Four new mechanisms to learn: S N 2 vs E2 and S N 1 vs E1

Transcription

1 cleophilic ubstitution & Elimination hemistry 1 Four new mechanisms to learn: vs E2 and 1 vs E1 = substitution = a leaving group () is lost from a carbon atom () and replaced by nucleophile (:) = nucleophilic = nucleophiles (:) donate two electrons to carbon in a manner similar to bases donating to a proton (:) E = elimination = two vicinal groups (adjacent) disappear from the skeleton and are replaced by a pi bond 1 = unimolecular kinetics = only one concentration term appears in the rate law expression, ate = k[] 2 = bimolecular kinetics = two concentration terms appear in the rate law expression, ate = k[] [: or :] competes with E2 1 competes with E1 These electrons always leave with. 1 ompeting eactions (strong) (concerted) (weak) (multi-step) ompeting eactions E2 arbon Group Leaving Group E1 = methyl, primary, secondary, tertiary, allylic, benzylic E2 approach (usually from the backside in an "anti" conformation, "syn" is possible, but not common) : / : = is an electron pair donor to carbon (= nucleophile) or to hydrogen (= base). It can be strong (/E2) or weak ( 1/E1). approach (always from the backside, resulting in inversion of configuration) strong base strong nucleophile = -l, -, -I, - 2 (possible leaving groups in neutral, basic or acidic solutions) = - 2 (only possible in acidic solutions) ne step, concerted reactions, from the backside. product (a nucleophile substitutes for a leaving group) or forms, depending on configuration E2 product (a pi bond forms) E or Z forms, depending on conformation stable leaving group = substitution E = elimination : = strong nucleophile : = strong base = leaving group Terms 2 = bimolecular kinetics (second order, rate in slow step depends on and : /: ) + - = -l, -, -I, -Ts, 2 and E reactions (A is a pre-exponential term and can be considered to be the maximum possible rate constant when E a = 0) reactions = substitution nucleophilic bimolecular ate = k 2 [][: ] bimolecular kinetics, both and : participate in the slow step of the reaction; k 2 = Ax10 E2 reactions = elimination bimolecular ate = k E2 [][: ] bimolecular kinetics, both and : participate in the slow step of the reaction; k E2 = Ax10 1 reactions = substitution nucleophilic unimolecular ate = k 1 [] unimolecular kinetics, only participates in the slow step of the reaction; k 1 = Ax10 E1 reactions = elimination unimolecular ate = k E1 [] unimolecular kinetics, only participates in the slow step of the reaction; k E1 = Ax10 - Ea(1) 2.3xxT - Ea(E1) 2.3xxT - Ea(E2) 2.3xxT - Ea(2) 2.3xxT y:\files\classes\314\314 pecial andouts\314 & E pring 2013.doc

2 cleophilic ubstitution & Elimination hemistry 2 is the most important mechanism 2 3 methyl (Me) primary (1 o ) secondary (2 o ) tertiary (3 o ) allylic benzylic beta carbon (0-3 of these) -alpha carbon (only 1 of these) elative rates of reactions - steric hindrance at the carbon slows down the rate of reactions k 30 methyl (unique) k 1 ethyl (primary) reference compound k isopropyl (secondary) k 30 t-butyl (tertiary) (very low) methyl primary secondary Methyl has three easy paths of approach by the nucleophile. It is the least sterically hindered carbon in reactions, but it is unique. tertiary Primary substitution allows two easy paths of approach by the nucleophile. It is the least sterically hindered "general" substitution pattern for reactions. = Tertiary substitution has no easy path of approach by the nucleophile from the backside. We do not propose any reaction at tertiary centers. All of these are primary - structures at, but substituted differently at econdary substitution allows one easy path of approach by the nucleophile. It reacts the slowest of the possible substitution reactions. When the carbon is completely substituted the nucleophile cannot get close enough to make a bond with the carbon. Even - sigma bonds block the nucleophiles approach k 1 ethyl reference compound k 0.4 propyl k methylpropyl 3 k ,2-dimethylpropyl (1 o neopentyl) 33 A completely substituted carbon atom also blocks the : approach to the backside of the - bond. A large group is always in the way at the backside of the - bond. If even one bond at 33 has a hydrogen then approach by : to the backside of the - bond is possible and an reaction is possible. y:\files\classes\314\314 pecial andouts\314 & E pring 2013.doc

3 cleophilic ubstitution & Elimination hemistry 3 versus E2 overview Example - primary, requires strong nucleophile/base, > E2, except when potassium t-butoxide or sodium amide > E2 = strong = anything (unless t-butoxide) with negative charge, and neutral sulfur, phosphorous or nitrogen 1-bromopropane (also 2 = E2) 3 1-bromopropane E2 > (when t-butoxide) 3 alkene Example - secondary, requires strong nucleophile/base, or E2, depends on strength and size of nucleophile / base E2 ome examples more basic = E2 > at secondary and E2 depends on steric size and basicity of donor 3 (2)-2-bromobutane 3 and E2 depends on steric size and basicity of 3 b donor a less basic = > E2 at secondary b K a (2)-2-bromobutane 1-butene 2E-butene 2Z-butene Example - tertiary, requires strong nucleophile/base, only E2, generally favors more stable alkene = more substituted alkene E2 reaction 3 at 3 o with strong basenucleophile b only first 2 a 3 mechanism 3 3 is shown 2-methylbut-1-ene 2-methylbut-2-ene (2)-2-bromobutane y:\files\classes\314\314 pecial andouts\314 & E pring 2013.doc

