Cyclic ethers behave like acyclic ethers, except if ring is 3-membered Dioxane, tetrahydrofuran (THF) and furan are used as solvents 1,4-dioxane tetrahydrofuran (THF) furan
Epoxides (oxiranes) are three- membered cyclic ethers. The strain of the three-member ring of epoxides gives them unique chemical reactivity. 1 Nomenclature of Epoxides
The nonsystematic name, –ene oxide, describes the method of formation. The systematic name, epoxy, describes the location of the epoxide ring.
(nonsystematic) (nonsystematic)
(systematic) (systematic)
2 Name the following
A. B. C. H3C CH3 H3C HC CH O 2 H3C C C CH3
O O
3 Preparation of Epoxides
The simplest and commercially most important example is ethylene oxide, manufactured from ethylene, air, and a silver catalyst.
In the laboratory, epoxides are most commonly prepared from alkenes and organic peroxy acids. The reaction occurs in one step with syn stereochemistry.
alkene peroxy acid epoxide carboxylic acid 4 Epoxides from Halohydrins
Addition of HO-X to an alkene gives a halohydrin Treatment of a halohydrin with base gives an epoxide 1. Cl , H O Intramolecular Williamson ether synthesis 2 2 2. NaOH, H2O
5 18.8 Ring-Opening Reactions of Epoxides
Water adds to epoxides with dilute acid at room temperature. Because of ring strain, epoxides react under milder conditions. Product is a 1,2-diol (glycol).
Mechanism: acid protonates oxygen and water adds to opposite side (anti addition, trans product)
1,2-ethanediol from acid catalyzed hydration of ethylene oxide EG is primarily used as a raw material in the manufacture of polyester fibers and fabric industry, and polyethylene terephthalate resins (PET) used in bottling. Widely used as automobile antifreeze (lowers freezing point of water solutions)
7 18.8 Ring-Opening Reactions of O HO OH Epoxides (FormationH+ of 1,2-alkoxyalcohol) C C + H OH C C
Other nucleophiles (such as alcohols)glycol add similarly to epoxides. O HO OR H+ C C R OH C C
2-alkoxyalcohol
O R OMgX R OH H2O OrganometallicC C + R MreagentgX C C C C H+
R R' R R' H+ HC CH + R'' ONa HC CH O HO OR'' 8 HO OH OO HO OH H++ + H CC CC + HH OOHH CC CC 18.8 Ring-Opening Reactionsgglylyccool l of Epoxides O HO OR O + HO OR HH+ CC CC RR OOHH CC CC The reactions with organometallic reagents (RMgX and RLi) are useful two-carbon chain22-a--allengtheningklkooxxyyaalclcoohhool l reactions.
R OMgX R OH OO R OMgX R OH ether HH2OO C C + R MgX C C 2 C C C C + R MgX C C + C C HH+
Halohydrins from Epoxides Anhydrous HF, HBr, HCl, or HI combines with an epoxide, gives trans product Where X = F, Br, Cl, or I H HX O ether
H 9 Regiochemistry of Acid-Catalyzed Opening of Epoxides (2o vs 1o, 3o vs 1o)
When both epoxide carbons are 1 or 2, halogen attack occurs primarily at the less hindered site. Secondary Primary O HCl H3C C C H ether H H
When one epoxide carbon is 3, halogen attack occurs at the more highly substituted site. The mechanism is midway
between SN2 and SN1. The reaction occurs by backside attack (SN2), but a positive charge is stabilized by a tertiary carbocation-like transition state (SN1). Tertiary O Primary HCl H3C C C H ether H3C H 10 Complete the following reactions.
H+ A. H2C CH2 H C CH + HO CH3 2 2 O OH OCH3
H C CH OH 3 3 + HC CH H H3C O B. + CH HC O HO CH3
H C 3 CH3 CH3 HC CH2 + H Br C. HC CH2 + HC CH2 O OH Br Br OH major minor
11 Complete the following reactions.
H3C CH3 + H3C CH3 D. H HC CH CH CH + H3C ONa O HO OCH3
H C CH H C CH 3 3 H+ 3 3 E. HC CH CH CH + H5C2 ONa O HO OC2H5
H O+ H2C CH2 3 + H3C CH2 CH2 CH2 MgBr H3C CH2 CH2 CH2 CH2 CH2 OH O F.
