more, f. r 3 oxidations of alcohols (methyl, 1 o and 2 o ) without water & acid = P, r= addition, acid/base and E2 to form = (aldehydes and ketones) 3 2 primary alcohols r r = +6 P = pyridinium chlorochromate oxidation of primary alcohol to an aldehyde (no water to hydrate the carbonyl group), r 3 is reduced and alcohol carbon is oxidized. pyridine 3 2 r pyridinium ion 3 pyridinium ion aldehydes 3 pyridine 2 2 r E2 r r = r secondary alcohols P = pyridinium chlorochromate oxidation of primary alcohol to an aldehyde (no water to hydrate the carbonyl group), r 3 is reduced and alcohol carbon is oxidized. r pyridine pyridinium ion pyridinium ion pyridine 3 3 ketones 2 2 r 3 E2 r 3 Z:\classes\315\315 andouts\arrow pushing mechs probs key.doc

13 314/315 reactions and mechanisms through topic 11 and some of topic r 3 oxidations of alcohols (methyl, 1 o and 2 o ) with water & acid = Jones reagent, r= addition by alcohol, acid/base and E2 to form =, then hydration of = and repeat reactions when 1 o alcohol (forms carboxylic acids from primary alcohols and ketones from secondary alcohols) r r r primary alcohols 2 Jones = r 3 / 2 / acid primary alcohols oxidize to carboxylic acids (water hydrates the carbonyl group, which oxidizes a second time ) hydration of the aldehyde r aldehydes (cont. in water) r 2 second oxidation of the carbonyl hydrate 3 2 r r r 3 2 carboxylic acids 3 2 g. Formation of alkoxide from + a or K (acid/base reaction) a a a react with X, 2 > E2 at methyl & 1 o X Z:\classes\315\315 andouts\arrow pushing mechs probs key.doc

14 314/315 reactions and mechanisms through topic 11 and some of topic h. ehydration to alkene (E1) from / (possibility of rearrangements) Water ends up as 3 + in This is our only proposed, potentially useful E1 reaction rearrangement + Water ends up as 3 + in 2 4. nly the major alkene is shown. Z:\classes\315\315 andouts\arrow pushing mechs probs key.doc

15 314/315 reactions and mechanisms through topic 11 and some of topic Epoxide reactions a. Examples of important patterns to know from our starting materials. We can make epoxides from alkenes using either 1. 2 / 2, 2. a. or we can make epoxides using mpa. step 1 - make bromohydrin from alkenes bromohydrin a little tricky, requires 3 arrows to make bromonium bridge 1-like attack at more d+ carbon, from the backside step 2 - make epoxide by reacting with step 2 - make epoxide by reacting with mild base anti attack epoxide synthesis from bromohydrin mild base anti attack bromohydrins epoxides trong nucleophile conditions - 2 like attack at less hindered epoxide carbon, and workup (overall addition) a 2. workup a 2 hydroxide diol 2 Z:\classes\315\315 andouts\arrow pushing mechs probs key.doc

16 314/315 reactions and mechanisms through topic 11 and some of topic a alkoxides (ethoxide) a 2. workup 2 2 a a 2. workup 2 terminal acetylide 2 a terminal acetylide a 2. workup n-butyl lithium 3 2. workup 2 2 ucleophilic hydride = sodium borohydride (a 4 ) and lithium aluminum hydride (Al 4 = LA), [deuterium is used below to show reaction site] a a sodium borodeuteride sodium borhydride a 2. workup 2 2 Al lithium aluminium deuteride lithium aluminium hydride (LA) 2. workup 2 2 Z:\classes\315\315 andouts\arrow pushing mechs probs key.doc

17 314/315 reactions and mechanisms through topic 11 and some of topic Epoxide reactions in acid conditions 1-like conditions, attack at more δ+ carbon. (compare to base reaction) (compare to base reaction) ur only E2 reaction for epoxides. Uses very basic, sterically bulky LA (always a base). Make LA = lithium diisopropylamide (a very strong base) pk a = 50 pk a = workup LA = lithium diisopropylamine (always a base) allylic alcohols 2. workup allylic alcohols other allylic alcohols we can make (from epoxides, which come from alkenes) Z:\classes\315\315 andouts\arrow pushing mechs probs key.doc