4 cleophilic ubstitution & Elimination hemistry 4 1 / E1 overview: Always 1 > E1 in our course, except when / 2 4 / 1 and E1 reactions begin exactly the same way. The leaving group,, leaves on its own, forming a carbocation. 1 and E1 reactions are multistep reactions. The - bond ionizes with help from the polar, protic solvent, which is also usually the weak nucleophile/base. solvated carbocation addition of a weak nucleophile ( 1 type reaction) Loss of a beta hydrogen atom, ( - in most E1 reactions that we study). rearrangement to a new carbocation of similar or greater stability add : ( 1) lose beta (E1) rearrange weak base = weak nucleophile weak base solvated carbocation E1 approach comes from parallel - with either lobe of 2p orbital. 1 approach is from either the top face or the bottom face. weak nucleophile 1 E1 E1 products (pi bond forms) ften a final proton transfer is necessary. stable leaving group 1 product (a nucleophile substitutes for a leaving group) = substitution E = elimination -: = weak nucleophile -: = weak base = leaving group Terms 1 = unimolecular kinetics (first order reaction, the rate in the slow step depends only on ) - = -l, -, -I, -Ts, 2 + = = usually a polar, protic solvent (or mixture) of 2, or 2 1 and E1 relative reactivities of - compounds with weak base/nucleophiles (-: / -:) - 1 > E1 (usually) one exception where E1 > 1 = "", / relative rates = = 1,000,000 These rates are probably by reaction. eference compound elative 1/E1 reactivity: methyl << primary << secondary << tertiary. y:\files\classes\314\314 pecial andouts\314 & E pring 2013.doc

5 cleophilic ubstitution & Elimination hemistry 5 elative tability of arbocations, + ydride Affinity A larger hydride affinity means a less stable carbocation. = energy released = Potential Energy methyl & primary We will not propose these carbocations in solution in this book. Inductive effects secondary ome of these values are esitimated from different sets of data. tertiary "" resonance "" resonance other / misc esonance effects adjacent pi bond adjacent lone pair empty sp orbital -386 ethynyl carbocation (see problem below) empty 2p orbital -287 vinyl carbocation (see problem below) empty sp 2 orbital -300 phenyl carbocation (see problem below) y:\files\classes\314\314 pecial andouts\314 & E pring 2013.doc

6 cleophilic ubstitution & Elimination hemistry 6 These structures represent your hydrocarbon starting points to synthesize target molecules (TM) that are specified. You will need to propose a step-by-step synthesis for each target molecule from these given structures. Every step needs to show a reaction arrow with the appropriate reagent(s) above each arrow and the major product of each step. This is often accomplished by using retrosynthetic thinking. You start at the target molecule (the end) and work your way backwards (towards the beginning), one step at a time until you reach an allowed starting material. The starting material of each step becomes the target molecule for the next step until you reach the beginning. Allowed starting structures our main sources of carbon 1. free radical substitution of alkane sp 3 - bonds to form sp 3 - bonds at the weakest - position and 2. Anti-Markovnikov addition to alkenes makes 1 o / 2 / 2 / 2 / 2 / 2 / 2 / 3 K E2 reaction K E2 reaction K E2 reaction K E2 reaction K E2 reaction 2 2 / 2 2 / 2 2 / We need to make these 1 o from anti-markovnikov free radical addition of - () to alkenes. 2 / 2 / 2 / Examples of allylic compounds: This is just free radical substitution at allylic sp 3 - position of an alkene. benzylic, f rom above y:\files\classes\314\314 pecial andouts\314 & E pring 2013.doc

7 cleophilic ubstitution & Elimination hemistry 7 1. Mechanism for free radical substitution of alkane sp 3 - bonds to form sp 3 - bonds at weakest - position overall reaction 1. initiation 2a propagation 3 2 weakest bond ruptures first E = +95 kcal/mole E = -88 kcal/mole = +7 kcal/mole (overall) = 46 kcal/mole = -15 2b propagation E = +46 kcal/mole E = -68 kcal/mole = -22 kcal/mole (overall) both steps 3. termination = combination of two free radicals - relatively rare because free radicals are at low concentrations 3 = -68 kcal/mole very minor product 3 = -80 kcal/mole 2. Free radical addition mechanism of - alkene pi bonds (alkenes can be made from E2 or E1 reactions at this point in course) (anti-markovnikov addition to alkenes) overall reaction (cat.) initiation (two steps) 2a propagation 3 2 (cat.) reagent 3 2 = 40 kcal/mole E = +88 kcal/mole E = -111 kcal/mole = -23 kcal/mole E = +63 kcal/mole E = -68 kcal/mole = -5 kcal/mole y:\files\classes\314\314 pecial andouts\314 & E pring 2013.doc

8 cleophilic ubstitution & Elimination hemistry 8 2b propagation E = +88 kcal/mole E = -98 kcal/mole = -10 kcal/mole 3. termination = combination of two free radicals - relatively rare because free radicals are at low concentrations very minor product = -15 both steps (2a + 2b) = -68 kcal/mole eagent list for our course (hem 314) What kind of mechanisms are possible? What is the major mechanism occuring? e able to write in ALL mechanism details (lone pairs, formal charge, curved arrows, etc.) for each step of each reaction studied. Mechanism choices at this point in organic chemistry:, E2, 1, E1,acid/base reaction, free radical substitution, free radical addition to alkenes and no reaction. clephile/ases (and other reagents) to choose from include: purchase / given - You can invoke these whenever you need them. ome of these will disappear when we learn how to make them. 2 l 2 Al sodium hydroxide lithium aluminium hydride (nucleophilic) dithiane 2 sodium amide sodium borohydride (nucleophilic) sodium hydride (only basic) K potassium hydride (only basic) 3 sodium azide water ethanol monohydrogen sulfide sodium cyanide diisopropylamine Al 3 ethanoic acid propanone lithium aluminium sodium (acetic acid) (acetone) n-butyl lithium hydride borohydride (nucleophilic) (nucleophilic) t-butyl alcohol These two are exceptions to our P strong nucleophiles = anions. Ph Ph Ph Ph They are good neutral necleophiles. Ph oth are used to make ylids (one diphenyl sulfide triphenylphosphine sulfur and one phosphorous) (useful for making epoxides) (used for making Wittig reagents) strong acids: l,, I, 2 4 (buy all of these = given) strong bases:,, K, n-u, 2, (buy all of these = given) t-uk, LA (make these) strong nucleophiles:, Al 4, Al 4, 4, 4,, Ph 2, Ph 3 P, (buy all of these = given), 2,, -enolates, -dithiane (make these) weak nucleophiles: 2,, 2 (buy all of these = given) common electrophiles: (= l,, I) (make these) free radical reactions: alkane - substitution ( 2 /), anti-markovnikov addition to alkenes (/ (cat)/) ome of our reagents have to be made (often by acid/base reactions) Make alkoxides and use as nucleophiles only at Me- and 1 o 2 - in reactions. alcohols alkoxides ethers y:\files\classes\314\314 pecial andouts\314 & E pring 2013.doc

