Download presentation
Presentation is loading. Please wait.
1
Ether, Epoxide, Thiol/Thioether
Preparation of Ethers Reaction of Ethers *Reaction of Epoxide *Epoxide in synthesis Preparation of Thiols and Thioethers Reaction of Thiol as nucleophile
2
Introduction to Ethers
An ether group includes an oxygen atom that is bonded to TWO –R groups, -R groups can be alkyl, aryl, or vinyl groups Ether in nature
3
Naming Ethers: Common Name
Common names are used frequently Name each –R group Arrange them alphabetically End with the word, “ether”
4
IUPAC Nomenclature of Ethers
IUPAC systematic names are often used as well Make the larger of the –R groups the parent chain Name the smaller of the –R groups as an alkoxy substituent
5
Practice: Naming Ethers
Name the following molecule Draw the structure for (R)-1-methoxycyclohexen-3-ol
6
3 Structure and Properties of Ethers
The bond angle in ethers is very similar to that found in water and in alcohols Ethers typically have much lower boiling point than alcohol with same formula (lack of H-bonding). Larger R group has higher boiling point.
7
Use of Ethers in Organic Chemistry
Ethers are often used by organic chemists as solvents Relatively low boiling points allow them to be evaporated after the reaction is complete Their dipole moment allows them to stabilize charged or partially charged transition states. HOW? They are NOT protic.
8
Ether as Polar Aprotic Solvent
Metal atoms with a full or partial positive charge can be stabilized by ether solvents Ethers are generally used as the solvent in the Grignard reaction In this reaction ether is inert to the reaction intermediates.
9
5 Ethers from Acid Dehydration
Symmetrical ether (such as diethyl ether) can be prepared by the acid-catalyzed dehydration of alcohol (SN2) Intermolecular dehydration Only for symmetrical ethers
10
Williamson reaction The Williamson ether synthesis (1. NaH; 2. R’X) is a viable approach for many asymmetrical ethers Mechanism: First, formation of alkoxide (nucleophile); Then SN2 rxn of alkoxide with alkyl halide
11
Use of Williamson Reaction
R’X as primary halide: The alkoxide ion is also a strong base, so elimination rxn might occur with secondary/tertiary halides. Use the Williamson ether approach to prepare MTBE
12
Practice: Preparation of Ethers
Use the Williamson ether approach to synthesize the following molecule
13
Ether from Oxymercuration-demercuration
Recall conversion from alkene to alcohols Regiochemistry: Markovnikov (OH on more substituted carbon) Stereochem: Anti addition of Hydride Similarly, alkoxymercuration-demercuration can be used to synthesize ethers. Markovnikov; anti
14
Practice: Preparation of Ethers
Predict the alkoxymercuration-demercuration product
15
6 Ether Reactions: Acidic Cleavage of Ether
Reaction: R-O-R’ + excess HX R-X + R’-X Mechanism: Protonation and SN2
16
More Acidic Cleavage of Ethers
Phenol will NOT react with HX to protonate to form Aryl halide Cyclic ether reacts with excess HX to form dihalide
17
Nucleophilicity in Cleavage of Ethers
SN2 follows protonation, thus nucleophilicity of halide affects the reactivity Recall the nucleophilicity of halides: I > Br > Cl F due to polarizibility of ions HI and HBr are generally effective HCl is less effective, and HF does not cause significant cleavage
18
Practice: Reactions of Ethers
Predict products and draw a complete mechanism
19
Autooxidation of Ethers
Ethers can undergo autooxidation Hydroperoxides can be explosive, so laboratory samples of ether must be frequently tested for the presence of hydroperoxides before they are used The autooxidation occurs through a free radical mechanism
20
7 Epoxides For cyclic ethers, the size of the ring determines the parent name of the molecule Oxiranes are also known as epoxides Epoxides are most reactive among the above.
