Chapter 18 Ethers and Epoxides; Thiols and Sulfides Ethers

Home , Alkoxide, Bromoethane, Ether cleavage, Halohydrin, Primary alcohol

• Ethers (R–O–R’): – Organic derivatives of water, having two organic groups bonded to the same oxygen atom

3 Nomenclature: Common Names

• Simple ethers are named by identifying two organic substituents and adding the word ether – Name the groups in alphabetical order – Symmetrical: Use dialkyl or just alkyl

• The more complex alkyl group is the parent name • The group with the oxygen becomes an alkoxy group

• Epoxides (oxiranes) H2C CH2 O • Oxetanes • Furans (Oxolanes) O O • Pyrans (Oxanes) O O O • Dioxanes O

• Name the starting alkene and add “oxide”

• The oxygen can be treated as a substituent (epoxy) on the compound • Use numbers to specify position • Oxygen is 1, the carbons are 2 and 3 • Substituents are named in alphabetical order

• Possess nearly the same geometry as water – Oxygen atom is sp3-hybridized – Bond angles of R–O–R bonds are approximately tetrahedral • Polar C—O bonds

• Hydrogen bond is a attractive interaction between an electronegative atom and a hydrogen atom bonded to another electronegative atom • Ethers cannot hydrogen bond with other ether molecules, so they have a lower boiling point than alcohols • Ether molecules can hydrogen bond with water and alcohol molecules • They are hydrogen bond acceptors

• Very useful as solvents in the laboratory – They can dissolve nonpolar and polar substances – They are unreactive toward strong bases • Ionic substance are moderately soluble in ethers – Lithium iodide • The small lithium cation is strongly solvated by the ether’s lone pairs of electrons • Ether cannot serve as hydrogen bond donors – Does not solvate small anions well

• Name the following ethers: a) b)

• Solution: – a) Di-isopropyl ether – b) Allyl vinyl ether

12 ETHER PREPARATION

13 Synthesis of Ethers • Simple symmetrical ethers are prepared

industrially by sulfuric acid (H2SO4) catalyzed reaction of alcohols – Bimolecular condensation of alcohols – Limited to use with primary alcohols • 2o and 3o alcohols dehydrate by to form alkenes – If temperature is too high, alkene forms

• Best method for the preparation of ethers

• This method involves an SN2 attack of the alkoxide on an unhindered primary halide or tosylate – The alkoxide is commonly made by adding a strong base (i.e. NaH) to the alcohol

• Reaction of alcohols with Ag2O directly with alkyl halide forms ether in one step

Glucose reacts with excess iodomethane in the presence of

Ag2O to generate a pentaether in 85% yield

• How are the following ethers prepared using a Williamson synthesis? a) Methyl propyl ether b) Anisole (methyl phenyl ether) • Solution:

17 To convert two alcohols to an ether, convert the more hindered alcohol to its alkoxide. Convert the less hindered alcohol to its tosylate (or an alkyl halide). Make sure the tosylate (or halide) is a

good SN2 substrate.

18 Alkoxymercuration of Alkenes

• Alkene is treated with an alcohol in the presence of mercuric acetate or mercuric trifluoroacetate

– Demercuration with NaBH4 yields an ether – Markovnikov addition of alcohol to alkene

• Primary, secondary and tertiary alcohols will react with this synthesis – Ditertiary ethers can not be prepared due to steric hindrance

• Rank the following halides in order of their reactivity in Williamson synthesis: a) Bromoethane, 2-bromopropane, bromobenzene b) Chloroethane, bromoethane, 1-iodopropene

• Solution: Most reactive Least reactive a)

20 REACTIONS OF ETHERS

21 Cleavage of Ethers

• Ethers are unreactive, which makes them ideal solvents for a lot of different reactions • They can be cleaved by heating with concentrated HBr and HI • Reactivity: HI > HBr

• Step 2: The halide will attack the carbon and displace the alcohol (SN2).