9 cleophilic ubstitution & Elimination hemistry 9 Make potassium t-butoxide and use as sterically large, strong base at 1 o 2 -, 2 o 2 - and 3 o 3 - in E2 reactions. Make carboxylates and use as nucleophiles at Me-, 1 o 2 - and 2 o 2 - in reactions. ethanoic acid (acetic acid) ethanoate (acetate) esters Make terminal acetylides and use as nucleophiles only at Me- and 1 o 2 - in reactions. terminal alkynes 2 terminal acetylides alkynes Make thiolates and use as nucleophiles at Me-, 1 o 2 - and 2 o 2 - in reactions. thiols alkylthiolates sulfides ynthesis of lithium diisopropyl amide, LA, sterically bulky, very strong base used to remove α - proton of carbonyl groups. (acid / base reaction) to make carbonyl enolates. given 2 given K eq = K a = = K a Think - sterically bulky, very basic that goes after weakly acidic protons. LA = lithium diisopropyl amide eact ketone enolate (nucleophile) with - electrophile (Me, 1 o and 2 o compounds) Make enolate (ketones) given -78 o 2 LA ketones (and other carbonyl compounds) K eq = K a = = K a ketone enolates (resonance stabilized) y:\files\classes\314\314 pecial andouts\314 & E pring 2013.doc

10 cleophilic ubstitution & Elimination hemistry 10 eact ketone enolate with compounds (methyl, 1 o and 2 o ) 2 ketone enolates (resonance stabilized) reactions -78 o 1 o key bond Larger ketone made from smaller ketone. eact ester enolate (nucleophile) with - electrophile (Me, 1 o and 2 o compounds) Make enolate (esters) given -78 o 2 LA ketones (and other carbonyl compounds) K eq = K a = = K a ketone enolates (resonance stabilized) eact ester enolate with compounds (methyl, 1 o and 2 o ) 2 ester enolates (resonance stabilized) reactions -78 o 1 o key bond Larger ester made from smaller ester. y:\files\classes\314\314 pecial andouts\314 & E pring 2013.doc

11 cleophilic ubstitution & Elimination hemistry 11 - patterns - typical reaction patterns in our course (bold = atypical result) eagents methyl 1 o primary 2 o secondary 3 o tertiary 1 o neopentyl allylic benzylic only > E2 E2 > only E2 no reaction very fast very fast only > E2 E2 > only E2 no reaction very fast very fast 2 only > E2 > E2 only E2 no reaction very fast very fast K -( 3 ) 3 t-butoxide only E2 > only E2 only E2 no reaction A A only > E2 > E2 only E2 no reaction very fast very fast only > E2 E2 > only E2 no reaction very fast very fast 3 only > E2 > E2 only E2 no reaction very fast very fast 1. 3 () 2. Al 4 () 3. workup (acid/base) makes 1 o amines makes 1 o amines makes 1 o amines only E2 no reaction makes 1 o amines makes 1 o amines only > E2 > E2 only E2 no reaction very fast very fast only > E2 > E2 only E2 no reaction very fast very fast 3 only > E2 > E2 only E2 no reaction very fast very fast 3 only > E2 > E2 only E2 no reaction very fast very fast Al 3 only > E2 > E2 only E2 no reaction very fast very fast Al 3 only > E2 > E2 only E2 no reaction very fast very fast only > E2 > E2 only E2 no reaction very fast very fast ketone enolates ester enolates only > E2 > E2 only E2 no reaction very fast very fast The following are synthetic approaches to some of the target molecules above. They are presented as examples of how you might approach synthesis problems (these and others like them). You need to not only look at structures that I provide above but think about other possibilities using all of the structures available to you. I do not list every possibility (there are too many), but you need to be able to consider every possibility. The best strategy is to work backwards from the target molecule to an allowed starting structure (cover up everything but the target structure and write out an answer for how you could make that molecule, then start all over on target molecule minus one, which is called retrosynthetic analysis ). That way you are only thinking about one backward step at a time, instead of an unknown number of steps forward from a starting structure you are not sure of. This is the way I presented the approaches below. You should also know the mechanism for every reaction below. I can write these pages until I am blue in the face, but they can t help you learn, unless you do the work of trying them out. My job is to give you an opportunity to learn, and your job is to take advantage of that opportunity. These schemes were made quickly, so be on the lookout for mistakes. (I hope not too many.) y:\files\classes\314\314 pecial andouts\314 & E pring 2013.doc

12 cleophilic ubstitution & Elimination hemistry ynthesis of compounds - Free radical substitution at sp 3 - and free radical addition to alkenes (anti- Markovnikov addition). Making these represents our most common starting points. These are our target molecules (TM). ample - from - using 2 / - you have to make these 3 methyl 1 o 2 o 3 o allylic allylic allylic 2 o 1 o benzylic Free radical substitution mechanism: ( light) of each step is controlled by relative bond energies 1. initiation 2a and 2b. propagation 3. termination. 2 o benzylic 1 o 1 o 1 o Free radical addition mechanism: (alkene + / + light) of each step is controlled by relative bond energies 1. initiation 2a and 2b. propagation 3. termination. TM 1 o we need these 1 o we need these (cat.) free radical addition (cat.) free radical addition TM - 1 alkene alkene K E2 potassium t-butoxide K E2 potassium t-butoxide TM o TM TM - 1 TM o TM TM - 1 K TM (cat.) free radical addition E2 potassium t-butoxide 2 free radical substitution 2 free radical substitution 2 free radical substitution allowed starting material propane allowed starting material 2-methylpropane (isobutane) allowed starting material ethylbenzene allylic compounds - ( is more likely reagent, but we only know 2 ). You will need to make the starting alkene (E2 reactions) TM TM - 1 K TM - 2 allowed 2 starting material 2 free radical E2 free radical substitution potassium 2-methylpropane 1 o allylic substitution t-butoxide 3 o (isobutane) y:\files\classes\314\314 pecial andouts\314 & E pring 2013.doc