21
Epoxides in nature An epoxide can have up to 4 –R groups
Although they are unstable, epoxides are found commonly in nature
22
Naming Epoxides There are two methods for naming epoxides
The oxygen is treated as a side group (epoxy), and two numbers are given as its locants Oxirane is used as the parent name
23
Practice: Naming Epoxides
Name the molecules below by both methods if possible
24
8 Epoxides from Alkene + MCPBA
Recall that epoxides can be formed when an alkene is treated with a peroxy acid MCPBA and peroxyacetic acid are most commonly used
25
Syn Stereochemistry of MCPBA Addition
Recall that the process is stereospecific
26
Epoxides from Halohydrin+NaOH
Recall Halohydrin can be prepared from the addition of halogen/water to alkene: Markovnikov regioselectivity (HOd--Xd+). Anti stereochemistry (similar to halogenation) When a Halohydrin is treated with NaOH, a ring-closing reaction can yield epoxide
27
Epoxide from Halohydrin: Intramolecular SN2
28
Stereochemistry of AlkeneEpoxide
Assess the overall stereochemistry of the epoxidation that occurs through the halohydrin intermediate
29
9 Enantioselectivity in Epoxidation
The epoxidation methods we have discussed so far are NOT enantioselective Draw the products racemic mixture
30
10 Ring-opening of Epoxides
Because of their significant ring strain, epoxides have great synthetic utility as intermediates Strong nucleophiles react readily with epoxides Predict whether each step is product or reactant favored, and explain WHY
31
Ring opening of epoxide
In general, alkoxides are not good leaving groups The ring strain associated with the epoxide increases its potential energy making it more reactive
32
Ring-opening of Epoxides by Nucleophiles
Epoxides can be opened by many other strong nucleophiles as well, via SN2 mechanism (1>2>>3). Both regioselectivity and stereoselectivity must be considered – see next few slides
33
Regio/Stereochemistry of Ring-opening
Given that the epoxide ring-opening is SN2, predict the outcome of the following reactions (Pay attention to regio- and stereoselectivity)
34
Acidic Ring-opening of Epoxides
Acidic ring-opening of epoxide Halohydrin Mechanism: Protonation SN2 protonated RO- group as better leaving group (similar to protonated –OH group in alcohol).
35
Acidic ring-opening of Epoxides by ROH
Water or an alcohol as nucleophile under acidic conditions reacts with epoxide to form alcohol SN1 regioselectivity (3>2>>1). Predict the products and draw a complete mechanism Antifreeze (ethylene glycol)
36
Ring-opening of Epoxides: Observation
Experiments: First rxn: Nuc attack on primary over secondary, SN2 Second rxn: Tertiary carbon undergoes change. SN1
37
More on Ring-opening of Epoxides
If the nucleophile preferentially attacks the tertiary carbon under acidic conditions, the mechanism is likely SN1. Considering the observations below:
38
Stabilized Carbocation in Ring-opening of Epoxides
When the nucleophile attacks a tertiary center of the epoxide, the intermediate it attacks takes on some carbocation character (SN1), but not completely
39
12 Synthetic Strategies Involving Epoxides
Epoxides can be used to install functional groups on adjacent carbons Give necessary reagents for the reaction below
40
Rxn of Epoxides with Grignard Reagent
By reacting an epoxide with a Grignard reagent (nucleophile), the carbon skeleton can be modified Or You may think of an epoxide as the starting material
41
Synthesis from Epoxides and Grignard Reagent
An epoxide can be used to install a TWO carbon chain between an R group and an OH group Recall that a carbonyl can be used to install a ONE carbon chain between an R group and an OH group
42
Practice: Synthesis involving Epoxides
Give necessary reagents for the reaction below
43
11 Thiols Alcohol ROH Thiol RSH
Thiols (–SH group) analogous to Alcohol (–OH group) The name of a compound with an –SH group ends in “thiol” rather than “ol” Note that the “e” of butane is not dropped in the name of the thiol
44
Naming Thiols Thiols are also known as mercaptans
The –SH group can also be named as part of a side group, mercapto, rather than as part of the parent chain The mercaptan name comes from their ability to complex mercury (forming S-Hg-S bond) 2,3-dimercapto-1-propanol is used to treat mercury poisoning.