12 18.9 Crown Ethers
Large cyclic ethers were discovered in 1960. Central cavity is electronegative and attracts cations
They are named in the general format: X-crown-Y ether X= total atoms in ring Y= number of oxygens
O O O
O O O O
O O O O O O O O O O O O O O O
30-Crown-10 ether 24-Crown-8 ether 13-Crown-4 ether 13 Uses of Crown Ethers
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
14 Crown Ethers
Crown ethers are able to solvate metal cations, different size crown ethers solvate different size cations. O O O O O O + O + O + Li Na K MnO4 O O O O O O O
15 12-Crown-4 ether 15-Crown-5 ether 18-Crown-6 ether 18.10 Spectroscopy of Ethers
IR Spectroscopy: Ethers are difficult to identify since many other types of absorptions occur at the 1050 – 1150 cm-1 range where ethers absorb. NMR: 13C NMR ether carbons absorb in 50 – 80 range. 1H NMR hydrogens on carbons next to an ether oxygen absorb in 3.4 – 4.5 range. Hydrogens on carbons next to an epoxide oxygen absorb near 2.5 – 3.5 , and –OH in 3 –8 range.
16 18.11 Thiols and Sulfides
Sulfur is the element just below oxygen in the periodic table, and many oxygen-containing organic compounds have sulfur analogs.
Thiols, R-SH, are sulfur analogs of alcohol
Sulfides, R-S-R’, are sulfur analogs of ethers. 17 Thiol Nomenclature
Thiols are named in a similar way as alcohols, in terms of the numbering of carbons, keep the terminal -e and add the suffix –thiol. The –SH group itself is referred to as the mercapto group when it is a lower priority (“capturer of mercury”). ethanethiol cyclohexanethiol m-mercaptobenzoic acid
18 Mercaptans
Gases like hydrogen sulfide H2S are mixed to give natural gases their pungent smell. Mercaptans were in the news with the Porter Ranch, CA leaks (2015-16). Human noses can easily detect sulfur compounds that belong to the Thiol class. Other compounds like ethanethiol and propanethiol are added to increase the amount of smell that these gasses give. These compounds are called warning agents, because they help warn you of a gas leak. Besides utility companies need for mercaptan, there are other trades that use it. Industries use it for jet fuel, pharmaceuticals and livestock feed additives. It is used in many chemical plants. Mercaptan is less corrosive and less toxic than similar sulfur compounds and found naturally in rotten eggs, onions, garlic, skunks, and, of course, bad breath. In other words, forms of mercaptan can be found in things that smell. 19 Properties of Thiols
Thiols have low boiling points (because of reduced hydrogen bonding. Thiols have a strong, disagreeable odor. It is added to natural gas, and is responsible for the odors of skunks. Thiols are easily oxidized but yield different products than their alcohol analogs. (Thiols form disulfides)
20 Skunks
The family of chemicals that a skunk sprays are (E)-2-butene-1-thiol, 3-methyl-1-butanethiol and thioacetates. They're volatile, which means they disperse easily in the air, and they're easily picked up by the human nose.
(E)-2-butene-1-thiol 3-methylbutane-1-thiol thioacetate
21 http://www.compoundchem.com/wp-content/uploads/2014/04/The- 22 Chemistry-of-Body-Odours-2015.png Sulfide Nomenclature
Sulfides (R-S-R), are sulfur analogs of ethers Named by rules used for ethers, with sulfide in place of ether for simple compounds and alkylthio in place of alkoxy
dimethyl sulfide methyl phenyl sulfide 3-(methylthio)cyclohexene
23 Problems: Draw the structures for the following:
2-butanethiol 2,2,6-trimethyl-4-heptanethiol ethyl methyl sulfide
24 Thiols: Formation and Reaction
Formation of alkyl thiols is done by SN2 nucleophilic displacement with sulfhydryl ion. Yields are often poor unless excess nucleophile is used. R-X + SH
CH3CH2Br + NaSH
Thiourea can be used to get a better yield,
RCH2Br RCH2SH
25 Oxidation of Thiols to Disulfides
Thiols are easily oxidized to disulfide compounds by a mild oxidizing agent such as hydrogen peroxide, iodine or bromine. This reaction is reversible using Zn and Acid.
I2, H2O 2 RSH thiol Zn, H+
26 Thiol to Thiolate to Sulfide
Thiols react with aqueous base (NaOH or NaH) to give thiolates,
RSH + NaOH
which can react with a 1, or 2 alkyl halide to form a
sulfide by SN2 mechanism.
CH3CH2SNa + CH3CH2I
27 Sulfides as Nucleophiles
Preparation of Sulfides
R-S + R’CH2Br Sulfur compounds are more nucleophilic than oxygen analogs due to the valence electrons on the sulfur being farther from the nucleus and less tightly held.
Sulfides react with primary alkyl halides (SN2) to give + trialkylsulfonium salts (R3S )
THF S H3C I H3C CH3 +
28 Oxidation of Sulfides
Sulfides are easily oxidized with H2O2 to a sulfoxide (R2SO) Oxidation of a sulfoxide with a peroxyacid yields a sulfone (R2SO2) Dimethyl sulfoxide (DMSO) is often used as a polar
aprotic solvent 29 Preview of Carbonyl Compounds
Your textbook has a preview of carbonyl compounds between chapters 18 & 19 on Pages 743 – 752. Be sure to review and study these pages to help you better understand the material to come.