13 cleophilic ubstitution & Elimination hemistry 13 TM TM - 1 K TM o allylic free radical substitution E2 potassium t-butoxide 3 o TM TM - 1 TM E2 2 o allylic free radical substitution potassium t-butoxide 2 free radical substitution 2 free radical substitution propane cyclohexane allowed starting material allowed starting material 2. alcohol synthesis starting from (later there will be many other approaches) These are our target molecules (TM). ample alcohols - reactions using (- + ) at Me, 1 o, 2 o, allylic or 1 reactions using (- + 2 ) at 2 o, 3 o or 1 or 1 alcohols - various approaches, at methyl and primary using and 1 at secondary and tertiary using 2 TM TM o alcohol 1 > E2 o see above, from propene ydroxide and alkoxides are K nucleophiles at methyl and 1 o, but E2 > at 2 o and only E2 at 3 o. TM TM > E1 2 o alcohol 1 o free radical substitution allowed starting structure Generally, 1 > E1 at 2 o and 3 o if we don't have to worry about rearrangements. o 1/E1 at methyl and 1 o. TM 2 1 > E1 TM o alcohol 3 o 2 free radical substitution allowed starting structure Generally, 1 > E1 at 2 o and 3 o if we don't have to worry about rearrangements. o 1/E1 at methyl and 1 o. mechanisms using aqueous hydroxide introduces a new alcohol functional group (-) 3 key bond 3 y:\files\classes\314\314 pecial andouts\314 & E pring 2013.doc

14 cleophilic ubstitution & Elimination hemistry key bond key bond mechanisms (if no rearrangement) using water introduces a new alcohol functional group (-) 1 > E1 at 2 o and 3 o and we don't have to worry about rearrangements here. 2 water is a nucleophile water is a base 1 > E1 2 water is a nucleophile water is a base 1 > E1 3. ether synthesis - starting from ( at Me and 1 o with alkoxide, 1 at 2 o and 3 o and ) ample ethers - reactions using (- + There are many more possibilities. ) at Me, 1 o, 2 o, allylic or 1 reactions using (- + ) at 2 o, 3 o ( 1 or ) ( 1 or ) ethers - various approaches, at methyl and primary using and 1 at secondary and tertiary using TM target molecule 1. acid / base 2. > E2 Generally, 1 > E1 at 2 o and 3 o. o 1/E1at methyl and 1 o. TM - 1 TM > E1 2 free radical substitution TM - 1 TM - 2 allowed starting structure 2 free radical substitution allowed starting structure y:\files\classes\314\314 pecial andouts\314 & E pring 2013.doc

15 cleophilic ubstitution & Elimination hemistry 15 TM 1. TM - 1 acid / base 2. Ph > E2 already target molecule made TM - 1 TM - 1 TM - 2 Ph 2 free radical substitution given 1 > E1 already made Ph Ph = phenyl mechanisms using aqueous alkoxide introduces a new ether functional group (-- ) key bond key bond 3 key bond mechanisms (if no rearrangement) using alcohol introduces a new ether functional group (-- ) y:\files\classes\314\314 pecial andouts\314 & E pring 2013.doc

16 cleophilic ubstitution & Elimination hemistry ester synthesis (using the oxygen side and using the carbon enolate side, also ketone examples using an enolate) These are our target molecules (TM) - using the oxygen side (carboxylates). ample alcohols - reactions using (- + 2 ) at Me, 1 o, 2 o, allylic or 1 reactions using (- + 2 ) at 2 o, 3 o esters - various approaches, at methyl, primary and secondary using 2. 1 at secondary and tertiary using 2 but possible rearrangement. TM already made arboxylates are K nucleophiles TM acid / base at methyl, 1 o and 2 o but 2. only E2 at 3 o. target molecule given > E2 TM - 1 TM - 1 TM already made 1 > E1 given 1 > E1 mechanism using carboxylate at center introduces a new ester functional group ( 2 ) 3 key bond 3 y:\files\classes\314\314 pecial andouts\314 & E pring 2013.doc

17 cleophilic ubstitution & Elimination hemistry 17 1 mechanisms (if no rearrangement) using carboxylic acid introduces a new ester functional group ( 2 - ) 1 > E1 at 2 o and 3 o and we don't have to worry about rearrangements here. 1 > E1 acid is a nucleophile resonance acid is a base acid is a 1 > E1 nucleophile resonance acid is a base These are our target molecules (TM) - using the carbon side (ketone enolates from only propanone for now). ample alcohols - reactions using (- + ketone enolate) at Me, 1 o, 2 o, allylic new bond new bond new bond new bond new bond new bond new bond new bond etc, etc, etc y:\files\classes\314\314 pecial andouts\314 & E pring 2013.doc

18 cleophilic ubstitution & Elimination hemistry 18 TM via ester enolates target molecule key bond o LA (makes enolate) acid / base 2. TM - 1 > E2 n-butyl lithium acid / base already made allowed starting structure diisopropylamine Enolates are K nucleophiles at methyl, 1 o and 2 o but only E2 at 3 o. mechanism using ester enolate at center makes a larger ester on the carbon side ( 2 ) 2 3 (alkylation) -78 o 2 (3 = 2 + 1) key bond (alkylation) -78 o 2 (4 = 2 + 2) key bond (alkylation) -78 o 2 (5 = 2 + 3) key bond ketone enolates (good nucleophiles at epoxides, carbonyls and 3, 1 o and 2 o ) bigger ketones (alkylation) -78 o (alkylation) -78 o 3 2 (4 = 3 + 1) 2 key bond key bond y:\files\classes\314\314 pecial andouts\314 & E pring 2013.doc

