Chem 350 Jasperse Ch. 11 Handouts 1. Summary of Alcohol Reactions, Ch. 11.

Transcription

1 Chem 350 Jasperse Ch. 11 andouts 1 Summary of Alcohol eactions, Ch. 11.??? 1 + NaZ Na Acid-Base + Z 1. Deprotonation by a base. 2. Controlled by relative stability of versus Z. 3. Consider relative electronegativity and whether either anion is resonance stabilized. 2 Na Potassium (K) analogous. Na Key way to convert alcohol to alkoxide, reactive as S N 2 nucleophile and E2 base Na 2. '-X ' Alkoxide fmation-s N 2 route to ether The electrophile '-X must be S N 2 reactive, preferably 1º with a good leaving group 4 5 Aldehydes 1º Alcohols nly 2 Cr 4 2º Alcohols nly Ketones 2 Cr 4 = Na 2 Cr 2 7, 2 S 4 Cr 3 / 2 Key access to aldehydes, which are useful f me Grignard chemistry. Note difference between and 2 Cr 4 does not react with 2º alcohols very rapidly Key access to ketones. does not react very fast with 2º alcohols 6 2 Cr 4 1º Alcohols nly Acids Note difference between and 2 Cr 4 when reacting with 1º alcohols. 7 2 Cr 4 Aldehydes Acids 8 I, Cl analogous 3º alcohols Mech: Be able to draw! Converts alcohol into a bromide that can be used in Grignards, E2 reactions Cation mechanism Usually not method of choice f 1º, 2º alcohols

2 Chem 350 Jasperse Ch. 11 andouts 2 9 1º 2º alcohols P 3 Converts alcohol into a bromide that can be used in Grignards, E2, S N 2 reactions Inversion of stereochem Not good f 3º alcohols P 3 Mg Quick 2-step conversion of alcohol into a nucleophilic Grignard P/I 2 Via PI 3 I 1º 2º alcohols 1º 2º alcohols SCl 2 etention of stereo! Cl TsCl 13 Ts NEt 3 Tosylates are super leaving groups, better even than iodides. Tosylates are well suited to S N 2 and E2 reactions. 14 Markovnikov addition 15 peroxides anti-markovnikov addition , hv adical mechanism, 3º > 2º > 1º 2 S 4, heat Zaytsev elimination

3 Chem 350 Jasperse Ch. 11 andouts 3 Mechanisms f! eactions - 3º - 3º mostly, sometimes 1º Mech f 3º : Mech f 1º : P 3-1º, 2º 1º, 2º P 2 Mech: P 2 + -P 2

4 Ch. 11 eactions of Alcohols Chem 350 Jasperse Ch. 11 andouts 4 A. Conversion to Alkoxides (Sections 11.14, 10.6) alkoxide = anion 1. By acid-base deprotonation (Section 10.6) A rather reactive anion base is required that is *less* stable than an alkoxide anion Carbanions (Mg) nitrogen anions can do this Na can t 2. By redox reaction with sodium potassium ( some other metals)??? 1 + NaZ Na Acid-Base + Z 1. Deprotonation by a base. 2. Controlled by relative stability of versus Z. 3. Consider relative electronegativity and whether either anion is resonance stabilized. 2 Na Potassium (K) analogous. Na Key way to convert alcohol to alkoxide, reactive as S N 2 nucleophile and E2 base. B. Conversion to Ethers via Alkoxide (11-14) 3 1. Na 2. '-X ' Alkoxide fmation-s N 2 route to ether The electrophile '-X must be S N 2 reactive, preferably 1º with a good leaving group 1. Na 2. C. xidation of Alcohols to Carbonyl Compounds (11.1-4) Summary: 2 xidants 1. = mild 1º alcohols! aldehydes Pyridinium chlochromate : soluble in water-free dichlomethane Mild, selective f 1º over 2º alcohols, and when 1º alcohols are used stops at aldehyde 2. 2 Cr 4 = strong a. 2º alcohols! ketones b. 1º alcohols! carboxylic acids c. 3º alcohols! no reaction d. aldehydes! carboxylic acids 2 Cr 4 = Cr Na 2 Cr S 4 (make in the reaction flask) Always made and used in the presence of some water Very strong, when 1º alcohols are used goes 1º C 2! C! C 2 without stopping at aldehyde

