CHM252/Spring 12 Assignment: Chapter 17 & 18

CHM252/Spring 12 Assignment: Chapter 17 & 18 We will spend the first 2 weeks reviewing and covering the chemistry of alcohols, phenols, ethers, epoxides & their sulfur analogs the thiols and sulfides. Read Ch. 17 and 18 in McMurry. Week one recitation will be a review problem session. Students who took CHM 251 prior to the Fall 11 semester are encouraged to review their CHM251 notes on functional groups, IR, addition and substitution reactions. WL homework for Ch. 17 and 18 will be due on the dates specified on the WL website. Quiz #1 on alcohol and phenol chemistry will be given in recitation Week 2. Topics (Ch. 17) Nomenclature of alcohols & phenols; primary, secondary & tertiary structures Physical properties: effect of hydrogen bonding Acidity of phenols & stability of phenoxide ion Review of reactions to prepare alcohols: Hydration of alkenes Reduction of aldehydes & ketones to alcohols, hydride reagents Reduction of acids or esters The Grignard reaction with aldehydes & ketones Alcohol reactions: Dehydration (E1 type) Formation of alkyl halides xidation of alcohols to carbonyl compounds Tosylates & protecting groups Preparation of phenols xidation of phenols & antioxidant behavior Spectroscopy of alcohols & phenols Topics (Ch. 18) Ether structure & nomenclature & properties Ether synthesis Williamson reaction Alkoxymercuration Cleavage of ethers in acid Claisen rearrangement Epoxides: structure & synthesis by reaction of alkenes with peroxyacids Ring-opening of epoxides acid-catalyzed base-catalyzed Spectroscopy of ethers Thiols & sulfides

I. Alcohols and Phenols: Structure, nomenclature & properties Examples: H 1 o 2 o 3 o H H CH 3 H 3 C CH 3 C C C H CH 3 H 3 C H 3 C Nomenclature IUPAC: 1. Find the longest chain/largest ring containing the group 2. Start numbering at end closest to 3. Add suffix ol to root of name 4. Number & name other substituents in the usual manner Poly alcohols: number all groups and use diol, triol etc. suffix Common names: Many alcohols can be named as alkyl group + alcohol or have special names Ethyl alcohol Benzyl alcohol Ethylene glycol Glycerol Carbohydrates (sugars) are polyalcohols which have groups on most of the C atoms. These are generally named by a common naming system, suffix = ose Phenol: Substituted phenols are named using the nomenclature rules for benzene derivatives: ortho, meta, para and numerical prefixes for tri or poly-substituted Alcohols & phenol groups are widely prevalent in nature, commonly occurring in combination with other functional groups in natural products and biomolecules

Name these alcohols IR spectroscopy: Evidence for alcohols Alcohols: Phenols: H stretch: 3300 3600 cm -1 H stretch: 3300 3400 cm -1 broad, strong if H-bonded Aromatic ring absorptions present C stretches: 1050 1150 cm -1, strong C stretch: > 1200 cm -1 Compare cyclohexanol vs. phenol

Properties of alcohols & phenols Physical behavior is dominated by their ability to form hydrogen bonds like water. This affects: Boiling points: Compare an alcohol with a hydrocarbon of similar size and MW 1-propanol vs. butane Trend: Boiling and melting points of alcohols are significantly higher than hydrocarbons or alkyl halides Solubility: 1-propanol is soluble in water while butane is insoluble Ethanol is very soluble in water while pentanol is only slightly soluble Ribose (a 5-C sugar with 4 groups) is very soluble Trend: The smaller the R group or greater the number of groups, the greater the solubility of a compound Acid/base behavior: Alcohols & phenols can be protonated (basic behavior) at the oxygen atom. (recall dehydration mechanism) They may also lose the H + (acidic behavior) to form their conjugate bases: R + H 2 R- + H 3 + Alcohol alkoxide ion However, the ability to do so varies greatly (see pk a table 17.1)

Some general trends: 1. Alcohols require very strong bases such as alkali metals or hydrides to deprotonate 2. Alkoxide ions are stabilized by presence of electron WD groups, making the alcohol itself a stronger acid. 3. Phenols are much more acidic due to resonance-stabilization of the phenoxide ion - therefore they can be deprotonated by weaker bases.