19 cleophilic ubstitution & Elimination hemistry (alkylation) -78 o key bond (6 = 3 + 3) 5. azide and primary amine synthesis (azides can be made into primary amines via 1. Al 4 2. workup) Proposed mechanisms -2 = 3 2-azidopropane 3 Al lithium aluminium hydride 2. workup 2 alkyl azide nitrogen 1 o amines at nitrogen, 2 leaving group y:\files\classes\314\314 pecial andouts\314 & E pring 2013.doc

20 cleophilic ubstitution & Elimination hemistry alkene synthesis (via one E2 reaction with and t-uk, we will see other ways to make alkenes later) ample alkenes using E2 reactions: - + t-butoxide; alkenes can make allylic - compounds ample allylic bromides from alkenes ( 2 / ) alkenes TM 1. acid / base inexpensive base is K because is tertiary TM TM - 1 already made K acid / base Use steric bulk and/or extreme basicity to drive E2 >. TM - 1 K already made E2 > (need strong, bulky base to favor E2 at 1 o ) relative alkene stabilities = tetrasub. > trisub. > trans-disub > cis-disub gem-disub > monosub > unsub. allowed starting structure Use steric bulk and/or extreme basicity to drive E2 >. TM already made TM - 1 already made K already made K E2 E2 already made 7. alkyne synthesis (via two E2 reactions with 2 and 2x 2, two times) ample alkynes using double E2 reactions of workup Make starting alkynes using two leaving groups and very basic 2 (2 equivalents) 1. 2 sodium amide (very strong base) E2 twice 2. workup Use steric bulk and/or extreme basicity to drive E2 >. and (2 equivalents) 2 free radical substitution (2 equivalents) 1. 2 sodium amide (very strong base) E2 twice 2. workup (2 equivalents) 2 free radical substitution y:\files\classes\314\314 pecial andouts\314 & E pring 2013.doc

21 cleophilic ubstitution & Elimination hemistry 21 (2 equivalents) 1. 2 sodium amide (very strong base) E2 twice 2. workup (2 equivalents) 2 free radical substitution ample alkynes using reactions of 1. terminal alkyne only at methyl or primary - (can do twice with ethyne) new bond 1. 2 sodium amide (very strong base) (1 equivalent) acid / base 2. 3 > E2 new bond 1. 2 sodium amide (very strong base) (1 equivalent) acid / base 2. > E2 Terminal acetylides are K nucleophiles at methyl and 1 o, but E2 > at 2 o and only E2 at 3 o. Possible steps in mechanism (E2 twice then 2. acid/base or 2. electrophile) a b 2 2. workup 2. 2 b a y:\files\classes\314\314 pecial andouts\314 & E pring 2013.doc

22 cleophilic ubstitution & Elimination hemistry equivalent 1. 2 (4 = 2 + 2) terminal alkyne 2. 1 equivalent 1. 2 (5 = 3 + 2) internal alkyne 1 equivalent (6 = 3 + 3) terminal alkyne 2. 1 equivalent 1. 2 acid/base 1. excess 2. workup (neutralize) (zipper reaction) like tautomers (5 = 3 + 2) internal alkyne 1 equivalent 1. 2 acid/base 2. (6 = 4 + 2) terminal alkyne 1 equivalent 1. 2 acid/base 2. terminal acetylides ( only at methyl and 1 o ) larger alkynes (6 = 3 + 3) internal alkyne 1. excess 2. workup (neutralize) (zipper reaction) like tautomers y:\files\classes\314\314 pecial andouts\314 & E pring 2013.doc

23 cleophilic ubstitution & Elimination hemistry nitrile synthesis (via reaction at Me, 1 o, 2 o ) ample nitriles using reactions of cyanide + methyl, primary or secondary - 3 nitriles allowed > E2 already made yanides are K nucleophiles at methyl, 1 o and 2 o but only E2 at 3 o. allowed > E2 already made cyanide nitriles y:\files\classes\314\314 pecial andouts\314 & E pring 2013.doc

24 cleophilic ubstitution & Elimination hemistry thiols (via reaction with -- at Me, 1 o, 2 o ) and sulfides synthesis (via reaction with -- at Me, 1 o, 2 o ) ample thiols using reactions of 3 + methyl, primary, secondary, allylic, benzylic - ample sulifides using reactions of + methyl, primary or secondary - (many possibilities) thiols and sulfides sulfide 1. acid / base 2. > E2 thiol (pk a 8) > E2 already made ulfides are K nucleophiles at methyl, 1 o and 2 o but only E2 at 3 o. Possible mechanisms 3 key bond key bond key bond y:\files\classes\314\314 pecial andouts\314 & E pring 2013.doc

25 cleophilic ubstitution & Elimination hemistry key bond key bond 3 key bond introducing nucleophilic hydride or deuteride into organic molecules (via reaction) ample deuterium added using reactions of Al 4 or 4 + methyl, primary, secondary, allylic, benzylic - 3 Al Al lithium aluminium hydride = LA = ( Al 4 ) and sodium borohydride ( 4 ) are both nucleophilic hydride. For now we will consider them to be equivalent reagents. lithium aluminium hydride (Al 4 ) and sodium borohydride ( 4 ) = nucleophilic hydride (using deuteride shows where the hydrogen goes) Al Al key bond 3 key bond ethane y:\files\classes\314\314 pecial andouts\314 & E pring 2013.doc