5 4 5 Aldehydes 1º Alcohols nly 2 Cr 4 2º Alcohols nly Ketones 2 Cr 4 = Na 2 Cr 2 7, 2 S 4 Cr 3 / 2 Chem 350 Jasperse Ch. 11 andouts 5 Key access to aldehydes, which are useful f me Grignard chemistry. Note difference between and 2 Cr 4 does not react with 2º alcohols very rapidly Key access to ketones. does not react very fast with 2º alcohols 6 2 Cr 4 1º Alcohols nly Acids Note difference between and 2 Cr 4 when reacting with 1º alcohols. Draw the products f the following oxidation reactions Cr Cr Cr 4

6 Chem 350 Jasperse Ch. 11 andouts 6 xidation Combined with Grignard eactions (in either der): Indirectly Enables Substitution of Carbon f ydrogen 1. 1º alcohol +! aldehyde + Mg! 2º alcohol 2. 2º alcohol + 2 Cr 4! ketone + Mg! 3º alcohol xidation followed by Grignard reaction essentially substitutes a carbon group f a hydrogen 3. Aldehyde + Mg! 2º alcohol + 2 Cr 4! ketone Grignard reaction followed by oxidation essentially substitutes a carbon group f a hydrogen 1 1º º 2 2º 1. 2 Cr º 3 aldehyde Cr 4 Mg ketone Cr Mg Cr

7 Chem 350 Jasperse Ch. 11 andouts 7 Jones Test 2 Cr 4 f Alcohols (11-2C) (test responsible) 2 Cr 4 (Jones eagent) is clear ange Treatment of an unknown with Jones reagent: o Solution stays clear ange! no 1º 2º alcohol present (negative reaction) o Solution gives a green/brown precipitate! 1º 2º alcohol present (positive reaction) o 3º, vinyl, and aryl alcohols do not react. N do ketones, ethers, esters. Structure and Mechanism (not test responsible) 2 Cr 4 = chromic acid = Na 2 Cr 2 7 = Cr 3 / 2 = Cr +6 oxidation state Water soluble Cr Pyridinium carbons renders soluble in ganic solvents, thus it is functional in ganic solvent and in the absence of water N Cr Cl = Pyridinium ChloChromate General Mechanism C Cr Ester Fmation C Cr Elimination + 2 C + Cr operates analogously 1º Alcohols, Aldehydes, and the Presence Absence of Water: Q: Why does Anhydrous stop at Aldehyde but Aqueous 2 Cr 4 Continues to Carboxylic Acid? C 1º alcohol 2 Cr 4 Aldehyde 2, + C 2 Cr 4 C Acetal Carboxylic Acid 1. Both and 2 Cr 4 convert 1º alcohols to aldehydes 2. In the presence of acidic water, aldehydes undergo an equilibrium addition of water to provide a small equilibrium population of acetal 3. The acetal fm gets oxidized (very rapidly) to carboxylic acid The aldehyde fm cannot itself get oxidized to carboxylic acid Since is used in absence of water, the aldehyde is not able to equilibrate with acetal and simply stays aldehyde. Since it can t convert to acetal, therefe no oxidation to carboxylic acid can occur 4. Chromic acid, by contrast, is in water Therefe the aldehyde is able to equilibrate with acetal The acetal is able to be oxidized. Thus, the aldehyde via the acetal is able to be indirectly oxidized to carboxylic acid, and in fact does so very rapidly.

