Ethers and Epoxides; Thiols and Sulfides Chapter 18 Ethers and Epoxides; Thiols and Sulfides Suggested Problems – 1-18, 23-28, 38-41, 44-5,54-5

Ethers Ethers (R–O–R’): Organic derivatives of water, having two organic groups bonded to the same oxygen atom Ether and THF are typically used as solvents. Ether boils around 35oC, THF at 66oC. Anisole is higher boiling and is commonly used in perfumery.

Names and Properties of Ethers Simple ethers are named by identifying two organic substituents and adding the word ether If other functional groups are present, the ether part is considered an alk-oxy substituent

Names and Properties of Ethers Possess nearly the same geometry as water Bond angles of R–O–R bonds are approximately tetrahedral Oxygen atom is sp3-hybridized Relatively stable and unreactive in many aspects Very useful as solvents in the laboratory Ethers on exposure to oxygen over long periods can form peroxides. Low molecular weight peroxides can be explosive.

Worked Example Name the following ethers: a) b) Solution: a) Di-isopropyl ether b) Allyl vinyl ether

Synthesis of Ethers Prepared industrially by sulfuric-acid-catalyzed reaction of alcohols Limited to use with primary alcohols This acid catalyzed route to ethers is only useful with primary alcohols because secondary and tertiary alcohols dehydrate by an E1 mechanism to yield alkenes under these conditions.

Williamson Ether Synthesis Reaction of metal alkoxides and primary alkyl halides and tosylates in an SN2 reaction Best method for the preparation of ethers Alkoxides are prepared by reaction of an alcohol with a strong base such as sodium hydride, NaH Williamson ether synthesis is the most generally useful method of preparing ethers. Alkoxides prepared by reacting an alcohol with sodium hydride, NaH, react with an alkyl halide or a tosylate in an SN2 reaction.

Silver Oxide-Catalyzed Ether Formation Reaction of alcohols with alkyl halides in the presence of Ag2O forms ethers in one step Glucose reacts with excess iodomethane in the presence of Ag2O to generate a pentaether in 85% yield

Williamson Ether Synthesis Primary halides and tosylates work best Competitive E2 elimination with more hindered substrates Unsymmetrical ethers best synthesized by reaction between more hindered alkoxide and less hindered halide.

Williamson Ether Synthesis tert-Butyl methyl ether is best prepared by reaction of tert-butoxide ion with iodomethane rather than by reaction of methoxide ion with 2-chloro-2-methylpropane.

Worked Example How are the following ethers prepared using a Williamson synthesis? a) Methyl propyl ether b) Anisole (methyl phenyl ether) Solution: a) b) Methyl propyl ether can be performed in two ways depending on which half is derived from an alcohol and which half is derived from an alkyl halide. Because aryl halides do not undergo SN2 displacements, methyl phenyl ether must be made from the phenoxide and a methyl halide.

Alkoxymercuration of Alkenes Alkene is treated with an alcohol in the presence of mercuric acetate or trifluoroacetate Demercuration with NaBH4 yields an ether Overall Markovnikov addition of alcohol to alkene Note the similarities between this reaction and the Markovnikov addition of water to alkenes. The mechanism is very similar. The principal difference is an alcohol replaces water in oxymercuration demercuration of alkenes to form an ether. The reaction is initiated by electrophilic addition of Hg2+ to the alkene, followed by reaction of the intermediate cation with alcohol and reductionof the C-Hg bond by NaBHr.

Worked Example 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) b)

Reactions of Ethers: Acidic Cleavage Cleaved by strong acids HI, HBr produce an alkyl halide from less hindered component by SN2 Ethers are unreactive to many reagents used in organic chemistry, a property that accounts for their wide use as reaction solvents. However, ethers are cleaved by strong acids. Acidic ether cleavages take place by either SN1 or SN2 mechanisms depending on the structure of the substrate. Ethers with only primary and secondary alkyl groups react by an SN2 mechanism, in which I- or Br- attacks the protonated ether at the less hindered site. This usually results in a selective cleavage into a single alcohol and a single alkyl halide.

Reactions of Ethers: Acidic Cleavage Ethers with tertiary, benzylic, or allylic groups cleave by either an SN1 or E1 mechanism Intermediates are stable carbocations Tert-Butyl ethers react by an E1 mechanism on treatment with trifluoroacetic acid.

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

Worked Example

Reactions of Ethers: Claisen Rearrangement Specific to allyl aryl ethers and allyl vinyl ethers Caused by heating ally aryl ether to 200-250°C Leads to an o-allylphenol Result is alkylation of the phenol in an ortho position The net result of this reaction is alkylation of a phenol in the ortho position.