18 314/315 reactions and mechanisms through topic 11 and some of topic Alkene and Alkyne reactions Examples of important patterns to know. other patterns showing regioselectivity and stereoselectivity alkynes We can make alkenes from X (E2 reactions) and ( 2 4 / = E1), and alkynes from X 2 (a 2 ), for now. a. = addition reaction with -l (- and -I are similar), Markovnikov addition forms most stable carbocation There isn't any lone pair, so you have to use the pi electrons as the nucleophile. 3 l eaction with acid forms the most stable carbocation ( rearrangements are possible ) 3 l l 3 l adds to top and bottom, but no difference in this example b. = aqueous acid hydration reaction, goes via top/bottom addition (hydration of an alkene) There isn't any lone pair, so you have to use the pi electrons as the nucleophile hydration of an alkene with aqueous acid form most stable carbocation ( rearrangements are possible ) most stable (/) Z:\classes\315\315 andouts\arrow pushing mechs probs key.doc

19 314/315 reactions and mechanisms through topic 11 and some of topic = addition reaction (hydration of an alkene), with rearrangement There isn't any lone pair, so you have to use the pi electrons as the nucleophile. rearrangement hydration of an alkene with aqueous acid form most stable carbocation ( rearrangements are possible ) c. = addition reaction (ether synthesis from an alkene by addition of alcohols) There isn't any lone pair, so you have to use the pi electrons as the nucleophile alcohol ( 3 / Ts) hydration of an alkene with aqueous acid form most stable carbocation ( rearrangements are possible ) ether Z:\classes\315\315 andouts\arrow pushing mechs probs key.doc

20 314/315 reactions and mechanisms through topic 11 and some of topic d. = addition reaction (ether synthesis from an alkene by addition of alcohols), with rearrangement There isn't any lone pair, so you have to use the pi electrons as the nucleophile. rearrangement ( 3 / Ts) 3 alcohol ether synthesis from an alkene with alcoholic acid form most stable carbocation ( rearrangements are possible ) ether e. Mercuration, reduction minimizes rearrangements f. ydration of alkynes (Markovnikov addition forms most stable carbocation), enol intermediate tautomerizes to keto tamtomer. (The g +2 has been left out of the mechanism to simplify the mechanism.) There isn't any lone pair, so you have to use the pi electrons as the nucleophile. g +2 catalyst g. omination of alkenes, goes via anti addition a little tricky, requires 3 arrows to make bridge bridging cation prevents rearrangement, anti attack at more partial positive carbon Z:\classes\315\315 andouts\arrow pushing mechs probs key.doc

21 314/315 reactions and mechanisms through topic 11 and some of topic = addition reaction alkenes / alkynes 3 3 no rearrangement 3 bromide attacks anti because of bridging at more partial positive stereoselective = anti addition cation carbon regioselective = none h. omhydrin formation from alkenes, goes via anti addition a little tricky, requires 3 arrows bridging cation prevents rearrangement, attack at more partial positive carbon water attacks anti at more partial positive carbon 2 bromohydrins can form epoxides in mild base = addition reaction 3 alkenes / alkynes no rearrangement because of bridging cation 3 water attacks anti at more partial positive carbon 3 stereoselective = anti addition regioselective = Markovnikov 3 bromohydrins can form epoxides in mild base Z:\classes\315\315 andouts\arrow pushing mechs probs key.doc

22 314/315 reactions and mechanisms through topic 11 and some of topic i. ydroboration of alkenes = anti-markovnikov addition (opposite regioselectivity to normal hydration conditions) anti-markovnikov addition to = (hydration makes alcohols), two steps: / step 1 = concerted addition to = by borane alkenes concerted syn-addition twice more trialkylborane step 2 = oxidation by hydrogen peroxide and rearrangement to anti-markovnikov alcohol trialkylborane a (a/ 2 2 ) rearrange anti-markovnikov alcohol twice more j. bromination anti looks very similar to hydration reaction, just above anti-markovnikov addition to = (bromination makes -), two steps: / 3 step 1 = concerted addition to = by borane alkenes concerted syn-addition twice more trialkylborane step 2 = oxidation by bromine and rearrangement to anti-markovnikov - trialkylborane 3 a (a 3 / 2 ) twice more 3 rearrange 3 3 anti-markovnikov bromoalkane Z:\classes\315\315 andouts\arrow pushing mechs probs key.doc

23 314/315 reactions and mechanisms through topic 11 and some of topic k. ydroboration of alkynes = anti-markovnikov addition (opposite regioselectivity to normal conditions) anti-markovnikov addition to (hydration makes aldehydes), two steps: / step 1 = concerted addition to by dialkylborane concerted syn-addition alkenes = sterically large group so addition only occurs once step 2 = oxidation by hydrogen peroxide and rearrangement to anti-markovnikov aldehyde trialkylborane a (a/ 2 2 ) rearrange enolate = anti-markovnikov aldehyde Z:\classes\315\315 andouts\arrow pushing mechs probs key.doc