8 General ecognition of xidation/eduction in rganic Chemistry C 1º alcohol C 2º alcohol oxidation reduction Aldehyde Ketone oxidation reduction Chem 350 Jasperse Ch. 11 andouts 8 Carboxylic Acid xidation: The number of oxygen bonds to a carbon increases, and the number of hydrogens bonded to a carbon decreases eduction: The number of oxygen bonds to a carbon is reduced, and the number of hydrogens bonded to a carbon increases. Me General: # of bonds to heteroatoms versus to hydrogens Classify the following transfmations as oxidations reductions 1. N reduction N 2 oxidation 2. N 2 C N 3. C 3 reduction 4. reduction 11.3, 11.4 ther methods f xidizing Alcohols. (No test) There are lots of other recipes used f oxidizing alcohols (and f other oxidation reactions) 1. KMn 4 2. Cu 3. Jones : 2 Cr 4 with acetone added to temper reactivity 4. Collins: 2 Cr 4 with pyridine added to temper reactivity 5. Swern : (CCl) 2 and (C 3 ) 2 S= then NEt 3 6. N 3 7. Biological xidant 1: NAD + nictonamide adenine dinucleotide N sugar N 2 NAD + oxidized fm oxidizing agent + C 1º alcohol Aldehyde 8. Biological xidant 2: Quinones and hydroquinones (Ch ) Quinone oxidized fm oxidizing agent + C 1º alcohol + N sugar N 2 NAD reduced fm reducing agent Aldehyde DihydroQuinone reduced fm reducing agent

9 Chem 350 Jasperse Ch. 11 andouts 9 In General: ecognizing xidizing versus educing Agents xidizing Agents: ften have: educing Agents: ften involve: ighly xidized Metals Nonmetals ydrides in Fmulas Extra xygen ighly educed Metals Metals + 2 s 4 (+8) KMn 4 (+7) Cr 4 (+6) 2Cr 4 (+6) N 4 (+5) 2 2! 2 C 3! C 2 3! 2 Metals + acid LiAl 4 NaB 4 Li, Na, K, Mg, Zn, Al, etc. Pd/ 2, Pt/ 2, Ni/ 2 etc. Zn/Cl, Fe/Cl, Zn/g/Cl, etc.. The ability to qualitatively recognize when a transfmation involves an oxidation reduction can be very helpful. The ability to recognize a reactant as an oxidizing agent a reducing agent can be very helpful ften on standardized tests! Some Biological Alcohol xidations (Not f Test) 1. xidation of carbohydrates sugars is the primary source of bioenergy multiple enzymes are involved f the many steps A carbohydrate basically has a fmula with one per carbon C 6 6 () 6 "carbohydrates" C sugars enzymes 6 C energy 2. Most alcohols are biooxidized to give toxic carbonyl derivatives ( intoxication ) the presence of substantial aldehydes and especially ketones in the blood is symptomatic of various problems o intoxication o alcoholism o uncontrolled diabetes o etc (other metabolic disders)

10 Conversion of Alcohols to Alkyl alides Chem 350 Jasperse Ch. 11 andouts I, Cl analogous 3º alcohols Mech: Be able to draw! 1º 2º alcohols Converts alcohol into a bromide that can be used in Grignards, E2 reactions Cation mechanism Usually not method of choice f 1º, 2º alcohols P 3 Converts alcohol into a bromide that can be used in Grignards, E2, S N 2 reactions Inversion of stereochem Not good f 3º alcohols P 3 Mg Quick 2-step conversion of alcohol into a nucleophilic Grignard P/I 2 Via PI 3 I 1º 2º alcohols 1º 2º alcohols SCl 2 etention of stereo! Cl Section 11-9 Summary: Class - -I -Cl 1º P 3 P/I 2 SCl 2 2º P 3 P/I 2 SCl 2 3º I Cl Vinyl Aryl Nothing wks Nothing wks Nothing wks Straight eaction with -X (Section 11.7) o Ideal only f 3º, o sometimes wks with 1º alcohols, with a complex mechanism o nly occasionally f 2º alcohols o Method of choice f 3º, but not f 1º 2º 1 2 I I 3

