Chapter 13 - Ethers and Epoxides; Thiols and Sulfides Flashcards
What are epoxides?
High-energy compounds that are a special category of ethers.
What is the general structure of an ether?
An oxygen atom bonded to two R groups (alkyl, aryl, or vinyl).
What is the common name for (CH3CH2)2O?
Diethyl ether.
What is the systematic name for an ether with a larger R group as the parent?
The larger group is named as the parent alkane with the smaller as an alkoxy substituent.
What is the boiling point of dimethyl ether?
-25°C.
True or False: Ethers can function as hydrogen bond donors.
False.
What is the primary reason for the lower boiling points of ethers compared to alcohols?
Ethers cannot form hydrogen bonds with each other.
What is the boiling point of ethanol?
78°C.
Name three common solvents that are ethers.
- Diethyl ether
- Tetrahydrofuran
- 1,4-Dioxane
What are crown ethers?
Compounds with multiple ether groups that can bind tightly to metal ions.
What is the naming convention for crown ethers?
X-crown-Y, where X is the total number of atoms in the ring and Y is the number of oxygen atoms.
What is the internal cavity of 18-crown-6 capable of hosting?
A potassium cation (K+).
Fill in the blank: Ethers are often used as solvents for organic reactions because they are fairly _______.
unreactive.
What compounds can interfere with neurotransmitter action in the context of inhalation anesthetics?
- Release of neurotransmitters
- Binding of neurotransmitters
- Ionic conductance
- Reuptake of neurotransmitters
What does the term ‘unsymmetrical ether’ refer to?
Ethers with two different alkyl groups.
What is the role of ethers in the formation of Grignard reagents?
They stabilize the charge on the magnesium atom.
What are the boiling points of diethyl ether and dipropyl ether?
- Diethyl ether: 35°C
- Dipropyl ether: 91°C
What is the primary mechanism by which inhalation anesthetics disrupt synaptic transmission?
A combination of interfering with neurotransmitter release, binding, ionic conductance, and reuptake.
What are some examples of pharmaceuticals that contain an ether group?
- (R)-Fluoxetine
- Tamoxifen
- Propanolol
What is the significance of the geometry of the oxygen atom in ethers?
It influences the bond angles and interactions with other molecules.
Fill in the blank: The geometry of an oxygen atom in ethers is similar to that in _______ and _______.
water; alcohols.
What is the effect of larger alkyl groups on the boiling point of ethers?
Higher boiling points due to London dispersion forces.
What is the main drawback of diethyl ether as an anesthetic?
Unpleasant side effects and recovery issues.
What is the role of 18-crown-6 in the dissolution of KF in benzene?
It generates a complex that dissolves in benzene, allowing fluoride ions to become free nucleophiles
The presence of 18-crown-6 enables substitution reactions with F− as a nucleophile.
What is the complex formed by 18-crown-6 and potassium cation?
A space-filling model shows that potassium cation fits inside the internal cavity of 18-crown-6
This model illustrates the specific binding of cations by crown ethers.
What is the significance of fluoride ions in substitution reactions?
Fluoride ions can serve as nucleophiles when made free by 18-crown-6 in nonpolar solvents
Free fluoride ions are difficult to use in polar solvents due to strong interactions.
Which crown ether solvate lithium ions?
12-crown-4
This specific crown ether is effective for lithium ion solvation.
Which crown ether is used to solvate sodium ions?
15-crown-5
This crown ether specifically binds sodium ions.
What is host-guest chemistry?
A field of chemistry focused on the interactions between host molecules and guest ions or molecules
It was significantly advanced by the discovery of crown ethers.
What is the primary purpose of using chelating agents like citrate in food and medicine?
To trap metal cations and suppress their reactivity
This prevents undesired reactions and protects food and blood supplies.
What type of compound is oxalic acid considered in relation to metal cations?
A chelating agent because it can form tight complexes with metal cations
Oxalic acid deprotonates to form oxalate ions, which bind to cations like Ca2+.
What is calcium citrate and its role?
A compound formed from citrate ions and calcium ions that prevents undesired calcium reactivity
It is used in blood preservation to prevent coagulation.
What is the primary compound found in most kidney stones?
Calcium oxalate
It forms from the strong attraction between oxalate ions and Ca2+.