II. Preparing alcohols from other organics Hydroxyl groups are very versatile: they can be made from or converted into many other functional groups, so alcohols are frequently found in synthetic routes. Review: Familiar reactions used to convert alkenes to alcohols (Think about regiochemistry and stereochemistry!) 1. Acid-catalyzed hydration: ccurs most readily with 3 o alcohols, may get rearrangement with 1 o or 2 o 2. xymercuration/demercuration Produces alcohols with Markovnikov orientation, no rearrangement 3. Hydroboration/oxidation Produces non-markovnikov alcohols, syn-stereochemistry from cycloalkenes 4. Alkene oxidation by osmium tetroxide / bisulfite Produces diols with syn stereochemistry 5. S N 2 or S N 1 substitution of - /H 2 on alkyl halide (can be made from alkene) May result in inversion or racemate depending on mechanism

New methods for preparing alcohols: 1. Hydride reductions of carbonyl groups 2. Grignard addition to carbonyls (adds new R group, converts to R) 1. Reduction of carbonyl groups by hydride donor reagents An Inorganic definition of reduction = gain of electrons An rganic definition of reduction = gain of bonds to hydrogen, decreasing the electrophilicity of the carbon atom Focus on functional group changes that take place: Ketones Aldehydes Acids & esters secondary alcohols primary alcohols primary alcohols Hydride (H - ) donors: H- is a strong nucleophile that comes from reagents in which H is bonded to a metal atom. (Must be used under anhydrous conditions) LiAlH 4 NaBH 4 Lithium aluminum hydride is a very strong reducing agent, highly reactive and reacts violently with water. Sodium borohydride is a more selective reducing agent, less reactive but also reacts with water NADH, NADPH Stoichiometry: 1 mole NaBH 4 can furnish 4 moles of H- In biochemical reactions, nicotinamide adenine dinucleotide functions as hydride carrier for most reactions that convert carbonyls to alcohols

Hydride addition to aldehydes or ketones produces 1 o or 2 o alcohols: Mechanism: nucleophilic addition H - can be used to convert esters to alcohols in a two step process 1) substitution to form aldehyde, followed by 2) addition to form alcohol (requires LiAlH 4 since these groups are less reactive) Example of a biochemical reduction using NADPH:

The Grignard Reaction: Grignard reagents are designed to add a particular R group to a carbonyl compound. The reactive species behaves like a carbanion or strong base and can react with electrophilic C: CH 3 CH 2 -MgBr = CH 3 CH 2 - + + MgBr Grignard reagents undergo addition to aldehydes or ketones to produce alcohols. At the same time, a bond to a new R group is introduced. Ex: H 1) CH 3 CH 2 MgBr 2) H 3 + H C 1) PhMgBr 2) H 3 + C Practical issues with Grignard reactions 1. Since Grignard reagents react readily with any source of H +, like water, it must be excluded until reaction is complete (the same goes for alcohols): 2. Grignard reagents may react with the alkyl halide itself in an S N 2 reaction: 3. Grignard reagents can t be prepared from multifunctional alkyl halides that possess an additional functional group with which it could react: aldehydes, ketones, amides, nitriles, alcohols, amines, acids, nitro, sulfonic acids

Further examples of Grignard reactions: Adds one carbon plus an alcohol group to the reactant Assembly of a larger C skeleton Addition of Grignard to C 2 adds a carboxylic acid group: Addition of Grignard to ethylene oxide adds a 2-C unit:

III. Reactions of alcohols 1. Elimination reactions of alcohols: Dehydrations A common biochemical reaction, occurring in carbohydrate and fatty acid metabolism, dehydration is catalyzed in vivo by specific enzymes In the lab, dehydration is an acid-catalyzed mechanism involving formation of a carbocation intermediate in an E1-type mechanism: Ex: Dehydration products form based on Zaitsev's rule Relative reactivities: 3 o R > 2 o R > 1 o R Reaction is reversible Rearrangements are possible To avoid rearrangement and allow dehydration of secondary alcohols, use PCl 3 in pyridine Reaction conditions (basicity of pyridine) favor E2-type mechanism Turns into a better leaving group.