Reactions of Ethers: Claisen Rearrangement A similar rearrangement takes place with allyl vinyl ethers A g,d-unsaturated ketone or aldehyde results

Reactions of Ethers: Claisen Rearrangement Takes place in a single step through a pericyclic mechanism Reorganization of bonding electrons occurs in a six-membered, cyclic transition state Mechanism is consistent with 14C labeling Evidence for this mechanism comes from the observation that the rearrangement takes place with an inversion of the allyl group. That is, allyl phenyl ether containing a 14C label on the allyl ether carbon atom yields o-allylphenol in which the label is on the terminal vinylic carbon. (See the carbon labeled in green above.)

Worked Example 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 Redraw bonds to arrive at the intermediate enone, which rearranges to the more stable phenol

Worked Example

Cyclic Ethers Behave like acyclic ethers with the exception of three-membered ring epoxides Strain of the three-membered ring gives epoxides a unique chemical reactivity Dioxane and tetrahydrofuran are used as solvents

Cyclic Ethers Three-membered ring compounds called 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 implies the presence of a double bond in the molecule The strain of the three-membered ring gives epoxides unique chemical reactivity. The name, ethylene oxide, is not a systematic one because the –ene ending implies a double bond in the molecule. The systematic name for ethylene oxide is 1,2-epoxyethane.

Preparation of Epoxides By treating alkenes with a peroxyacid (RCO3H) Also prepared from halohydrins In the laboratory, epoxides are usually prepared by treatment of an alkene with a peroxyacid such as m-CPBA.

Epoxides 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

Worked Example Explain why reaction of cis-2-butene with m-chloroperoxybenzoic acid yields an epoxide different from that obtained by reaction of the trans isomer 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

Worked Example In the epoxide product the methyl groups are cis Reaction of trans-2-butene with m-chloroperoxybenzoic acid yields trans-2,3- epoxybutane

Reactions of Epoxides: Ring-Opening Water adds to epoxides with dilute acid at room temperature Product is a 1,2-diol Epoxides are more reactive than other ethers because of the ring strain. 1,2-diols are also called vicinal glycols; vicinal means adjacent. A glyclol is a diol Epoxide opening takes place by SN2-like backside attack of a nucleophile on the protonated epoxide, giving a trans-1,2-diol as product.

Reactions of Epoxides: Ring-Opening Also can be opened by reaction with acids other than H3O+ Anhydrous HF, HBr, HCl, or HI combine with an epoxide Gives a trans product Here the product is a trans halohydrin

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 A mixture of products is often formed in the ring-opening of an epoxide. When both epoxide carbon atoms are either primary or secondary, attack of the nucleophile occurs primarily at the less highly substituted site – an SN2-like result. When one of the epoxide carbona toms is tertiary, however, nucleophilic attack occurs primarily at the more highly substituted site – an SN1-like result. Thus, 1.2-epoxypropane reacts with HCl to give primarily 1-chloro-2-propanol, but 2-methyl-1,2-epoxypropane gives 2-chloro-2-methyl-1-propanol as the major product.

Ring-Opening of 1,2-epoxy-1-methylcyclohexane with HBr The mechanism of epoxide opening has characteristics of both SN2 (backside attack leading to a trans product) and SN1 (attack at the more hindered tertiary carbon) reactions.

Worked Example Predict the major product of the following reaction: Solution: The rules for acid catalyzed opening of an epoxide are: An epoxide with only primary and secondary carbons usually undergoes cleavage by SN2-like attack of a nucleophile on the less hindered carbon. An epoxide with a tertiary carbon atom usually undergoes cleavage by backside attack on the more hindered carbon.

Base-Catalyzed Epoxide Opening Epoxide rings can be cleaved by bases and nucleophiles, as well as acids Strain of the three-membered ring is relieved on ring-opening Hydroxide cleaves epoxides at elevated temperatures While an ether oxygen is a poor leaving group in an SN2 reaction, the strain of the three-membered ring causes epoxides to react with hydroxide ion at elevated temperatures. Base-catalyzed epoxide opening is a typical SN2 reaction in which attack of the nucleophile takes place at the less hindered epoxide carbon.

Base-Catalyzed Epoxide Opening Amines and Grignard reagents can be used for epoxide opening Ethylene oxide is frequently used Allows conversion of a Grignard reagent into a primary alcohol Many different nucleophiles can be used for epoxide opening, including amines (RNH2 or R2NH) and Grignard reagents. The reaction of ethylene oxide with the Grignard reagent above allows for the conversion of the Grignard reagent into a primary alcohol having two more carbons than the starting alkyl halide.

Worked Example Predict the major product of the following reaction: Solution: Addition of a Grignard reagent takes place at the less substituted epoxide carbon Note the contrast of the site of reaction here which occurs at the less substituted carbon under anionic conditions. Under acidic conditions a nucleophile would be expected to attack at the more substituted tertiary carbon.

