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. OWL homework for Ch. 17 and 18 will be due on the dates specified on the OWL 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 Oxidation of alcohols to carbonyl compounds Tosylates & protecting groups Preparation of phenols Oxidation 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

OH

I. Alcohols and Phenols: Structure, nomenclature & properties Examples: Nomenclature IUPAC: 1. Find the longest chain/largest ring containing the OH group

2. Start numbering at end closest to OH 3. Add suffix “ol” to root of name 4. Number & name other substituents in the usual manner

Poly alcohols: number all OH 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 OH 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

C

H H

CH3

C

H CH3

H3CHO OH

C

H3C CH3

H3C OH

1o 2o 3o

Name these alcohols

IR spectroscopy: Evidence for alcohols Alcohols: Phenols: O – H stretch: 3300 – 3600 cm-1 O – H stretch: 3300 – 3400 cm-1 broad, strong if H-bonded Aromatic ring absorptions present C – O stretches: 1050 – 1150 cm-1, strong C – O stretch: > 1200 cm-1

OH

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 OH groups) is very soluble

Trend: The smaller the R group or greater the number of OH 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: ROH + H2O RO- + H3O+ Alcohol alkoxide ion

However, the ability to do so varies greatly (see pKa 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:

Occurs most readily with 3o alcohols, may get rearrangement with 1o or 2o 2. Oxymercuration/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. SN2 or SN1 substitution of OH-/H2O 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 ROH)

1. Reduction of carbonyl groups by hydride donor reagents An “Inorganic” definition of reduction = gain of electrons An “Organic” definition of reduction = gain of bonds to hydrogen, decreasing

the electrophilicity of the carbon atom Focus on functional group changes that take place: Ketones secondary alcohols Aldehydes primary alcohols Acids & esters 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) LiAlH4 Lithium aluminum hydride is a very strong reducing agent, highly

reactive and reacts violently with water. NaBH4 Sodium borohydride is a more selective reducing agent, less reactive

but also reacts with water

Stoichiometry: 1 mole NaBH4 can furnish 4 moles of H- NADH, NADPH

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 1o or 2o 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 LiAlH4 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: CH3CH2-MgBr = CH3CH2

- + +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: 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 SN2 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

O OH

HH1) CH3CH2MgBr

2) H3O+

C

O

C

OH1) PhMgBr

2) H3O+

Further examples of Grignard reactions:

Addition of Grignard to CO2 adds a carboxylic acid group: Addition of Grignard to ethylene oxide adds a 2-C unit:

Adds one carbon plus an alcohol group to the reactant

Assembly of a larger C skeleton

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: 3o ROH > 2o ROH > 1o ROH

Reaction is reversible

Rearrangements are possible

To avoid rearrangement and allow dehydration of secondary alcohols, use POCl3 in pyridine

Reaction conditions (basicity of pyridine) favor E2-type mechanism Turns OH 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 SN2 chemistry Problem: -OH is a poor leaving group… Solution: 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 OH group to make H2O, a good leaving group Second step = substitution of halide by SN1 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 SN2 mechanism PBr3 (phosphorus tribromide): formation of a bromophosphite group SOCl2 (thionyl chloride): formation of a chlorosulfite group p-toluenesulfonyl chlorides: formation of tosylates

-OTs group is an especially good leaving group and can be replaced like Br- or I- so substitution proceeds with inversion of configuration

Review: Practical applications of the SN2 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:

C C CH3 CH3CH2 C C CH3 + Br-Alkynes:

Alcohols: CH3CH2 + OHBr

CH3CH2 Br

CH3CH2 +OH Br-

Ethers: CH3CH2 Br +

+

OCH3 CH3CH2 +OCH3 Br-

CH3CH2 Br + NH3 CH3CH2 NH3BrAmines:

Esters: CH3CH2 Br C CH3

O

HO+ CH3CH2 C CH3

O

O + Br-

C N CH3CH2 C N + Br-Nitriles: CH3CH2 Br

Thiols: CH3CH2 Br +

+

SCH3 CH3CH2 +SCH3 Br-

Coupling: CH3CH2 Br + RMgBr CH3CH2 R + MgBr2 Intermolecular reactions (above examples) involve two separate molecules Intramolecular SN2: 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

NH2

NHH

Br-

Classification of alcohols: 1o, 2o or 3o? The Lucas test: Use of substitution rxn to determine the class of an unknown alcohol: R - OH HCl/ZnCl2 R - Cl (soluble) (insoluble) room temp Outcome: 3o ROH react immediately by SN1 pathway

2o ROH react slowly by SN1 pathway 1o ROH do not undergo SN1! BUT: 2o ROH undergo SN1 in presence of catalyst (reaction = 5 minutes)

1o ROH react very slowly by SN2 pathway (reaction >> 10 minutes) The role of zinc in the Lucas reaction:

Cl- is a poor nucleophile in aqueous acid solution

Use of Zn2+ activates the OH group to leave SN2 reaction of n-butanol with ZnCl2 & heat: Modern method for determining alcohol class: Examine C - O stretch in IR C – O stretches: 1050 – 1150 cm-1 depending on 1o, 2o or 3o closer to 1050 for 1o, closer to 1150 for 3o

> 1200 cm-1 for phenols

3. Organic Oxidations: Formation of more bonds from C to O, N or X Loss of bonds to hydrogen

Increasingly oxidized functional groups

alkanes alkenes/ynes alcohols ketones, aldehydes acids, esters Oxidation of alcohols: focus on functional group changes!

3o alcohol no reaction!