2. Substitution reaction of alcohols with nucleophiles: making alkyl halides Synthetic utility: The alkyl halide can then be further converted to another functional group using S N 2 chemistry Problem: Solution: - is a poor leaving group Make it into a better leaving group! Alkyl halides can be prepared from tertiary alcohols by acid-catalyzed mechanism: Use HBr or HCl First step = protonation of the group to make H 2, a good leaving group Second step = substitution of halide by S N 1 mechanism To prepare alkyl halides from primary or secondary alcohols, first form a weakly basic leaving group, then replace it First step = reaction to form a better leaving group Second step = substitution of the halide by S N 2 mechanism PBr 3 (phosphorus tribromide): formation of a bromophosphite group SCl 2 (thionyl chloride): formation of a chlorosulfite group p-toluenesulfonyl chlorides: formation of tosylates -Ts group is an especially good leaving group and can be replaced like Bror I- so substitution proceeds with inversion of configuration

Review: Practical applications of the S N 2 reaction: A wide range of nucleophiles can react with alkyl halides, replacing the halide with new functional groups and making substitution a versatile synthetic tool: Alkynes: CH 3 CH 2 Br + C C CH 3 CH 3 CH 2 C C CH 3 + Br- Alcohols: CH 3 CH 2 Br + CH 3 CH 2 + Ethers: CH 3 CH 2 Br + CH 3 CH 3 CH 2 CH 3 + Br- Br- Amines: CH 3 CH 2 Br + NH 3 CH 3 CH 2 NH 3 Br Esters: CH 3 CH 2 Br + C CH 3 CH 3 CH 2 C CH 3 + Br- H Nitriles: CH 3 CH 2 Br + Thiols: CH 3 CH 2 Br + SCH 3 CH 3 CH 2 SCH 3 + C N CH 3 CH 2 C N + Br- Br- Coupling: CH 3 CH 2 Br + RMgBr CH 3 CH 2 R + MgBr 2 Intermolecular reactions (above examples) involve two separate molecules Intramolecular S N 2: If the alkyl halide also contains another nucleophilic group, it can undergo an intramolecular reaction between the halide C and the Nu, forming a ring: Br NH 2 H N H Br-

Classification of alcohols: 1 o, 2 o or 3 o? The Lucas test: Use of substitution rxn to determine the class of an unknown alcohol: R - HCl/ZnCl 2 R - Cl (soluble) (insoluble) room temp utcome: 3 o R react immediately by S N 1 pathway 2 o R react slowly by S N 1 pathway 1 o R do not undergo S N 1! BUT: 2 o R undergo S N 1 in presence of catalyst (reaction = 5 minutes) 1 o R react very slowly by S N 2 pathway (reaction >> 10 minutes) The role of zinc in the Lucas reaction: Cl- is a poor nucleophile in aqueous acid solution Use of Zn 2+ activates the group to leave S N 2 reaction of n-butanol with ZnCl 2 & heat: Modern method for determining alcohol class: Examine C - stretch in IR C stretches: 1050 1150 cm -1 depending on 1 o, 2 o or 3 o closer to 1050 for 1 o, closer to 1150 for 3 o > 1200 cm -1 for phenols

3. rganic xidations: Formation of more bonds from C to, N or X Loss of bonds to hydrogen Increasingly oxidized functional groups H 2 H 2 R C C R R C C R H 2 H H R C C R alkanes alkenes/ynes alcohols ketones, aldehydes acids, esters xidation of alcohols: focus on functional group changes! H R H 2 C C R R H 2 C C R R H 2 C R H 2 C CH 2 R H 2 C C H H 2 C C 1 o alcohol aldehyde carboxylic acid C CH 3 H R H 2 C C CH 3 R 2 o alcohol ketone 3 o alcohol no reaction! xidizing agents commonly contain elements in a high oxidation state As the organic group gets oxidized the inorganic oxidizing agent is reduced! Stronger oxidizing agents which employ metals with high oxidation states: Acidic solutions of Cr 3, Na 2 Cr 2 7, Na 2 Cr 4, KMn 4 Milder oxidizing agents oxidize 1 o alcohols only to aldehyde: PCC: pyridinium chlorochromate, Cr(VI) in CH 2 Cl 2 Dess-Martin periodinane I(V) Reduction of Cr(VI) is a visible change: Cr 6+ (orange) Cr 3+ (dark green) Mechanism of chromium oxidation: formation of chromate ester intermediate Practical uses of chromium oxidations: 1) Classification test for R & RCH (Jones reagent): Cr 3 in H 2 S 4, acetone 2) Breathalizer test (K 2 Cr 2 7 )