11 Chem 350 Jasperse Ch. 11 andouts 11 Mechanism f -X reactions with 3º Alcohols: Cationic Mech f 3º : Notes: 1. Memize the 3º alcohol mechanism (test responsible) a. Protonate b. Leave to give Cation. This is the slow step f 3º alcohols c. Capture 2. Analogous with I Cl Cl slower, nmally enhanced with ZnCl2, which enhances rate of cation fmation (Lucas test, see later) utside of 3º systems, side reactions are common and yields aren t often very good 3. utside of 3º alcohols, side reactions are common and yields aren t often very good Elimination reactions and cation rearrangements 4. S N 1 type: carbocation-fming step is the rate-determining step, so + stability key 3º alcohols fastest 2º alcohols are way slower 1º alcohols can t react at all via this mechanism, because 1º + are too unstable. Ditto f vinyl aryl alcohols 5. can also react with 1º to give 1º, although it is not often the method of choice The mechanism is different, but rather interesting (not test responsible) Mech f 1º : carbocation fmation never occurs bromide ion simply does S N 2 on the protonated alcohol, with water as an excellent leaving group yields tend to be pretty inconsistent eaction of 1º and 2º Alcohols with P 3 (Section 11-8) Default recipe f 1º and 2º alcohols P 2 Mech: 1º, 2º P 2 + -P 2 P 3 is an exceptional electrophile, and reacts even with neutral alcohols The first step activates the oxygen as a leaving group. The second step involves an S N 2 substitution o stereochemical inversion occurs chirality present (common f 2º alcohols) Because the second step is an S N 2 substitution, the reaction fails f 3º PCl 3 does not react as well, and is not useful f making chlides PI 3 is not stable and can t be sted in a bottle. owever, the combination of 1P I 2! PI 3 in the reaction container (in situ) o Thus P/I 2 essentially provides the PI 3 that does the job

12 Chem 350 Jasperse Ch. 11 andouts 12 1 P 3 2 P C P 3 3 C Conversions of Alcohols into ther eactive Species in Multi-Step Syntheses ' aldehyde ketone Grignard accept Electrophile 2 Cr 4 Alcohol P 3 Alkyl omide Mg Electrophile S N 2 S N 1 accept E2 E1 reactant Grignard eagent Nucleophile Grignard don 1. oxidation can convert an alcohol into a carbonyl = Grignard accept (electrophile) 2. P 3 /Mg /Mg can convert an alcohol into Mg = Grignard don (nucleophile) 3. P 3 can convert an alcohol into, capable of nmal substitution and elimination reactions. etrosynthesis Problems (In which you decide what to start from): Design syntheses f the following. Allowed starting materials include: omobenzene cyclopentanol any acyclic alcohol alkene with!4 carbons any esters ethylene oxide fmaldehyde (C2) any "inganic" agents (things that won't contribute carbons to your skeleton) Tips: 1. Focus on the functionalized carbon(s) 2. Try to figure out which groups of the skeleton began together, and where new C-C bonds will have been fmed 3. When breaking it up into sub-chunks, try to make the pieces as large as possible (4 carbon max, in this case, f acyclic pieces) 4. emember which direction is the true labaty direction. 5. Be careful that you aren t adding substracting carbons by mistake 3 C Mg 1. P 3

13 Chem 350 Jasperse Ch. 11 andouts Cr 4 1. P 3 Mg + + Mg 1. P 3 Nmal Synthesis Design: In which you are given at least one of the starting Chemicals. Provide eagents. You may use whatever reagents, including ketones aldehydes Grignards esters, that you need. Tips: Identify where the reactant carbons are in the product Is the iginal carbon still oxygenated?! it will probably function as a Grignard accept Is the iginal carbon not still oxygenated?! it should probably function as Grignard don Wking backwards helps. a. 1. P Mg b. c Cr 4 5. C 3 Mg d. 1. P C 3

14 Chem 350 Jasperse Ch. 11 andouts 14 e. 1. P Cr 4 f. 1. P Cr 4 etrosynthesis Problems: Design syntheses f the following. Allowed starting materials include: omobenzene cyclopentanol any acyclic alcohol alkene with!4 carbons any esters ethylene oxide fmaldehyde (C2) any "inganic" agents (things that won't contribute carbons to your skeleton) Tips: 1. Focus on the functionalized carbon(s) 2. Try to figure out which groups of the skeleton began together, and where new C-C bonds will have been fmed 3. When breaking it up into sub-chunks, try to make the pieces as large as possible (4 carbon max, in this case, f acyclic pieces) 4. emember which direction is the true labaty direction. 5. Be careful that you aren t adding substracting carbons by mistake 3 + Mg 1. P 3 2 Cr 4 Note: other routes could wk, but this is cleanest because it combines two 4-carbon pieces, and requires only one new C-C bond fmation. 4 2 S 4 Mg + 2 S 4 1. P 3 This isn't as good an alcohol precurs. Alcohol elimination would be as likely to occur inside the ring as outside. The better route involves an alcohol who should have a pretty clean Zaytsev elimination.