• Step 3: The alcohol reacts further with the acid to produce another mole of alkyl halide – This does not occur with aromatic alcohols (phenols)

• Phenol cannot react further to become a

halide because an SN2 reaction cannot occur on an sp2 carbon

26 Worked Example

• Predict the product(s) of the following reaction:

• Solution: – A primary alkyl group and a tertiary alkyl group is bonded to the ether oxygen

– When one group is tertiary, cleavage occurs by an SN1 or E1 route to give either an alkene or a tertiary halide and a primary alcohol

28 Reactions of Ethers: Claisen Rearrangement • Claisen rearrangement occurs with – Allyl aryl ethers – Allyl vinyl ethers

• Caused by heating ally aryl ether to 200-250°C

© 2016 Cengage Learning 29 Reactions of Ethers: Claisen Rearrangement • Takes place in a single step through a pericyclic mechanism – Reorganization of bonding electrons of a six- membered, cyclic transition state

• What products are expected from Claisen rearrangement of 2- butenyl phenyl ether?

• Solution: – Six bonds will either be broken or formed in the product - Represented by dashed lines in the transition state – Redrawing bonds to arrive at the intermediate enone – Rearranges to the more stable phenol

32 Cyclic Ethers

• Behave like acyclic ethers with the exception of three-membered ring called epoxides – Strain of the three-membered ring gives epoxides a unique chemical reactivity

33 Preparation of Epoxides

• Ethylene oxide is industrially important as an intermediate – Prepared by reaction of ethylene with oxygen at 300 °C over a silver oxide catalyst – -ene ending used because it is made from ethylene

• Epoxides are prepared in a laboratory

– By treating alkenes with a peroxyacid (RCO3H)

• Epoxides are prepared in a laboratory – From halohydrins • Addition of HO–X to an alkene gives a halohydrin • Treatment of a halohydrin with base gives an epoxide – Intramolecular Williamson ether synthesis

• Solution: – Epoxidation, in this case, is a syn addition of oxygen to a double bond – Original bond stereochemistry is retained; product is a meso compound

37 Worked Example

– Reaction of trans-2-butene with m- chloroperoxybenzoic acid yields trans-2,3 epoxybutane

38 REACTIONS OF EPOXIDES:

39 Reactions of Epoxides: Ring-Opening • Water adds to epoxides with dilute acid at room temperature – Product is a 1,2-diol

• Epoxides can be opened by reaction with acids + other than H3O

• Anhydrous HF, HBr, HCl, or HI combine with an epoxide

• Regiochemistry of acid- catalyzed ring-opening depends on the epoxide’s structure • Nucleophilic attack occurs primarily at the more highly substituted site, when one epoxide carbon atoms is tertiary

© 2016 Cengage Learning 42 Reactions of Epoxides: Ring-Opening • Regiochemistry of acid- catalyzed ring-opening depends on the epoxide’s structure • Nucleophilic attack occurs primarily at the more highly substituted site, when one epoxide carbon atoms is tertiary

Ring-Opening of 1,2-epoxy-1- methylcyclohexane with HBr

• Predict the major product of the following reaction:

• Solution:

• Epoxide rings can be cleaved by bases, nucleophiles, and acids – Strain of the three-membered ring is relieved on ring-opening • Hydroxide cleaves epoxides at elevated temperatures

• Amines can be used for epoxide opening

• Grignard reagents can be used for epoxide opening – Converts a Grignard reagent into a primary alcohol

• Predict the major product of the following reaction:

• Solution:

– Addition of a Grignard reagent takes place at the less substituted epoxide carbon

48 Crown Ethers

• Crown Ethers are – Large-ring polyethers – Named as x-crown-y • x is total number of atoms in the ring • y is the number of oxygen atoms • Central cavity is electronegative and attracts cations

• Crown ethers can complex metal cations in the center of the ring • Size of the ether ring will determine which cation it can solvate • Complexation by crown ethers often allows polar inorganic salts to dissolve in nonpolar organic solvents

• 15-Crown-5 and 12-crown-4 ethers complex Na+ and Li+, respectively – Make models of these crown ethers, and compare the sizes of the cavities

• Solution:

– Bases on ionic radii, the ion-to-oxygen distance in 15- crown-5 is about 40% longer than the ion-to-oxygen distance in 12-crown-4