Alcohol metabolism: oxidative processes Physiologically, alcohols are processed by enzyme-catalyzed oxidation reactions: (taking place in the liver) Alcohol dehydrogenase C H 3 C H Aldehyde dehydrogenase C H 3 C CH 3 CH 2 NAD + acetaldehyde NAD + acetic acid NADH NADH Persons with genetic ADH deficiency have very low tolerance for alcohol Acetaldehyde is toxic in large amounts and causes unpleasant physiological effects: nausea, dizziness, sweating, headaches = hangover Antabuse: drug used to treat alcoholism by inhibiting aldehyde dehydrogenase & causing buildup of acetaldehyde N S C S S S C N Methanol is toxic in very small amounts due to the high toxicity of formaldehyde: H 3 C ADH H C H Methanol poisoning is often treated by forcing patient to drink large quantities of ethanol, which has a higher affinity for the enzyme and will prevent the above rxn. (Do not attempt this at home!) Biological oxidation reactions are catalyzed by cofactors such as NADP + /NADPH (reverse of the NADH reduction)

4. Protecting alcohol groups from side reactions groups --commonly occur in molecules along with other functional groups --are easily oxidized --may undergo side reactions with reagents intended for other groups Solution: Protection of group with chlorotrialkylsilane 1) reacts with protecting reagent such as TMSCl 2) A relatively unreactive silyl ether is formed at the site 3) Molecule undergoes the desired reaction at another functional group 4) Protecting group is hydrolyzed off to re-form alcohol Example:

Phenols Summary of occurrence, preparation, reaction & uses ccurrence: Phenol (C 6 H 5 ) is produced industrially from oxidation of benzene Substituted phenols and polyphenols occur widely in nature, especially plants Examples: flavonoids, tannins, organic acids C H Salicylic acid quercetin a tannin Reactivity and uses: Compounds containing the phenol group undergo oxidation readily through a free radical mechanism -- commonly used as additives to prevent oxidation in foods (BHT, etc.) -- excellent scavengers of damaging free radicals -- produce quinones (a cyclic diketone) upon oxidation R Example: Ubiquinones function in the electron transport chain (R = long polyene) H H H

Preparation of synthetic phenols: 1) Cumene hydroperoxide rxn 2) Alkali fusion of benzenesulfonic acid (review from Ch. 14) S 3 H 3) Substitution of diazonium salts (Ch. 24) N N Reactions of Phenols: xidation (such as ubiquinone rxn) Phenols also readily undergo electrophilic aromatic substitution (Ch. 16) SUMMARY F ALCL REACTINS:

Ch. 18 Ethers: Structure, nomenclature & properties Ether group = ring R R' where R may be two separate groups or a and both carbons are sp 3 -hybridized Ethers are relatively stable, inert but flammable, volatile, slightly polar good solvents but may form explosive by-products (peroxides) diethyl ether, THF, dioxane somewhat higher-boiling and more water-soluble than alkanes of similar size anaesthetic properties: interacts with nonpolar cell membranes, causing swelling & decreased permeability (esp. CNS); muscle relaxant Diethyl ether was commonly used in the past, but is slow to act, causes nausea modern anaesthetics = halogenated ethers enflurane = H 2 FC CHF CHFCl propofol ipr IUPAC naming isoflurane = F 3 C CHCl CHF 2 ipr Larger ethers are usually named as alkoxy derivatives of a parent compound H Cl CH 2 CH 3 CH3 Simpler ethers are named by the common naming system of naming both alkyl groups followed by ether (amines are named the same way) H 3 C C CH 3 CH 3 CH 3

Preparation of ethers: several ways possible 1) Symmetrical ethers can be prepared by acid-catalyzed dehydration of 1 o alcohols: H 2 S 4 2 CH 3 CH 2 CH 3 CH 2 --CH 2 CH 3 S N 2-type mechanism; competing E2 mechanism makes this unfit for 2 o or 3 o 2) More S N 2: The Williamson Synthesis 1 st half of ether = alkoxide ion 2 nd half of ether = alkyl halide or tosylate Step 1: Preparation of alkoxide, requires strong base to deprotonate an alcohol R + NaH R - Na + + H 2 Step 2: S N 2 substitution on alkyl halide or tosylate: R - + R X R R Because rxn is S N 2: 1 o alkyl halides or tosylates work best More hindered alkyl group should be prepared as alkoxide E2 side products are likely if RX is not 1 o Ex:

Stereochemical considerations: use of bromide vs. tosylate 3) New twist to familiar reaction: alkoxymercuration/demercuration Alkenes Ethers by electrophilic addition in alcohol solvent CH 3 Hg(Ac) 2 or (CF 3 C 2 ) 2 Hg R CH 3 R Hg... CH 3 NaBH 4 R How would you prepare these ethers?