26 cleophilic ubstitution & Elimination hemistry 26 key bond Al propane Mechanisms Worksheet You need to be able to write your own mechanism from starting structures. I suggest you should practice using the nucleophiles from the list with the various compounds listed above. Writing mechanisms for each possibility would give you more than enough practice to learn the mechanism. ommon mistakes include lone pairs, formal charge, curved arrows, correct Lewis structures, correct products predicted. This stuff takes practice A correcting your mistakes. I have set up the following worksheet to give you templates to fill in so that you can use them multiple times by copying the basic framework and then filling in the details. You can do this IF YU TE WK! then E2 examples first, followed by 1 and E1 reactions Example (deuterium = and tritium = T are isotopes of hydrogen that can be distinguished from ) The only possible choice at methyl is. There is no - for E2 reactions, and methyl + is too high energy for solution chemistry, so no 1/1. strong = anything with negative charge, and neutral sulfur or nitrogen choose from our list Easier methyl example choose from our list bromomethane arder methyl example - T- choose from above, T T -bromodeuteriotritiomethane? Examples you might consider: -bromodeuteriotritiomethane only only (with strong nucleophiles) We cannot see inversion of configuration, but we assume it occurs if the kinetics is bimolecular. only (with strong nucleophiles) We can see inversion of configuration, because there is a chiral center and the kinetics is bimolecular. T weak nucleophile/bases = no reaction - in our course these are 1 and E1 conditions (weak) = strong = anything with negative charge, and neutral sulfur or nitrogen = strong = anything with negative charge, and neutral sulfur or nitrogen y:\files\classes\314\314 pecial andouts\314 & E pring 2013.doc

27 cleophilic ubstitution & Elimination hemistry 27 Example 2 - primary 2 - (deuterium = and tritium = T are isotopes of hydrogen that can be distinguished from ) is the main reaction unless the strong electron pair donor is bulky and basic, then E2 is the main reaction (only potassium t-butoxide in our course). Easiest primary example a = E2 b = 2 choose from our list a = E2 a = E2 b = b a a b arder primary example choose from our list Example 2 - primary b a bromoethane b vertical view a a (1,2)- 1-bromo-1,2-dideuteriopropane 3? b (unless t-butoxide) (1,2)- 1,2-dideuterio-1-bromopropane 3 >E2 >E2 or can be (unless t-butoxide) anti to a - (1,2)- 1,2-dideuterio-1-bromopropane b bromoethane a a b horizontal view a b a = E2 b = b = choose from our list 3 E-alkene 3 b a (1,2)- 1-bromo-1,2-dideuteriopropane 3 E2 3 Z-alkene =? strong = anything with negative charge, and neutral sulfur or nitrogen y:\files\classes\314\314 pecial andouts\314 & E pring 2013.doc

28 cleophilic ubstitution & Elimination hemistry 28 Example 3 - primary T T mechanism >E2 (unless t-butoxide) (1,2)-1,2-dideuterio-1-bromoethane (1,2)-1,2-dideuterio-1-nucleophile-ethane E2 mechanism or can be anti to a - (1,2)-1-bromo-1,2- dideuterio-1-tritioethane T (1,2)-1-bromo-1,2- dideuterio-1-tritioethane T (1,2)-1-bromo-1,2- dideuterio-1-tritioethane T (1,2)-1-bromo-1,2- dideuterio-1-tritioethane other primary to consider. 3 2 T 3 >E2 (unless t-butoxide) (1,2) (1,2) (1,2) T T T look at - fully substituted no or E2 at 1 o neopentyl, E2 is possible at 2 o neopentyl Mechanism predictions with weak nucleophile/bases: T E2 E-alkene (if is anti) T E2 T E-alkene (if is anti) E2 Z-alkene (if is anti) T E2 E-alkene (if is anti)? T T T Z-alkene (if is anti) Z-alkene (if is anti) T E-alkene (if is anti) Z-alkene (if is anti) = strong = anything with negative charge, and neutral sulfur or nitrogen E-alkene (if T is anti) E-alkene (if T is anti) Z-alkene (if T is anti) E-alkene (if T is anti) benzylic = fast o 1/E1 is possible at primary in solution chemistry. The primary + is too high in energy. y:\files\classes\314\314 pecial andouts\314 & E pring 2013.doc

29 cleophilic ubstitution & Elimination hemistry 29 Example 4 - secondary (deuterium is an isotope of hydrogen that can be distinguished from ) 3 choose from above (2,3,4)-2-deuterio-4-methyl-3-bromohexane? choose from above (2,3,4)-2-deuterio-4-methyl-3-bromohexane? ome examples more basic = E2 > at secondary 3 and E2 depends on basicity of donor 3 (2,3,4)-2-deuterio-3-bromo-4-methylhexane and E2 depends on basicity of donor 3 (2,3,4)-2-deuterio-3-bromo-4-methylhexane K 3 less basic = > E2 at secondary 3 still E2 3 3 still still Z-alkene 2E-alkene 3Z-alkene 3 (2,3)-3-deuterio-2-bromobutane 3 (2,3)-3-deuterio-2-bromobutane and E2 depends on basicity of donor and E2 depends on basicity of donor Z-alkene ome examples less basic = > E2 2E-alkene 3 2 more basic = E2 > 3 1-butene, neither E or Z still K y:\files\classes\314\314 pecial andouts\314 & E pring 2013.doc

30 cleophilic ubstitution & Elimination hemistry 30 other secondary to consider o neopentyl 3 3 allylic Mechanism predictions with:? Example 5 - tertiary (deuterium is an isotope of hydrogen that can be distinguished) 3? choose 2 from 2 3 our list 3 (2,3,4)-2-deuterio-4-methyl-3-bromohexane choose from our list 3 2 (2,3,4)-2-deuterio-4-methyl-3-bromohexane Usually 1 > E1 (except /.) 2 3 3? (2,3,4)-2-deuterio-4-methyl-3-bromohexane o reaction at 3 o, backside is too sterically hindered only E2 possible at 3 o and strong base-nucleophile, need b - though. ome examples K 3 E2 reaction at 3 o with strong basenucleophile only first mechanism 3 is shown (2,3,4)-2-deuterio-4-methyl-3-bromohexane 3 2 still 3 3 2Z-alkene (with ) still 3 3 2E-alkene (without ) still Z-alkene from "" (3E-alkene if "") 2 3 still 2 3 still 3 1-butene, neither E or Z y:\files\classes\314\314 pecial andouts\314 & E pring 2013.doc