51 THIOLS AND SULFIDES

52 Thiols and Sulfides

• Thiols – Sulfur analogs of alcohols – Named with the suffix –thiol – –SH group is called mercapto group

53 Thiols

• Prepared from alkyl halides by SN2 displacement with a sulfur nucleophile

• Reaction works poorly if nucleophile not in excess – Alkylthiol product can undergo further reaction with the alkyl halide • Gives symmetrical sulfide, a poorer yield of the thiol

© 2016 Cengage Learning 54 Thiols • Thiols are created with thiourea to prevent sulfide formation – Thiourea is a nucleophile – Gives an intermediate alkyl isothiourea salt, hydrolyzed by subsequent reaction with an aqueous base

• Thiols can be oxidized by Br2 or I2 – Yields disulfides (RSSR’) – Reaction is reversible – Key part of numerous biological processes

• Sulfur analogues of ethers – Named by rules used for ethers • Sulfide in place of ether for simple compounds • Alkylthio in place of alkoxy

57 Creating Sulfides

• Sulfides can be created from thiols – Thiols when treated with a base gives corresponding thiolate ion – Thiolate ion undergoes reaction with an alkyl halide to give a sulfide

• Sulfides and ethers differ substantially in their chemistry – Dialkyl sulfides react rapidly with primary alkyl halides to give sulfonium ions

• Sulfides and ethers differ substantially in their chemistry – Sulfides are easily oxidized • Sulfide reacts with hydrogen peroxide at room temperature – Yields sulfoxide – Further oxidation of the sulfoxide with a peroxyacid yields a sulfone

• Dimethyl sulfoxide is often used as a polar aprotic solvent – Easily absorbed through skin – Transmits dissolved substance through barriers

61 Worked Example

• Name the following compound:

• Solution: – 3-(Ethylthio)cyclohexanone

62 SPECTROSCOPY OF ETHERS

63 Spectroscopy of Ethers

• Infrared Spectroscopy – C–O single-bond stretching 1050 to 1150 cm-1 – Overlaps many other absorptions – Difficult to identify ethers with IR • Nuclear magnetic resonance spectroscopy – H on a C next to ether O is shifted downfield to 3.4  to 4.5  – Epoxides H’s absorb at 2.5  to 3.5  in their 1H NMR spectra – Ether C’s exhibit a downfield shift to 50  to 80 

64 Summary

• Compounds that have two organic groups bonded to the same oxygen atom are called ethers • Ethers are prepared either by Williamson ether synthesis or the alkoxymercuration reaction • Allyl aryl ethers and allyl vinyl ethers undergo Claisen rearrangement to give o-allylphenols and g,-unsaturated ketones • Thiols are sulfur analogs of alcohols

65 Summary

• Disulfide can be obtained through mild oxidation of a thiol • Sulfides are sulphur analogs of ethers • Alkylation of sulfides with a primary alkyl halide will yield a sulfonium ion • Sulfides can also be oxidized to sulfoxides and to sulfones

66 Solved Problem 18-1 (a) Why is the following reaction a poor method for the synthesis of tert-butyl propyl ether? (b) What would be the major product from this reaction? (c) Propose a better synthesis of tert-butyl propyl ether.

SOLUTION

(a) The desired SN2 reaction cannot occur on the tertiary alkyl halide. (b) The alkoxide ion is a strong base as well as a nucleophile, and elimination prevails. Solved Problem 18-1 Continued SOLUTION (c) A better synthesis would use the less hindered alkyl group as the substrate and the alkoxide of the more hindered alkyl group. Solved Problem 18-2 Predict the major products for the reaction of 1-methyl-1,2-epoxycyclopentane with (a) sodium ethoxide in ethanol

(b) H2SO4in ethanol SOLUTION (a) Sodium ethoxide attacks the less hindered secondary carbon to give (E)-2-ethoxy-1-methylcyclopentanol.

(b) Under acidic conditions, the alcohol attacks the more electrophilic tertiary carbon atom of the protonated epoxide. The product is (E)-2-ethoxy-2-methylcyclopentanol.