What is the use of sodium citrate in blood banks?
To chelate Ca2+ ions and prevent blood coagulation
Even trace quantities of free Ca2+ can catalyze coagulation.
What is EDTA and its common applications?
Ethylenediaminetetraacetate, a chelating agent used to bind metal cations
It is used in foods to prevent oxidation and in medicine for heavy metal poisoning.
How is diethyl ether industrially prepared?
Via the acid-catalyzed dehydration of ethanol
The mechanism involves an SN2 process.
What is the Williamson ether synthesis?
A two-step process for preparing ethers involving deprotonation of an alcohol and SN2 reaction with an alkyl halide
This method is named after Alexander Williamson.
What types of alkyl halides work best in Williamson ether synthesis?
Methyl or primary alkyl halides
Secondary halides are less efficient due to elimination, and tertiary halides cannot be used.
What is the main concern associated with the use of MTBE?
Potential groundwater contamination
Its use has declined due to environmental concerns.
What is a key limitation of the acid-catalyzed dehydration process for ether preparation?
It only works well for primary alcohols and produces symmetrical ethers
This limits its practical value for synthetic organic chemists.
What is the first step in the Williamson ether synthesis?
Deprotonation of the alcohol to form an alkoxide ion
This alkoxide ion acts as a nucleophile in the subsequent SN2 reaction.
What are the best leaving groups in ether synthesis?
Tosylates
Tosylates are excellent leaving groups due to their stability.
What is the role of sodium hydroxide in the synthesis of ethers?
Deprotonates phenol
This allows for the formation of phenoxide ion, which is a better nucleophile.
What is the first step in the Williamson ether synthesis?
Formation of an alkoxide ion
The alkoxide ion acts as a nucleophile in the reaction.
What is alkoxymercuration-demercuration?
A method for preparing ethers
It involves Markovnikov addition of alcohol across an alkene.
What are the reagents used in alkoxymercuration-demercuration?
Hg(OAc)2, ROH, NaBH4
These reagents facilitate the addition of an alcohol to the alkene.
What happens to ethers under acidic cleavage?
Converted into two alkyl halides
This occurs when ethers are heated with a strong acid like HX.
What is the mechanism for acidic cleavage of ethers?
Protonation followed by SN2 substitution
The first step involves protonation to form a good leaving group.
True or False: Ethers are completely unreactive under acidic conditions.
False
Ethers can undergo reactions such as acidic cleavage.
What is autooxidation in ethers?
Formation of hydroperoxides in the presence of oxygen
This process is slow but dangerous due to potential violent decomposition.
What are the common names for the cyclic ethers discussed?
Oxirane, Oxetane, Oxolane, Oxane
These names indicate the size of the ring in cyclic ethers.
What is the simplest epoxide?
Ethylene oxide
This compound has no R groups attached.
What are epothilones?
A class of novel anticancer agents
They were first isolated from the bacterium Sorangium cellulosum.
How can alkenes be converted into epoxides?
Treatment with peroxy acids
Common peroxy acids include MCPBA and peroxyacetic acid.
What is the stereochemical outcome of epoxide formation from alkenes?
Cis substituents remain cis, trans remain trans
This stereospecificity is maintained during the transformation.
What is the method for naming epoxides?
Identify the epoxide as a substituent or consider the oxirane ring
The naming depends on whether the oxygen is viewed as a substituent or as part of the ring.
What is the result of treating halohydrins with a strong base?
Formation of epoxides
This occurs via an intramolecular Williamson ether synthesis.
What is the significance of the configuration of groups in epoxide formation?
Maintains relative stereochemistry from the starting alkene
The configuration of groups in the starting material dictates the configuration in the epoxide.
What happens to ethers that are old and contaminated?
They may contain dangerous hydroperoxides
These can lead to violent decomposition when heated.
What is a common use for ethers in the laboratory?
Solvents for many reactions
Ethers are stable under basic or mildly acidic conditions.
What are pheromones?
Chemicals used by members of the same species to communicate.
What is carbamazepine used for?
Treatment of epilepsy and bipolar disorder.
What is the significance of carbamazepine-10,11-epoxide?
It exhibits activity similar to that of the parent compound and contributes to therapeutic effects.