45
Thiols in life Thiols are known for their unpleasant odor
Skunks use thiols as a defense mechanism Methanethiol as additive to natural gas (methane)
46
Synthesis of Thiols Thiols can be prepared from SN2 substitution with hydrosulfide (HS-, strong nucleophile and weak base) and alkyl halide
47
Review: Preparation of Thiols
Predict the outcome of the following reactions, and draw a complete mechanism
48
Thiols: Acidity, Nucleophilicity
Thiols have a pKa of about 10.5 Recall that water has a pKa of 15.7 Review: Predict whether the equilibrium below will favor products or reactants and draw the mechanism (by comparing Ka or pKa) Thiolates are excellent nucleophiles thiolate ion
49
Thiols to Disulfides A thiolate can attack Br2 to produce a disulfide. RSBr as intermediate. The reaction is the oxidation
50
Reduction of Disulfide to Thiol
Low bond dissociation energy for S-S bond (53 kcal/mol) Disulfides can be reduced by the reverse reaction The interconversion between thiol and disulfide can also occur directly via a free radical mechanism. Making curly hair: Reduction to “loosen” disulfide bonds, then oxidation to build new disulfide bonds.
51
Sulfide/Thioether Recall: In general/inorganic chemistry, “sulfide” refers to sulfide ion or metal sulfur compound such as Al2S3 Organic chemistry, sulfide = Sulfur analogs of ethers or thioethers Sulfides can also be named as a side group
52
Preparation of Sulfides
Nucleophilic attack of a thiolate (RS- anion) on alkyl halide Thiolates generally are prepared from deprotonation of thiol (RSH + base, such as OH- )
53
Reaction of Sulfides Sulfonium: The neutral sulfide is good nucleophile to attack on an alkyl halide, forming sulfonium ion. The process produces a strong alkylating reagent that can add an alkyl group to a variety of nucleophiles
54
Oxidation of Sulfides Sulfides can also be oxidized to form sulfoxide and sulfone. H2O2/NaHCO3 to remove skunk odor. Sodium meta-periodate can be used to form the sulfoxide
55
S-O Bond in Sulfoxide/Sulfone
Sulfoxides and sulfones have very little double bond character, indicating the polarized resonance contributor as the major contributor
56
Sulfides as Reducing Agent
Because sulfides are readily oxidized, they make good reducing agents Similar to the ozonolysis reaction of alkene and alkyne
57
Practice: Rxns of Thiols and Sulfides
Predict any products or necessary reagents in the reaction sequence below Verify the formal charge on the sulfur in the final product above
58
Supplemental topics: Crown Ethers
Crown ethers have been shown to form especially strong attractions to metal atoms. Note two carbon atoms as unit separate the oxygens
59
Size of Crown Ethers vs. Size of M+
The size of the metal must match the size of the crown to form a strong attraction 18-crown-6 fits a K+ ion just right
60
Solubility of Crown Ether-Metal Complex
Normally metal ions are not soluble in low polarity solvents. The crown ether – metal complex should dissolve nicely in low polarity solvents because of the nonpolar section of structure Thus crown ether could be used to aid reactions between ion (especially anions) and low polarity organic substrates
61
Crown Ether facilitate Anion rxn
Without the crown ether, KF is insoluble in benzene The F- ion below is ready to react because the K+ ion is sequestered by the crown ether The free F- ion readily undergo SN2 rxn despite as “poor” nucleophile:
62
Other Crown Ether-Metal Complexes
Smaller crown ethers bind smaller cations
63
*Non-enantioselective Epoxidation
The epoxidation forms a racemic mixture, because the flat alkene can react on either face
64
Enantioselective Epoxidation
To be enatioselective at least one of the reagents (or catalyst) in a reaction must be chiral The Sharpless catalyst forms such a chiral complex with an allylic alcohol
65
Sharpless Enantioselective Epoxidation
The desired epoxide can be formed if the right catalyst is chosen. Note the position of the –OH group
66
Additional Practice Problems
Name the following molecule Draw the structure for (4-methylcyclohexyl)phenylether
67
Additional Practice Problems
Fill in the missing intermediates and reagents in the scheme below
68
Additional Practice Problems
Fill in the missing intermediates and reagents in the scheme below
69
Additional Practice Problems
Give necessary reagents to complete the synthesis below
70
Mechanism of ether autooxidation
71
Mechanism of ether autooxidation
Recall that the net reaction is the sum of the propagation steps
72
Ring-opening of Epoxides
The epoxide reaction is both more kinetically and more thermodynamically favored, due to instability of epoxide and entropy increase
Similar presentations
© 2025 SlidePlayer.com Inc.
All rights reserved.