31 cleophilic ubstitution & Elimination hemistry 31 other tertiary to consider Mechanism predictions with:? Usually 1 > E1 (except /.) Example 5 - cyclohexane structures to consider ( must be axial to react by and E2) ( can be axial or equatorial to react by 1 and E1). Essential details can be filled in on the following templates. cyclohexane without branches cyclohexane with a branch Many substitution patterns are possible. a b c d e f g h i j Mechanism predictions with: ome examples weak nucleophiles K strong nucleophile/bases + other anions shown above y:\files\classes\314\314 pecial andouts\314 & E pring 2013.doc

32 cleophilic ubstitution & Elimination hemistry 32 imple Examples general patterns (this is as easy as it gets, more complicated examples follow) nucleophile / base 3 only > E2 E2 > only E2 only E2 3 o eaction (neopentyl) o eaction (neopentyl) nucleophile / base 3 only > E2 E2 > only E2 only E2 3 o eaction (neopentyl) o eaction (neopentyl) nucleophile / base 3 only > E2 > E2 only E2 o eaction only E2 (neopentyl) o eaction (neopentyl) y:\files\classes\314\314 pecial andouts\314 & E pring 2013.doc

33 cleophilic ubstitution & Elimination hemistry 33 nucleophile / base 3 only E2 > only E2 only E2 o eaction (neopentyl) only E2 K o eaction (neopentyl and t-butoxide) nucleophile / base 3 o eaction (1 o ) o eaction (1 o ) 1 > E1 1 > E1 o eaction (1 o neopentyl) 1 > E1 & & with rearrangement (main product?) y:\files\classes\314\314 pecial andouts\314 & E pring 2013.doc

34 cleophilic ubstitution & Elimination hemistry 34 nucleophile / base 3 o eaction (1 o ) o eaction (1 o ) 1 > E1 1 > E1 o eaction (1 o neopentyl) 1 > E1 & & with rearrangement (main product?) nucleophile / base 3 o eaction (1 o ) o eaction (1 o ) 1 > E1 1 > E1 o eaction (1 o neopentyl) 1 > E1 & & with rearrangement y:\files\classes\314\314 pecial andouts\314 & E pring 2013.doc

35 cleophilic ubstitution & Elimination hemistry 35 1 / E1 possibilities extra complications at β positions, 2 o, rearrangements T considered ( 2,, 2 ) Examples of weak nucleophile/bases in our course c a b water alcohols carboxylic acids 3 (3) edrawn (achiral) 2 same first step for 1/E1 3 2 E1 product from left carbon atom E1 product from right carbon atom 3 "" parallel to empty 2p orbital on top "" parallel to empty 2p orbital on bottom (achiral) carbocation choices add nuclephile (top/bottom) = 1 lose - (top/bottom) = E1 rearrangement to similar or more stable carbocation ( + ) (start all over) 2E-alkene 2Z-alkene "" parallel to empty 2p orbital on top "" parallel to empty 2p orbital on bottom E-alkene 3Z-alkene 1 product (a. add from top and b. add from bottom) 3 2 (achiral) 2 b a b a acid/base proton transfer acid/base proton transfer enantiomers (3) 2 (3) y:\files\classes\314\314 pecial andouts\314 & E pring 2013.doc

36 cleophilic ubstitution & Elimination hemistry 36 1 / E1 possibilities extra complications at β positions, 2 o, rearrangements T considered, with deuterium (makes it a little harder) Examples of weak nucleophile/bases c a b water alcohols carboxylic acids 3 (2,3,4) edrawn (2,4) 2 3 same first step for 1/E1 2 3 (2,4) 2 3 carbocation choices add nuclephile (top/bottom) = 1 lose - (top/bottom) = E1 rearrangement to similar or more stable carbocation ( + ) (start all over) E1 product from left carbon atom 2 (2,4) 3 2 "" parallel to empty 2p orbital on top (4) 3 4,2E-alkene without "" (2,4) "" parallel to empty 2p orbital on bottom (4) 3 4,2Z-alkene without "" (2,4) "" parallel to empty 2p orbital on top (4) 3 4,2Z-alkene with "" 2 (2,4) 3 2 "" parallel to empty 2p orbital on bottom (4) 3 4,2E-alkene with "" y:\files\classes\314\314 pecial andouts\314 & E pring 2013.doc

37 cleophilic ubstitution & Elimination hemistry 37 edrawn from above (2,4) E1 product from right carbon atom 3 (2,4) "" parallel to empty 2p orbital on top 3 (2) 2 3 2,3E-alkene with "" (2,4) 2 "" parallel to empty 2p orbital on bottom 3 (2) 2 3 2,3Z-alkene with "" 3 3 (2,4) 2 2 "" parallel to empty 2p orbital on top 3 (2) 2 3 2,3Z-alkene without "" 3 (2,4) 2 3 "" parallel to empty 2p orbital on bottom 3 (2) 2 3 2,3E-alkene without "" 2 1 product (a. add from top and b. add from bottom) (2,4) 3 2 b a b a acid/base proton transfer acid/base proton transfer 2 3 diastereomers 2 (2,3,4) (2,3,4) y:\files\classes\314\314 pecial andouts\314 & E pring 2013.doc

38 cleophilic ubstitution & Elimination hemistry 38 1 / E1 possibilities extra complications at β positions of 2 o, rearrangement to more stable 3 o + considered 3 edrawn (achiral) 2 3 same first step for 1/E E1 product from left carbon atom (without rearrangement) 2 3 (3,4) 2 (4) "" parallel to empty 2p orbital on top 3 (4) stereochemistry is lost 3 3 carbocation choices add nuclephile (top/bottom) = 1 lose - (top/bottom) = E1 rearrangement to similar or more stable carbocation ( + ) (start all over) 4,2E-alkene diastereomers 2 3 "" parallel to empty 2p orbital 2 on bottom (4) ,2Z-alkene E1 product from right carbon atom (without rearrangement) (4) "" parallel to empty 2p orbital on top E-alkene diastereomers (4) 3 2 "" parallel to empty 2p orbital on bottom product (a. add from top and b. add from bottom), (without rearrangement) 3 3 3Z-alkene b a (4) 3 b a (3,4) (3,4) 2 acid/base proton transfer acid/base proton transfer diastereomers 2 (3,4) (3,4) y:\files\classes\314\314 pecial andouts\314 & E pring 2013.doc