15 Chem 350 Jasperse Ch. 11 andouts Mg 1. P 3 Mg Mg This route is inferi. The other routes can involve only 2 C-C fming reactions. But given the limitation to 4-carbon acyclie alcohols, this route would require an additional C-C fming reaction to assemble the string number Mg Mg 1. P 3 6 Inferi Mg Mg + Mg 2 Cr Cr 4 1. P 3 Mg + Mg 7 2 Cr 4 Mg Mg + + Mg 1. P 3 2 C= Mg 1. P 3 2 C= Mg Mg 8 Mg + 2 Cr 4 1. P 3

16 Chem 350 Jasperse Ch. 11 andouts 16 Unknowns and Chemical Tests (Sections 11-2C, 11-7) 1. 2 /Pt test f alkenes 2. 2 test f alkenes 3. Jones reagent ( 2 Cr 4 ) Test f 1º 2º alcohols 3º alcohols do not react 2º alcohols keep the same number of oxygens but lose two hydrogens in the fmula 1º alcohols lose two s but also add one oxygen 4. Lucas Test: Cl/ZnCl 2 f 3º 2º alcohols - Cl/ZnCl 2 in water -Cl via 3º > 2º >>>> 1º 3º alcohols are fastest 1º alcohols don t react at all 3º > <1 min 2º >>> 1-5 min 1º never Why? stability: 3º > 2º >>> 1º stability is the key Test is based on solubility: The -Cl product is nonpolar and water insoluble, so it separates out from water. Alcohols are quite soluble especially in highly acidic water. Test fails is useless f alcohols with so many carbons that it doesn t even dissolve in the iginal Cl/ZnCl 2 /water solution Jones ( 2 Cr 4 ) Lucas (Cl/ZnCl 2 ) 2 /Pt equired Facts Possible Answers 1 C 5 10 Yes No Yes 1º ne Alkene etc. 2 C 6 12 Yes Yes, 1-5 min No 2º ne ring etc. 3 C 6 12 No Yes Yes 3º ne Alkene etc. 4 C 7 12 Yes Yes Yes, Produces C º ne Alkene ne ring carbonyl 5 C 3 6 No No Yes No ne alkene 6 C 3 6 No No No No ne ring Carbonyl 7 C 3 6 Yes, produces C No Yes 1º ne alkene etc. etc. 8 C 3 6 Yes, produces C 3 4 Yes No 2º ne ring 9 C 3 6 No No Yes No ne alkene

17 Chem 350 Jasperse Ch. 11 andouts 17 Section 11-5 Conversion of Alcohols to Tosylates, and their use as Exceptional Leaving Groups in S N 2, S N 1, E2, and E1 eactions TsCl 13 Ts NEt 3 + Cl S Po anion, po leaving group NEt 3 S Ts + Et 3 N Cl Tosylates are super leaving groups, better even than iodides. Tosylates are well suited to S N 2 and E2 reactions. Leaving Group Produces: S Great anion, like 'the hydrogen sulfate anion produced from sulfuric acid Notes: 1. Tosylates are easy to fm 2. Toluene sulfonate 3. Tosylate anion is really stable, comparable to the anion from sulfuric acid Both the electronegative sulfur and the resonance/charge sharing with the other oxygens helps 4. Whereas a nmal has a po leaving group (hydroxide anion), conversion to the tosylate provides a super good leaving group. 5. Leaving Group eactivity: Better than the best of the halides Ts >> I > > Cl 6. Tosylates are highly reactive toward S N 2, S N 1, E2, and E1 eactions 7. Triethylamine is used as an Cl scavenger in the tosylate fmation ften a weaker amine base called pyridine is used, to avoid unintentionally providing E2 on the tosylate Draw Products 1 1. TsCl, NEt 3 2. NaC 3 C Na 2. -C 3 C TsCl, NEt 3 2. NEt TsCl, NEt 3 2. NaC C 1. Na 2. 3 C 1. TsCl, NEt 3 2. Na 3 C 6 1. TsCl, NEt 3 2. Na