24 314/315 reactions and mechanisms through topic 11 and some of topic eduction of alkynes (Z and E alkenes) irch conditions (a / 3 ) radical anion 3 (solvent) single electron transfer a acid/base acid/base a single electron transfer E-alkenes more stable = E Pd / 2 quinoline (ndlar's cat) Pd metal destroys strong 2 bond Pd pi complex hydride transfer forms strong - bonds Pd catalyst = repeat reaction Pd regenerated Z-alkenes (syn addition) Z:\classes\315\315 andouts\arrow pushing mechs probs key.doc

25 314/315 reactions and mechanisms through topic 11 and some of topic Aldehyde and Ketone reactions Examples of important patterns to know from our starting materials. methanal (formaldehyde) We can make aldehydes and ketones from alcohols and alkynes (for now). There are many other possibilities. a. = addition with organolithium and organomagnesium (Grignard) reagents, and workup (use n-butyl lithium, methyl lithium or phenyl lithium, others are coming, with esters, nitriles, 3 o amides and acids). aldehyde n-butyl lithium 3 / 2. workup o alcohol 2. workup 2 or ketones 3 organolithium or organomagnesium reagents 3 l 2 3 o alcohols 3 l b. = addition with terminal acetylides to form propargylic alcohols or with cyanide to form cyanohydrins aldehyde or ketone a terminal acetylide a 2. workup 2 l 2 propargylic alcohols a l = addition with cyanide forming cyanohydrin aldehyde or ketone a cy anide a 2. workup 2 2 a l cyanohydrins l Z:\classes\315\315 andouts\arrow pushing mechs probs key.doc

26 314/315 reactions and mechanisms through topic 11 and some of topic c. ucleophilic hydride = sodium borohydride (a 4 ) and lithium aluminum hydride (Al 4 = LA), [deuterium is used below to show reaction site] a reacts 4x 2. workup 2 2 a 1 o alcohol aldehyde sodium borodeuteride otice: was nucleophilic hydrogen sodium borhydride and (on ) was electrophilic hydrogen ketone Al reacts 4x lithium aluminiumdeuteride (or LA) a / 2. workup o alcohol otice: was nucleophilic hydrogen and (on ) was electrophilic hydrogen d. ydration of = in acid or base conditions (also tautomerization conditions, a competing reaction) ydration of = is similar to making acetals and ketals and hydrolysis of esters acid conditions base conditions Z:\classes\315\315 andouts\arrow pushing mechs probs key.doc

27 314/315 reactions and mechanisms through topic 11 and some of topic e. Ketone to hemi-ketal to ketal and aldehyde to hemi-acetal to acetal (protects = as di-ether during neutral and basic reactions conditions). Ketals and acetals revert back to = in aqueous acid conditions. Making a ketal (acetals are similar) functional ketone & aldehydes group = Ts Ts Ts hemi-ketal common name = hemi-acetal ketal & acetal common name = water controls the direction of equilibrium emove 2 shifts equilibrium to the ketal & acetal Adding 2 shifts equilibrium to the ketone & aldehydes eprotection of ketal (acetal) to regenerate ketone or aldehyde, 1 reaction, then E1 reaction to form = (deprotection of a ketone or aldehyde) l ydrolysis of a ketal back to a ketone and ethylene glycol (acetals are similar and go back to aldehydes and ethylene glycol) ( 2 4 / 2 ) common name = ketal & acetal functional group = ketone & aldehydes emove 2 shifts equilibrium to the ketal & acetal Adding 2 shifts equilibrium to the ketone & aldehydes hemi-ketal hemi-acetal Z:\classes\315\315 andouts\arrow pushing mechs probs key.doc

28 314/315 reactions and mechanisms through topic 11 and some of topic f. Primary amines imines reduced to amines with sodium cyanoborohydride (can form 1 o, 2 o, 3 o amines) Making an imine from a ketone or aldehyde and 3, 2 or 2. Then making the imine into a 1 o, 2 o or 3 o amine using a 3 and workup. ketone or aldehyde 2 3, 2 or 2 Ts p 5 (- 2 ) 2 Ts water controls the direction of equilibrium remove to for imine emove 2 shifts equilibrium to the imine Adding 2 shifts equilibrium back to the ketone/aldehhde + amine imine 2 educe imine to amine with 1. sodium cyanoborohydride and 2. workup imine a a 2. workup 2 amine Transformations = + 3 primary amines = + 1 o amines secondary amines = + 2 o amines tertiary amines g. econdary amines enamines react with electrophiles + hydrolyze ketones with new bonds ketone or aldehyde Ts p 5 (- 2 ) Ts Water controls the direction of equilibrium emove 2 shifts equilibrium to the enamine Adding 2 shifts equilibrium back to the ketone/aldehhde + enamine remove to form enamine enamine - good carbon nucleophile Z:\classes\315\315 andouts\arrow pushing mechs probs key.doc