Reactions of ethers: Acidic cleavage In general, ethers are not the ideal starting material for preparing other functional groups by nucleophilic substitution due to poor leaving ability of -R group However, if you need to cleave off an ether group in a particular molecule --R can be activated by addition of HBr, HI --Resulting + charged group is more reactive --Products depend on mechanism, structure of the ether For ethers attached to 3 o or benzylic C, an S N 1/ E1 rxn: alcohol + alkene H 3 C C CH 3 CF 3 C H 3 C CH 3 For ether groups attached to 1 o or 2 o C, cleavage occurs by slow S N 2 pathway: --The less hindered half becomes an alkyl halide when HBr or HI used HBr CH 3 Taking large molecules apart In nature, many larger molecules have smaller units such as sugars attached by ether linkage; acidic cleavage is a good way to remove the sugars (for structure determination)

Epoxides Epoxides have bridging atom between 2 C atoms, forming 3-membered cyclic ether: Nomenclature: IUPAC: R: Epoxide group called oxirane, with the alkyl groups named & numbered Epoxide group named & numbered as an epoxy substituent CMMN: Named after alkene precursor with ending of oxide ( ethylene oxide ) Preparing epoxides by oxidation: Alkenes epoxides Peroxyacids (RC) such as m-chloroperoxybenzoic acid (MCPBA) can be used to add an oxygen atom across an alkene double bond: MCPBA CH 2 Cl 2 Preparing epoxides by elimination: Halohydrins epoxides (less harsh) 2 steps: Deprotonation of the group by strong base S N 2 attack of oxide ion on the halogenated carbon, displacing halide

Using ring strain to your advantage Since the ring strain makes the epoxide group much more reactive than ethers, epoxides can react under either acidic or basic conditions: (1) Acid-catalyzed xygen is activated by H + under even mildly acidic conditions A nucleophile can then attack and pop the ring open Mechanism resembles others involving bridged intermediates Aqueous acid: vicinal diols HX: halohydrins Regioselectivity: where does nucleophile attack? Depends on structure; mixtures of products are common 3 o site forms most stable carbocation 1 o site is less hindered Stereochemistry: trans-placement of functional groups

(2) Base-catalyzed ring-opening gives more predictable regiochemistry A strong base generally attacks the less-substituted carbon, breaking its bond to the oxygen: Synthetic utility of epoxides: Easy preparation of diols, halohydrins, alcohols Ethylene oxide can be used to add a 2-carbon unit via a Grignard reaction: Use of an epoxide to prepare an epoxy resin polymer:

Thiols (Section 18.8): Sulfur analogs of alcohols Thiols & sulfides: Sulfur analogs of alcohols & ethers Natural sources: onions, garlics, skunk spray proteins Thiols = R SH (analogous to R) Naming is analogous to R -SH = mercapto Sulfides = R S R (thioethers) Naming is analogous to ethers CH 3 CH 2 CH 2 SH = propanethiol Thiol & sulfide chemistry: Production: Thiols are produced from alkyl halides by S N 2 rxn with hydrosulfide salts (Na + SH-) or thiourea Reactions: Perhaps the most important in nature is oxidation of thiols disulfides Disulfide bridges are common in proteins, linking cysteine units to maintain 3- D structure of protein (cysteine = amino acid with thiol side chain) R SH I 2 (or other x.) Zn, H + (or other Red.) R S S R Thiols are more acidic than alcohols; their conjugate bases (thiolate ions) are less basic than alkoxides but still good nucleophiles. Reaction of thiolates with alkyl halides produces sulfides: CH 3 CH 2 -SH base CH 3 CH 2 -S - + HB CH 3 CH 2 -S - + Br-CH 3 CH 3 CH 2 -S-CH 3

How would you carry out these transformations?

How would you synthesize these alcohols starting with any alcohol having six C or less: Fill in the missing reagents