True or False: Clarithromycin inhibits the action of epoxide hydroxylase.
True.
What is the main effect of clarithromycin on carbamazepine?
Increases the concentration of the epoxide, enhancing its potency.
What is a key factor physicians must consider when prescribing carbamazepine?
Potential drug interactions.
What is formed when carbamazepine-10,11-epoxide is metabolized?
A trans diol through the action of epoxide hydroxylase.
What is the outcome of glucuronidation of the trans diol from carbamazepine?
A water-soluble adduct that can be excreted in urine.
What is the result of enantioselective epoxidation?
Formation of a chiral epoxide, favoring one enantiomer over the other.
What does a chiral catalyst do in the context of epoxidation?
Creates a chiral environment that favors epoxidation at one face of the alkene.
What are the components of Sharpless’ chiral catalyst?
Titanium tetraisopropoxide and diethyl tartrate (DET).
What is the role of (+)-DET and (–)-DET in the Sharpless epoxidation?
They determine whether the epoxide forms above or below the plane.
What is the significance of the stereochemical outcome in Sharpless epoxidation?
It allows control over which enantiomer is obtained.
What is observed when a strong nucleophile opens an epoxide?
A ring-opening reaction occurs.
In the context of epoxide reactions, what does regiochemistry refer to?
The position where the nucleophile attacks, typically the less hindered position.
What stereochemical outcome occurs when a nucleophile attacks a chiral center in an epoxide?
Inversion of configuration.
What is the mechanism of epoxide ring opening with a strong nucleophile?
An SN2 process followed by proton transfer.
What is the expected product of a reaction between a strong nucleophile and an epoxide?
A product formed through nucleophilic attack and inversion at a chiral center.
How does the energy of an epoxide affect its reactivity?
The high energy of the epoxide lowers the activation energy for reactions.
What happens to the configuration of the chiral center that is attacked during an epoxide ring opening?
The configuration is inverted.
Fill in the blank: The epoxide undergoes ______ when subjected to a strong nucleophile.
ring-opening.
What is the role of acid in the reaction with a strong nucleophile and an epoxide?
Protonates the alkoxide ion after nucleophilic attack.
What is the purpose of spirocyclic compounds in insects?
Used for communication
Compound 3 is an example of a spirocyclic compound.
What is the first step in the synthesis of compound 3?
Treatment of (S)-1,2-epoxypropane with lithium acetylide followed by acid workup
This gives compound 2.
What is ethylene oxide?
A colorless, flammable gas used to sterilize medical equipment
It is particularly effective for plastics that cannot withstand autoclave temperatures.
How does ethylene oxide kill microorganisms?
By alkylating functional groups in DNA, interfering with its normal function
This process involves a ring opening of the epoxide.
What mixture is used to mitigate the explosion hazard of ethylene oxide?
A mixture of ethylene oxide and carbon dioxide
An example is Carboxide, which contains 10% ethylene oxide and 90% CO2.
What is the main issue associated with the use of ethylene oxide?
It is toxic and explosive at high concentrations
Care must be taken to use it effectively.
What significant incident occurred at UCLA medical school in February 2015?
Patients were infected due to inadequate sterilization of duodenoscopes
This led to cases of carbapenem-resistant enterobacteria.
What is the driving force for the ring-opening reactions of epoxides?
Removal of ring strain associated with the three-membered ring
This is true for reactions with strong nucleophiles.
What is the mechanism of acid-catalyzed ring opening of an epoxide?
Involves proton transfer followed by nucleophilic attack (SN2)
Other nucleophiles like water or alcohol can also open an epoxide ring under acidic conditions.
What does the presence of a chiral center in a ring-opening reaction indicate?
Inversion of configuration is observed
This is consistent with an SN2-like process.
What are the two important features of ring-opening reactions?
- Regiochemical outcome
- Stereochemical outcome
In acid-catalyzed ring opening, when does the electronic effect dominate?
When the epoxide possesses a tertiary position
This favors nucleophilic attack at the more substituted position.
What is the main consequence of the electronic effect in ring-opening reactions?
The more substituted carbon is a stronger electrophile
This makes it more susceptible to nucleophilic attack.
What is the typical outcome when a nucleophile attacks a chiral center during ring-opening?
Inversion of configuration occurs
This is due to back-side attack of the nucleophile.