Crown Ethers 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 Produce similar effects when used to dissolve an inorganic salt in a hydrocarbon to that of dissolving the salt in a polar aprotic solvent 18-Crown-6 chelates strongly solvates potassium cations The anion associated with potassium is bare and therefore more nucleophilic In solvating only the cation crown ethers are similar to polar aprotic solvents like DMF, DMSO, and HMPA in increasing the nucleophilicity of an anion.

Worked Example 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

Thiols and Sulfides Thiols Sulfur analogs of alcohols Named with the suffix –thiol –SH group is called mercapto group Thiols are also called mercaptans. Like alcohols, thiols are weakly acidic; unlike alcohols they don’t typically form hydrogen bonds (S is not sufficiently electronegative). Thiols have an appalling odor. Skunk scent, for example, stems from the aroma of simple thiols. A small amount of ethanethiol is added to natural gas to permit detection of gas leaks.

Thiols Prepared from alkyl halides by SN2 displacement with a sulfur nucleophile Alkylthiol product can undergo further reaction with the alkyl halide Gives symmetrical sulfide, a poorer yield of the thiol The reaction shown above works poorly to produce a thiol unless an excess of the nucleophile is used because the initially generated thiol can undergo a second SN2 reaction to generate a sulfide.

Thiols Pure alkylthiol thiourea is used as the nucleophile Gives an intermediate alkyl isothiourea salt, hydrolyzed by subsequent reaction with an aqueous base The use of thiourea overcomes the problem of an initially generated thiol reacting with another equivalent of alkyl halide to form a sulfide.

Thiols Can be oxidized by Br2 or I2 Yields disulfides (RSSR’) Reaction is reversible Reduction back to thiol by zinc and acid Oxidation and reduction are key parts of numerous biological processes Disulfide formation is involved in defining the structure and three-dimensional conformations of proteins, where disulfide “bridges” often form cross-links between cysteine amino acid units in protein chains. Curly hair is a result of these disulfide linkages within protein chains.

Sulfides Sulfur analogues of ethers Named by rules used for ethers, with sulfide in place of ether for simple compounds and alkylthio in place of alkoxy Thiols when treated with a base gives corresponding thiolate ion Treatment of a thiol with a base, such as NaH, gives the corresponding thiolate ion (RS-), which undergoes reaction with a primary or secondary alkyl halide to give a sulfide. The reaction occurs by an SN2 mechanism, analoguous to the Williamson synthesis of ethers.

Sulfides Thiols can undergo further reaction with the alkyl halide to give a sulfide Sulfides and ethers differ substantially in their chemistry Through SN2 mechanism, dialkyl sulfides react rapidly with primary alkyl halides to give sulfonium ions Because the valence electrons on sulfur are farther from the nucleus and are less tightly held than those on oxygen, sulfur compounds are more nucleophilic than their oxygen analogs. Dialkyl sulfides react rapidly with primary alkyl halides by an SN2 mechanism to give sulfonium ions (R3S+).

Oxidation of Thiols Sulfides are easily oxidized by treatment 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 Dimethyl sulfoxide easily penetrates the skin carrying with it whatever is dissolved in this polar aprotic solvent.

Worked Example Name the following compound: Solution: 3-(Ethylthio)cyclohexanone

Spectroscopy of Ethers Infrared Spectroscopy C–O single-bond stretching 1050 to 1150 cm-1 overlaps many other absorptions Nuclear magnetic resonance spectroscopy H on a C next to ether O is shifted downfield to 3.4  to 4.5  In epoxides, these 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 

The Infrared Spectrum of Diethyl Ether The C-O stretch is not easily identified.

The 1H NMR Spectrum of Dipropyl Ether The electronegative oxygen shifts absorption by hydrogens on adjacent carbons downfield. Typically they occur between 2.5 and 3.5 ppm. Ether carbon atoms also exhibit a downfield shift in the 13C NMR. They usually absorb in the 50-80 ppm range.

Worked Example The 1H NMR spectrum shown is that of a cyclic ether with the formula C4H8O Propose a structure Note there are five chemical shift positions but only four carbons. This means there must be two diastereotopic protons. There is obviously a methyl and a methylene group. The remaining three signals correspond to methines. Since there are no aromatic rings based on the number of carbons, draw a straight chain of four carbon atoms. Since the methyl group is split into a triplet it must be next to the methylene. Thus one or both of the last two carbons must bear an oxygen substituent. Three signals correponding to three hydrogen atoms on two carbons together with an oxygen mandates the oxygen be shared by two carbons, ie… an epoxide.

Worked Example Solution: