DENT 1002 – Organic Chemistry
Lecture 18: Ethers, Epoxides and Thiols
Dr. Berna DOĞAN
[email protected] Lecture Overview
At the end of this lecture, you will be able to;
• Distinguish between ethers, epoxides, thiols and sulfides
• Name ethers, epoxides, thiols and sulfides
• Describe the preparation as well as reactions of these compound groups
• Explain why epoxides are more reactive than other ethers
• Explain why sulfur analogs are more reactive
• Define what are crown ethers and their usages
2
Ethers and Epoxides
• Ethers – another group of compounds that are derivatives of water
• An ether has two organic groups (alkyl, aryl, or vinyl) bonded to the same
oxygen atom, R–O–Rʹ
• Ethers commonly have medicinal usage as an anesthetic and industrial usage
as a solvent – specifically diethyl ether and tetrahydrofuran (THF)
• Epoxides – cyclic ethers containing three atoms in the ring
(an epoxide)
3
Thiols and Sulfides
• Thiols (R–S–H) and sulfides (R–S–Rʹ) are sulfur (for oxygen) analogs of
alcohols and ethers
• Both functional groups are found in various biomolecules, though not as
commonly as their oxygen-containing relatives
4
Naming Ethers
• Simple ethers are named by identifying the two organic substituents and
adding the word ether
• If other functional groups are present, the ether part is considered an alkoxy
substituent
5
Structure and Properties of Ethers
• Ethers have almost tetrahedral bond angle (112˚ in dimethyl ether)
• Oxygen atom in ethers is sp3-hybridized – lone pairs of oxygen!
• Oxygen atom gives ethers a slight dipole moment
• The boiling points of ethers are often slightly higher than the boiling points
of comparable alkanes
• Ethers cannot form hydrogen bonds with one another
6
Ethers as Solvents
• Ethers are relatively inert compounds – no reaction with dilute acids, dilute bases, or
with common oxidizing and reducing agents
• No reaction with metallic sodium – unlike alcohols
• Ethers dissolve most organic compounds – hence, ethers excellent solvents in which
to carry out organic reactions
• Ethers also used to extract organic compounds from their natural sources
• However, ethers are highly flammable – caution should be taken
• Some ethers react slowly with the oxygen in air to give peroxides, compounds that
contain an O–O bond
• Peroxides are explosive and extremely dangerous, even in tiny amounts
7
Synthesis of Ethers: Industrial Synthesis
• Diethyl ether and other simple symmetrical ethers are prepared industrially
by the sulfuric acid–catalyzed reaction of alcohols
• Reaction follows an SN2 mechanism – a water molecule displaced
• The method is limited to use with primary alcohols – other alcohols
dehydrate by an E1 mechanism to yield alkenes
8
Synthesis of Ethers: The Williamson Method
• Most useful method of preparing ethers is Williamson ether synthesis
• An alkoxide ion reacts with a primary alkyl halide or tosylate in an SN2
reaction
• Alkoxides prepared by reaction of an alcohol with a strong base such as
sodium hydride, NaH
9
Synthesis of Ethers: The Williamson Method
• A useful variation of the Williamson synthesis involves silver oxide, Ag2O
• Under this conditions, alcohol reacts directly with alkyl halide, so no need to
preform the metal alkoxide intermediate
• Sugars react particularly well with alkyl halides in the presence of Ag2O
• Glucose reacts with excess iodomethane in the presence of Ag2O to generate
a pentaether in 85% yield
10
Synthesis of Ethers: Alkoxymercuration of Alkenes
• An alkene treated with an alcohol in the presence of mercuric acetate or
mercuric trifluoroacetate, (CF3CO2)2Hg – alkoxymercuration
• Demercuration of the alkoxymercuration product by reaction with NaBH4 breaks
C-Hg bond and yields an ether
• The net result is Markovnikov addition of the alcohol to the alkene
11
Reactions of Ethers: Acidic Cleavage
• As mentioned, ethers are generally unreactive (inert)
• Undergo only one truly general reaction—they are cleaved by strong acids
• This is because ethers have unshared electron pairs on the oxygen atom and
are therefore Lewis bases
• Aqueous HBr and HI both work well, but HCl does not cleave ethers
• Depending on the alkyl groups in ether (R and Rʹ groups connected to O
atom) different reaction mechanisms followed
12
Reactions of Ethers: Acidic Cleavage
• Ethers with only primary and secondary alkyl groups react by an SN2
mechanism
• I– or Br– attacks the protonated ether at the less hindered site
• Other example reactions below
13
Reactions of Ethers: Acidic Cleavage
• Ethers with a tertiary, benzylic, or allylic group cleave by either an SN1 or
E1 mechanism as they can produce stable intermediate carbocations
• These reactions are often fast and take place at moderate temperatures and
do not require a strong nucleophile
• Mixtures of alkyl halides and alkenes can be generated as products
14
Reactions of Ethers: Claisen Rearrangement
• A rearrangement reaction specific to allyl aryl ethers and allyl vinyl ethers
observed – Claisen Rearrangement
• Heating the allyl aryl ether to 200–250˚C leads to an o-allylphenol
• The net result is alkylation of the phenol in an ortho position
15
Reactions of Ethers: Claisen Rearrangement
• Claisen rearrangement takes place in a single step – a reorganization of
bonding electrons through a six-membered, cyclic transition state
• A similar rearrangement takes place with allyl vinyl ethers, leading to a
unsaturated ketone or aldehyde
16
Cyclic Ethers
• For the most part, cyclic ethers behave like acyclic ethers
• The chemistry of the ether functional group is the same, whether it’s in an
open chain or in a ring
• Common cyclic ethers such as tetrahydrofuran (THF) and dioxane, for
example, are often used as solvents because of their inertness
• THF specifically used in preparation of Grignard reagents
• Realize that these cyclic ether can be cleaved by strong acids
17
Cyclic Ethers: Epoxides (Oxiranes)
• Cyclic ethers with three-membered ring compounds behave different than
other ethers
• These compound are called epoxides or oxiranes
• Simplest epoxide is ethylene oxide (oxirane; 1,2-epoxyethane) – an
industrially important intermediate
• Ethylene oxide prepared by reaction of ethylene with oxygen at 300˚C and
silver oxide, Ag2O catalyst
18
Cyclic Ethers: Epoxides (Oxiranes)
• In laboratory, epoxides prepared by different methods
• by treatment of an alkene with a peroxyacid such as m-chloroperoxybenzoic acid
• by base treatment of a halohydrins that are produced from alkenes
19
Reactions of Epoxides
• The strained ring system in epoxides causes their unique chemical reactivity
• Epoxides react with dilute aqueous acids at room temperature – hydrolysis of
epoxides to give 1,2 diols (vicinal glycols)
• For instance, ethylene glycol used as automobile antifreeze produced by
• The epoxide cleavage takes place by SN2-like backside attack of a nucleophile on the
protonated epoxide
20
Reactions of Epoxides
• Other nucleophiles add to epoxides in a similar way
• Epoxides can also be opened by reaction with acids other than H3O+
• If anhydrous HX is used, for instance, an epoxide is converted into a trans halohydrin
21
Reactions of Epoxides
• Unlike other ethers, epoxide rings can be cleaved by bases and nucleophiles as well
as by acid in a typical SN2 reaction
• With other nucleophiles under basic conditions reaction also observed – attack of the
nucleophile takes place at the less hindered epoxide carbon
22
Reactions of Epoxides
• Grignard reagents and organolithium compounds are strong nucleophiles capable of
opening the ethylene oxide ring