18 Chem 350 Jasperse Ch. 11 andouts 18 eaction of 1º and 2º Alcohols with SCl 2 (Section 11-9) Default recipe f 1º and 2º alcohols Mech: 1º, 2º Cl S Cl Cl S Cl S Cl Cl 2º S N 1 1º S N 2 Cl + S Cl + S Cl S 2 + Cl S 2 + Cl Cl Cl Mechanism: Not f test responsibility Mechanism differs f 1º and 2º alcohols 1º involve an S N 2 substitution 2º involve an S N 1 type substitution The chlide that captures the cation is nmally on the same side of the molecule on which the oxygen began, and often captures the cation very rapidly from that same side This results in a very unusual retention of stereochemistry. When they wk, these reactions are convenient because the side products, S 2 and Cl, are both gases. So wkup is really easy. Simply rotovap the mixture down, and everything except f product is gone. Draw Products Provide Appropriate eactants f the following Transfmations 4 P/I 2 I 5 SCl 2 Cl 6 SCl 2 Cl Draw the Mechanism:

19 Chem 350 Jasperse Ch. 11 andouts 19 Draw the mechanisms f the following reactions MeMg 2. 2 C MeMg C C 3 C 3 C 3 C 3 C Mg C C 3 1. LiAl 4 C 3 C NaB Mg Internal E2 eaction 7 1. Mg ester

20 Chem 350 Jasperse Ch. 11 andouts 20 EVIEW. To make ganometallic reagents, you must have compounds ( Cl I). Alkane Alkene 2, hv, peroxides (anti-mark) (Mark) 1º, 2º P 3 3º Mg Z ethers alcohols Z S N 2 E2 (nmal bulky base) Alkene Mg Grignard Accepts 1º, 2º, 3º etc. a. 1. P 3 3. C 3 C 2 C 4. + b C c. 1. (peroxides) 3. C 2 C d. 1. 2, hv 3. Ethylene oxide Cr 4

21 Chem 350 Jasperse Ch. 11 andouts 21 omoalkane Concept Map Alkane Alkene 2, hv, peroxides (anti-mark) (Mark) 1º, 2º P 3 3º Mg Z ethers alcohols Z S N 2 E2 (nmal bulky base) Alkene Mg Grignard Accepts 1º, 2º, 3º etc. Alcohol Concept Map - - Na S N 2 1. Mg 2. Grignard Accept (aldehyde, ketone, ester, epoxide) P 3 3. Grignard Accept 1. xidize 1. TsCl ( 2. Na (inverts 2 Cr 4 ) stereo) Alcohol Mark AntiMark NaB 4 LiAl 4 Mg Alkenes Aldehyde, Ketone, Ester Aldehyde, Ketone, Ester 1º 2º - P 3 SCl 2 1. TsCl 2. Base 1º 2º -Cl 3º - Aldehyde Ketone 2 Cr 4 1. Na 2 Cr 4 2. Acid Ether Ether 1. TsCl 2. Na 1. TsCl 2. Na Alcohol (inversion) 1. xidize 1.P 3 ( 2 Cr 4 ) 3. Grignard Accept Alcohol Alcohol 2 S 4 Alkene Alkene

22 Chem 350 Jasperse Ch. 11 andouts 22 Alkene Concept Map - addns - addns base E2 ethers Alcohol Alkene 2 S 4 1. TsCl, NEt 3 2. E2 Base 2 Addn alkane 2 xidative Cleavage Dihalide Epoxide Diol Aldehydes,Ketones, Acids Ether Concept Map Na' S N 2 Alkene 1., g(ac) 2 2. NaB 4 1. Na 2. '- ' 1. alkene, g(ac) 2 2. NaB 4 1. TsCl, NEt 3 2. Na' k