39 cleophilic ubstitution & Elimination hemistry 39 After rearrangement to 3 o carbocation ( + ) We will skip rearrangements in hem edrawn (achiral) E1 products from left carbon atom (top and bottom, after rearrangement) (4) 2 initial 2 o carbocation rearranges via hydride shift to a 3 o carbocation "" parallel to empty 2p orbital on top and bottom of right position stereochemistry is lost in new carbocation reaction possibilities start all over again with new carbocation 3 diastereomers E-alkene add nuclephile (top/bottom) = 1 lose - (top/bottom) = E1 rearrangement to similar or more stable carbocation ( + ) (none is possible here) Z-alkene 3 E1 product from right carbon atom (top and bottom, after rearrangement) diastereomers "" parallel to 2 3 empty 2p orbital on top and bottom 2 of right position Z-alkene E-alkene 3 E1 product from methyl carbon atom (top and bottom, after rearrangement, only one product from the methyl) "" parallel to 2 3 empty 2p orbital on top and bottom 2 of right 2 position product (a. add from top and b. add from bottom), (after rearrangement) alkene (does not have E/Z stereochemistry) b (achiral) a b a (3) (3) acid/base proton transfer acid/base proton transfer enantiomers (3) 2 (3) y:\files\classes\314\314 pecial andouts\314 & E pring 2013.doc

40 cleophilic ubstitution & Elimination hemistry 40 omework problems: The number of each type of product ( 1, E1,, E2) is listed after a reaction arrow for each starting structure (assuming I analyzed the possibilities accurately in my head, while sitting at the computer). ee if you can generate those products using a valid mechanism for each one. a. b. 1 E1 E a. b a. initial carbocation b. after rearrangement a. b a. b. 1 E1 E a. b a. initial carbocation b. after rearrangement a. b chair 1 chair 2 1 E1 1 1 E2 1 1 nly consider carbocation rearrangements that immediately go to a more stable carbocation (not equally stable carbocations = too many possibilities) E1 E2 a b. 1 2 condition 1 condition 2 1 E1 E2 a b E1 2 2 E E1 E E1 E E1 2 2 E E1 E E1 E2 a b. 4 5 c. 1 2 d. 1 2 consider any 3 o + possibility and consider stereoisomers y:\files\classes\314\314 pecial andouts\314 & E pring 2013.doc

41 cleophilic ubstitution & Elimination hemistry 41 When methyl on 1 is anti to -, no is possible and no E2 is possible from 1. a b E2 possible here full rotation at - is possible otation of - 1 brings a or b anti to -, which allows and two different E2 possibilities: a (Z) and b (E). ince 2 is a simple methyl, there is no 2 substituent to inhibit either of these reactions. a in chain b 3 3 a full rotation at - is possible in chain b o possible and no E2 from 1, but E2 from 2 (1-butene) is possible. Use these ideas to understand cyclohexane reactivity. o or E2 when "" is in equatorial position. 3 possible E2 from 1 (2Z- butene) E2 from 2 (1-butene) o is possible (1,3 diaxial positions block approach of nucleophile), and no E2 is possible because ring carbons are anti. possible if is not tertiary and there is no anti "" group. possible E2 from 1 (2E- butene) E2 from 2 (1-butene) alkene stabilities tetrasubstituted > trisubstituted > trans-disubstituted > gem-disubstituted cis-disubstituted > monosubstituted equatorial leaving group only partial rotation is possible in ring o is possible (1,3 diaxial positions block approach of nucleophile), and no E2 is possible because ring carbons are anti. only partial rotation is possible in ring axial leaving group o possible if there is an anti "" group. E2 possible with anti -. oth and E2 are possible in this conformation with leaving group in axial position. o E2 possible, no anti -. E2 possible with anti -. o or E2 when "" is in equatorial position. nly E2 is possible in this conformation. Leaving group is in axial position. y:\files\classes\314\314 pecial andouts\314 & E pring 2013.doc

42 cleophilic ubstitution & Elimination hemistry t-butyl substituent locks in chair conformation with equatorial t-butyl yclohexane structures have two chair conformations possible. K eq» 1 9, severe steric repulsion Examples - group A = l I Ts Is possible? equires an open approach at and. 2. Is E2 possible? equires anti ow many possible products are there? 4. What is the relationship among the starting structures? 5. What is the relationship among the products? 6. Are any of the starting structures chiral? 7. Are any of the product structures chiral? 1 Examples - group 2 Ts 4 Ts 6 Ts 8 Ts 10 Ts Ts Ts Ts 1. Which conformation is reactive? 2. Is possible? equires an open approach at and. 3. Is E2 possible? equires anti ow many possible products are there? 5. What is the relationship among the starting structures? 6. What is the relationship among the products? 7. Are any of the starting structures chiral? 8. Are any of the product structures chiral? Ts Ts Ts chair 1 chair 2 y:\files\classes\314\314 pecial andouts\314 & E pring 2013.doc

43 cleophilic ubstitution & Elimination hemistry 43 strong base/nucleophile conditions (E + = electrophile, : = nucleophile) n-butyl lithium (powerful nucleophile at epoxides and carbonyls (=), and the most powerful base at other times) hould be, but does not work well. Too many side reactions. Another approach is necessary,using cuprates ( 2 u ) hould be, but does not work well. Too many side reactions. Another approach is necessary,using cuprates ( 2 u ) hould be, but does not work well. Too many side reactions. Another approach is necessary,using cuprates ( 2 u ). y:\files\classes\314\314 pecial andouts\314 & E pring 2013.doc