What is benzo[a]pyrene?
A carcinogenic compound produced from incomplete combustion of organic materials
It is found in smoke from sources like gasoline and cigarettes.
What happens when benzo[a]pyrene is metabolized?
An arene oxide is formed, which is then opened by water to give a diol
This diol can alkylate DNA, causing genetic code alterations.
What are thiols?
Sulfur analogs of alcohols containing an SH group
Their nomenclature is similar to that of alcohols, with ‘thiol’ as the suffix.
What are thiols?
Compounds containing an SH group in place of an OH group
Thiols are the sulfur analogs of alcohols.
What is the nomenclature suffix for thiols?
thiol
The suffix replaces ‘ol’ used for alcohols.
What is a mercapto group?
The SH group when named as a substituent
Derived from the term ‘mercaptans’, which was abandoned by IUPAC.
What is dimercaprol used for?
To treat mercury and lead poisoning
It forms complexes with metals.
How are thiols prepared?
Via an SN2 reaction between sodium hydrosulfide (NaSH) and an alkyl halide
This reaction can occur even at secondary substrates.
What happens during the oxidation of thiols?
They produce disulfides
Requires an oxidizing reagent like bromine.
What is the bond strength of the S–S bond in disulfides?
Approximately 220 kJ/mol
This is about half the strength of many other covalent bonds.
What are sulfides?
Sulfur analogs of ethers, also known as thioethers
Nomenclature is similar to ethers with ‘sulfide’ instead of ‘ether’.
How can sulfides be prepared from thiols?
By using hydroxide to deprotonate thiols and then performing an SN2 reaction with an alkyl halide
This is the sulfur analog of the Williamson ether synthesis.
What do sulfides undergo in terms of reactions?
Oxidation to give sulfoxides and sulfones
The initial product is a sulfoxide, which can be further oxidized to a sulfone.
What reagent can be used to oxidize sulfides to sulfoxides without further oxidation to sulfones?
Sodium meta-periodate (NaIO4)
This allows for good yields of sulfoxides.
What is the role of DMS (dimethyl sulfide) in chemical reactions?
It serves as a reducing agent in ozonolysis
The by-product of this reaction is dimethyl sulfoxide (DMSO).
What should be considered when proposing a synthesis involving epoxides?
Whether there are changes in the carbon skeleton or in the functional groups
This helps dictate the synthetic pathway.
What does the opening of an epoxide provide?
Two functional groups on adjacent carbon atoms
This can be useful for synthesizing target molecules.
How is the regiochemistry determined when opening an epoxide?
By the nucleophile attacking at the more substituted position under acidic conditions
This ensures regioselectivity in the reaction.
What is the key to controlling the location of the resulting functional group when using Grignard reagents?
The choice of electrophile and reaction conditions
Different electrophiles can lead to different functional group locations.
What is the result of the reaction between a Grignard reagent and a ketone or aldehyde?
Preparation of an alcohol
This process involves the formation of a new C–C bond adjacent to a hydroxyl group.
What new electrophile is introduced when reacting a Grignard reagent with an epoxide?
Formation of an alcohol
The newly formed C–C bond is not immediately adjacent to the hydroxyl group.
In the first product generated from a Grignard reaction with an aldehyde, how are the newly formed C–C bonds positioned?
Between α and β positions
This indicates proximity to the hydroxyl group.
In the product from a Grignard reaction with an epoxide, how are the newly formed C–C bonds positioned?
Between β and γ positions
This distance from the hydroxyl group affects retrosynthesis planning.
What is the importance of understanding the proximity of C–C bonds to hydroxyl groups in retrosynthesis?
Determines the type of electrophile to use (aldehyde/ketone or epoxide)
This is crucial for efficient synthesis planning.
What is the first step in proposing a synthesis for transformations involving Grignard reactions?
Identify changes in carbon skeleton or functional group(s)
This helps in determining the necessary reactions.
What reaction can produce a ketone from an alcohol?
Oxidation of the corresponding alcohol
This is a common reaction in organic synthesis.
What type of disconnection leads to a Grignard reagent nucleophile and an epoxide electrophile?
Disconnection one bond farther from the hydroxyl group
This is important for proper retrosynthetic analysis.