29 314/315 reactions and mechanisms through topic 11 and some of topic eact enamine with 1. electrophile and 2. workup to reform =, joined with the electrophile 2. workup new ketone with added electrophile h. TP protection of alcohols & deprotection a. protection conditions - alkene addition reaction alcohol Ts P = dihydropyran TP ethers do not react under strong base/nucleophiles and neutral conditions. They are hydrolyzed back to the alcohol under aqueous acid conditions. TP = TP = tetrahydropyran protected alcohol b. deprotection conditions - aqueous acid conditions hydrolyzes acetal back to alcohol TP = tetrahydropyran protected alcohol desired alcohol etc. Z:\classes\315\315 andouts\arrow pushing mechs probs key.doc

30 314/315 reactions and mechanisms through topic 11 and some of topic i. Wittig reactions P X compound made from -, - or alkene. 2 P Wittig salt a very strong base 3 P ylid nucleophile P aldehydes and ketones P triphenylphosphine oxide Z-alkene is typically the major product P oxyphosphatane P betaine j. uprate reactions (with X, with acid chlorides, with α,β-unsaturared =) Make the cuprate metal 2 reacts with acid chlorides to make ketones organolithium reagents u cuprous salt u organocuprate reacts with acid chlorides reacts with X compounds reacts with α,β-unsaturated = u l acyl substitution l new bond reacts with X compounds u 2 new bond alkane - hard to tell where the new bond formed 2 u conjugate addition 2. workup new bond Z:\classes\315\315 andouts\arrow pushing mechs probs key.doc

31 314/315 reactions and mechanisms through topic 11 and some of topic arboxylic acids and derivatives reactions Examples of important patterns to know from our starting materials. methanoic acid (formic acid) methanoate esters (formic esters) methanamides (formamides) (1 o, 2 o and 3 o amides are possible) methanoyl chloride is not stable l ethanoyl chloride l l l l l We can make carboxylic acids from 1 o alcohols, aldehydes and nitriles (for now). a. ase hydrolysis of esters ester base hydrolysis = saponification = acyl substitution ester carboxylic acid a a 2. workup (neutralize carboxylate) alcohol ometimes we want the alcohol part of the ester, sometimes the acid part of the ester and sometimes both parts. a a Z:\classes\315\315 andouts\arrow pushing mechs probs key.doc

32 314/315 reactions and mechanisms through topic 11 and some of topic b. acid chloride + = esters (notice two different groups joined together by an oxygen) ester synthesis from acyl substition at an acid chloride with an alcohol l acid chloride acyl substitution c. acid chloride + 2 = 2 o amides (notice two different groups joined together by a nitrogen) l l ester secondary amide synthesis from acyl substition at an acid chloride with a primary amine acyl l substitution l l acid chloride 2 d. ynthesis of acid chlorides using thionyl chloride + carboxylic acids, acyl substitution, twice amide 3 l l l l acid chloride l l l acylium ion l l l l l ase l l ase Z:\classes\315\315 andouts\arrow pushing mechs probs key.doc

33 314/315 reactions and mechanisms through topic 11 and some of topic e. acyl substitution, then two elimination reactions synthesis of a nitrile from an 1 o amide + thionyl chloride (l 2 ) 1 o amides l l l l l l l ase l l l nitrile l l l l ase Z:\classes\315\315 andouts\arrow pushing mechs probs key.doc

34 314/315 reactions and mechanisms through topic 11 and some of topic Z:\classes\315\315 andouts\arrow pushing mechs probs key.doc f. addition reaction (hydration) to imidate, tautomers to amide, acyl substitution to carboxylic acid l / 2 hydrolysis of a nitrile to an amide (in 2 4 / 2 / hydrolysis continues on to a carboxylic acid) 3 3 stop here in l/ 2 3 see structures directly above most stable cation drives equilibrium to completion hydroxamic acid 1 o amides carboxylic acids (in 2 4 / ) (continue on in 2 4 / 2 )