• Initial product is a magnesium alkoxide or lithium alkoxide
• After hydrolysis, a primary alcohol with two more carbon atoms than the
organometallic reagent obtained when ethylene oxide is used
23
Crown Ethers
• Macrocyclic (large-ring) polyethers are called crown ethers
• Rings consist repeating (-OCH2CH2-) or similar units
• Named as x-crown-y
• x is the total number of atoms in the ring
• y is the number of oxygen atoms
• 18-crown-6 ether: 18-membered ring containing 6 oxygens atoms
24
Crown Ethers
• Central cavity in crown ethers is
electronegative and attracts cations
• Due to this, they sequester specific metal
cations in the center of the polyether cavity
• Complexes between crown ethers and ionic salts
are soluble in nonpolar organic solvents
• Creates reagents that are free of water that have
useful properties
• Inorganic salts dissolve in organic solvents
leaving the anion unassociated, enhancing
reactivity
25
Thiols
• Thiols (RSH) are sulfur analogs of alcohols – sometimes called mercaptans
• Named by the same system used for alcohols – suffix -thiol instead of –ol
• SH group is called “mercapto group” (“capturer of mercury”)
• Thiols are slightly more acidic than alcohols; the pKa of CH3SH is 10.3
• Unlike alcohols, however, thiols don’t typically form hydrogen bonds
because the sulfur atom is not sufficiently electronegative
• The most striking characteristic of thiols is their appalling odor
26
Thiols Preparation
• Thiols are usually prepared from alkyl halides by SN2 displacement with a
sulfur nucleophile such as hydrosulfide anion –SH
• This reaction works poorly as thiol can undergo a second reaction with alkyl
halide to give a sulfide as a by-product
• Hence, thiourea (NH2(C=S)NH2) used as the nucleophile
27
Thiols Oxidation
• Thiols easily oxidized to disulfides, compounds containing an S–S bond via
reaction with bromine or iodine
• The reaction is easily reversed – disulfide reduced back to a thiol by
treatment with zinc and acid
• Thiol–disulfide interconversion is key part of numerous biological processes
• Disulfide formation is involved in defining the structure and three-dimensional
conformations of proteins
• Disulfide “bridges” often form cross-links between cysteine amino acid units
in the protein chains
28
Sulfides
• Sulfur analogs of ethers are called sulfides (RSR’)
• Named by following same rules used for ethers – suffix sulfide instead of
ether for simple compounds
• For more complex substances, alkylthio used in place of alkoxy
• Despite their close structural similarity, sulfides and ethers differ
substantially in their chemistry
• Sulfur compounds are more nucleophilic than their oxygen-compound
analogs
29
Sulfides Preparation
• Sulfides are prepared from Thiolates (RS−) that themselves prepared from
treatment of thiol with bases such as NaH
• The reaction occurs by an SN2 mechanism, analogous to the Williamson
synthesis of ethers
• Side note – Thiolates are excellent nucleophiles and react with many
electrophiles
30
Sulfides Reactions
• Unlike dialkyl ethers, dialkyl sulfides react rapidly with primary alkyl
halides (SN2) to give trialkylsulfonium salts (R3S+)
• Sulfides are easily oxidized with H2O2 to the sulfoxide (R2SO) or sulfone
(R2SO2)
Side Note – Dimethyl sulfoxide (DMSO) is often used as a polar
aprotic solvent
31
Reading Materials
• Organic Chemistry By McMurry, 8th Ed. (chapter 18)
• Organic Chemistry: a short course by David J. Hart, Christopher M. Hadad, Leslie
E. Craine, Harold Hart, 13th Ed. (chapter 8 and part of Chapter 7)
Web pages
• http://ocw.uci.edu/upload/files/51b_chapter9_f2014.pdf
• https://crab.rutgers.edu/~alroche/Ch14.pdf
• https://chem.libretexts.org/Bookshelves/Organic_Chemistry/Supplemental_Modules
_(Organic_Chemistry)/Thiols_and_Sulfides/Thiols_and_Sulfides
32