Oxidizing 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 CrO3, Na2Cr2O7, Na2CrO4, KMnO4 Milder oxidizing agents oxidize 1o alcohols only to aldehyde:

PCC: pyridinium chlorochromate, Cr(VI) in CH2Cl2 Dess-Martin periodinane I(V)

Reduction of Cr(VI) is a visible change: Cr6+ (orange) Cr3+ (dark green) Mechanism of chromium oxidation: formation of “chromate ester” intermediate Practical uses of chromium oxidations: 1) Classification test for ROH & RCHO (Jones reagent): CrO3 in H2SO4, acetone 2) Breathalizer test (K2Cr2O7)

H2C

H2C RR C

HCH

RR H2C C RR

OH

H

H2C C RR

OH2C C ORR

O

H2C CH2R

OH H2C C HR

OH2C C OHR

O

1o alcohol aldehyde carboxylic acid

H2C C

HR

OH H2C C CH3R

O

2o alcohol ketone

CH3

Alcohol metabolism: oxidative processes Physiologically, alcohols are processed by enzyme-catalyzed oxidation reactions: (taking place in the liver) Alcohol Aldehyde dehydrogenase dehydrogenase CH3CH2OH 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 Methanol is toxic in very small amounts due to the high toxicity of formaldehyde:

HC

H

O

H3C OHADH

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)

H3CC

H

O

H3CC

OH

O

S SC C

N N

S S

4. Protecting alcohol groups from side reactions OH 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 OH group with chlorotrialkylsilane 1) OH 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 Occurrence: Phenol (C6H5OH) is produced industrially from oxidation of benzene Substituted phenols and “polyphenols” occur widely in nature, especially plants Examples: flavonoids, tannins, organic acids

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

Example: Ubiquinones function in the electron transport chain (R = long polyene)

O

OH

OH

OR

HO

OH O

OH

COOH

O

OH

OH

OH

HO

OHO

OH

OH

OH

HO

OHO

OH

OH

OH

HO

OH

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

SUMMARY OF ALCOHOL REACTIONS:

N N

SO3H

Ch. 18 Ethers: Structure, nomenclature & properties

Ether group = where R may be two separate groups or a ring

O and both carbons are sp3-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

propofol enflurane = H2FC – O – CHF – CHFCl

isoflurane = F3C – CHCl – O – CHF2 IUPAC naming Larger ethers are usually named as alkoxy derivatives of a parent compound

Simpler ethers are named by the common naming system of naming both alkyl groups followed by “ether” (amines are named the same way)

OH

iPr

iPr

H3CO

CCH3

CH3

CH3

OCl CH2 CH3

RO

R'

OCH3

HO

Preparation of ethers: several ways possible 1) Symmetrical ethers can be prepared by acid-catalyzed dehydration of 1o alcohols: H2SO4 2 CH3CH2OH CH3CH2-O-CH2CH3 SN2-type mechanism; competing E2 mechanism makes this unfit for 2o or 3o 2) More SN2: The Williamson Synthesis 1st half of ether = alkoxide ion 2nd half of ether = alkyl halide or tosylate Step 1: Preparation of alkoxide, requires strong base to deprotonate an alcohol R – OH + NaH R – O - Na+ + H2 Step 2: SN2 substitution on alkyl halide or tosylate: R – O - + R’ – X R – O – R’ Because rxn is SN2: 1o alkyl halides or tosylates work best More hindered alkyl group should be prepared as alkoxide E2 side products are likely if RX is not 1o Ex:

Stereochemical considerations: use of bromide vs. tosylate

3) New twist to familiar reaction: alkoxymercuration/demercuration Alkenes Ethers by electrophilic addition in alcohol solvent

How would you prepare these ethers?

CH3 Hg(OAc)2 or(CF3CO2)2Hg

ROH

CH3

OR

Hg...

NaBH4

CH3

OR

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 -OR group However, if you need to cleave off an ether group in a particular molecule

--OR 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 3o or benzylic C, an SN1/ E1 rxn: alcohol + alkene For ether groups attached to 1o or 2o C, cleavage occurs by slow SN2 pathway:

--The less hindered half becomes an alkyl halide when HBr or HI used

OCH3

HBr

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)

CH3O

C

H3C

H3C

CH3

CF3COOH

Epoxides Epoxides have “bridging” O atom between 2 C atoms, forming 3-membered cyclic ether: Nomenclature:

IUPAC: Epoxide group called “oxirane”, with the alkyl groups named & numbered

OR: Epoxide group named & numbered as an “epoxy” substituent COMMON: Named after alkene precursor with ending of “oxide” (“ethylene oxide”) Preparing epoxides by oxidation: Alkenes epoxides Peroxyacids (RCOOOH) such as m-chloroperoxybenzoic acid (MCPBA) can be used to add an oxygen atom across an alkene double bond:

Preparing epoxides by elimination: Halohydrins epoxides (less harsh) 2 steps: Deprotonation of the OH group by strong base SN2 attack of oxide ion on the halogenated carbon, displacing halide

OO

OMCPBA

CH2Cl2

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 Oxygen 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 3o site forms most stable carbocation 1o 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 -SH = “mercapto” proteins Thiols = R – SH (analogous to ROH) Sulfides = R – S – R’ (thioethers) Naming is analogous to ROH Naming is analogous to ethers CH3CH2CH2SH = propanethiol

Thiol & sulfide chemistry: Production: Thiols are produced from alkyl halides by SN2 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) I2 (or other Ox.)

R – SH R – S – S – R Zn, H+ (or other Red.)

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: CH3CH2-SH base CH3CH2-S - + HB CH3CH2-S - + Br-CH3 CH3CH2-S-CH3

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