What is the general method for preparing ethers?
Williamson Ether Synthesis
This involves the reaction of an alkoxide ion with an alkyl halide.
What happens to ethers when treated with a strong acid (HX)?
Undergo acidic cleavage into two alkyl halides
This is a key reaction of ethers in organic chemistry.
What is oxirane?
A three-membered cyclic ether
It is more reactive than other ethers due to significant ring strain.
How can alkenes be converted into epoxides?
By treatment with peroxy acids or via halohydrin formation and subsequent epoxidation
Both methods are stereospecific.
What is a Sharpless asymmetric epoxidation?
A method using chiral catalysts to achieve enantioselective epoxidation
It favors one enantiomer over another, leading to enantiomeric excess.
What are the two conditions under which epoxides undergo ring-opening reactions?
1) Strong nucleophile 2) Acid-catalyzed conditions
The choice of conditions affects the reaction pathway.
What defines symmetrical ethers?
Ethers with two identical alkyl groups
Unsymmetrical ethers have two different alkyl groups.
What structural feature is common in many natural compounds and pharmaceuticals?
The ether group
Ethers are widely utilized in organic chemistry.
What is the boiling point trend for ethers based on their molecular weight?
Ethers of low molecular weight have low boiling points; larger alkyl groups lead to higher boiling points
This is due to London dispersion forces.
What are chiral catalysts used for?
To achieve the enantioselective epoxidation of allylic alcohols
In a Sharpless asymmetric epoxidation, the catalyst favors the production of one enantiomer over the other, leading to an observed enantiomeric excess.
Under what conditions do epoxides undergo ring-opening reactions?
- Involving a strong nucleophile
- Under acid-catalyzed conditions
When a strong nucleophile attacks an epoxide, where does it attack?
At the less substituted (less hindered) position
What influences the regiochemical outcome of acid-catalyzed ring-opening of epoxides?
The nature of the epoxide, electronic effects, and steric effects
What happens to the stereochemistry during ring-opening reactions of epoxides?
Inversion of configuration at the position being attacked, if that position is a chiral center
What is the definition of thiols?
Sulfur analogs of alcohols containing an SH group instead of an OH group
What is the name of the SH group when another functional group is present?
Mercapto group
How can thiols be prepared?
Via an SN2 reaction between sodium hydrosulfide (NaSH) and a suitable alkyl halide
What products are formed when thiols undergo oxidation?
Disulfides
What are sulfides?
Sulfur analogs of ethers, with nomenclature similar to ethers
How are sulfides prepared from thiols?
By a process analogous to the Williamson ether synthesis, involving a thiolate ion instead of an alkoxide ion
What do sulfides attack to produce alkylating agents?
Alkyl halides
What are the products of sulfide oxidation?
Sulfoxides and then sulfones
What functional groups are produced when an epoxide is opened?
Two functional groups on adjacent carbon atoms
What is the outcome when a Grignard reagent reacts with an epoxide?
A C–C bond is formed, introducing a chain of carbon atoms with a functional group at the second carbon atom
What is the first step in naming an ether using common names?
Treat both sides as substituents and list them alphabetically
What is the systematic naming process for ethers?
Choose the parent, identify all substituents, assign locants, assemble substituents alphabetically with locants, assign the configuration of any chiral centers
What is the first step in preparing an ether via Williamson ether synthesis?
Identify the two groups on either side of the oxygen atom
What is the role of a suitable base in Williamson ether synthesis?
To deprotonate the alcohol
What is the first step in preparing epoxides?
Identify the four groups attached to the epoxide ring
What is an important consideration when predicting the product of a reaction between a strong nucleophile and an epoxide?
Identify the regiochemistry by selecting the less-hindered position as the site of nucleophilic attack
In acid-catalyzed ring opening, what should be determined first?
Whether steric or electronic effects will dominate
What are the three steps of the mechanism for acid-catalyzed ring opening?
- Proton transfer
- Nucleophilic attack
- Proton transfer
What reagent is used to convert an alkene into an epoxide?
MCPBA
How does a Grignard reagent attacking an epoxide differ from attacking an aldehyde or ketone?
In the epoxide case, the R group and hydroxyl group are separated by two carbon atoms; in the aldehyde/ketone case, they are connected to the same carbon atom