30 Chapter 19. Aldehydes and Ketones: Nucleophilic Addition Reactions
31 Aldehydes and Ketones
Aldehydes and ketones are characterized by the the carbonyl functional group (C=O) aldehyde ketone
The compounds occur widely in nature as intermediates in metabolism and biosynthesis Aldehydes and ketones are bonded to substituents that cannot stabilize a negative charge and therefore cannot act as leaving groups. Aldehydes and ketones behave similarly and undergo many of the same reactions. 32 Aldehydes and Ketones
carbonyl oxygen carbonyl carbon alkyl group acyl hydrogen
.The carbonyl carbon atom is sp2-hybridized and forms three bonds, 120o bond angle. .Carbon –oxygen double bonds are polarized because of the high electronegativity of oxygen relative to carbon. The carbonyl carbon is positively polarized, it is electrophilic (a Lewis acid) and reacts with nucleophiles. Conversely, the carbonyl oxygen is negatively polarized and nucleophilic (a Lewis base). 33 Physical Properties of Aldehydes
A. The melting point of aldehydes varies nonsystematically with increasing molecular weight. B. Aldehydes have higher boiling points than the boiling points of alkanes of similar molecular weight, due to dipole–dipole interaction
C. The boiling points of aldehydes are lower than the corresponding alcohol due to the lack of hydrogen bonding interactions. D. There is a systematic increase of the boiling point with molecular weight. 34 Physical Properties of Ketones
A. The melting point of ketones is systematic with increasing molecular weight. B. Ketones have higher boiling points than the boiling points of alkanes of similar molecular weight. C. The boiling points of ketones are lower than the corresponding alcohol due to the lack of hydrogen bonding interactions. D. There is a systematic increase of the boiling point with molecular weight.
35 A number of aldehydes and ketones contribute to the aroma of fresh-baked bread. http://www.compoundche m.com/2016/01/20/bread- aroma/
36 Biochemical Interest: What Are Ketones?
Ketone bodies are acids made when your body begins using fat instead of carbohydrates for energy. When there is not enough insulin to get sugar from the blood and into the cells, the body turns to fat for energy. When fat is broken down, ketone bodies are made and can accumulate in the body. High levels of ketones are toxic to the body. The condition is called ketoacidosis. [When your body burns fat, by-products called ketones are released. You'll expel most of them in urine and perspiration, but some will be expelled in your breath -- and ketones don't smell good. According to a survey by the Physicians Committee for Responsible Medicine, 40 percent of people following a low-carb diet reported having bad breath].
Ketones are most likely to show up when there is not enough insulin in the body. This can happen if people who have type 1 diabetes don’t take insulin or don’t take enough to meet higher demands, such as during illness or stress, or when a pump gets clogged or unattached. It can also happen in people with type 2 diabetes who are insulin-deficient if they get sick.
37 http://www.healthline.com/health/type-2-diabetes/facts-ketones 19.1 Nomenclature
Aldehydes are named by replacing the terminal -e of the corresponding alkane name with –al The parent chain must contain the CHO group The CHO carbon is always numbered as C1 If the CHO group is attached to a ring, use the suffix carbaldehyde.
38 Provide structures for the following
2-ethyl-4-methylpentanal cyclopentanecarbaldehyde
2-naphthalenecarbaldehyde benzaldehyde
ethanal (acetalaldehyde) propanal
39 Naming Ketones Replace the terminal -e of the alkane name with –one Parent chain is the longest one that contains the ketone group Numbering begins at the end nearer the carbonyl carbon Common names for ketones are constructed by giving, in alphabetical order, the names of the groups attached, and then adding the word ketone. Provide structures for the following
3-hexanone (ethyl 1-propyl ketone) propanone (acetone, dimethyl ketone)
4-hexen-2-one 2,4-hexanedione
40 Ketones and Aldehydes as Substituents
The R–C=O as a substituent is an acyl group is used with the suffix -yl from the root of the carboxylic acid
The prefix oxo- is used if other functional groups are present and the doubly bonded oxygen is labeled as a substituent on a parent chain
41 Draw the following:
2-pentanone pentanal (methyl 1-propyl ketone) cyclopentanone
2-oxopropanal cyclohexanecarbaldehyde 3-pentyn-2-one
42 Name the following
O O CH3 O
H3C CH2 C CH3 H C CH(CH 3)2 H3C CH CH2 C H
Cl CHO O
O H3C CH2 CH CH C H Br
43 19.2 Preparation of Aldehydes and Ketones The best method of preparing aldehydes and ketones is alcohol oxidation. Primary alcohols are oxidized to give aldehydes. Pyridinium chlorochromate (PCC) in dichloromethane is usually chosen for making aldehydes
Secondary alcohols are oxidized to give ketones. PCC,
CrO3, and Na2Cr2O7 are all-effective for making ketones.
44 19.2 Preparation of Aldehydes and Ketones
Aldehyde: Reduce an ester with diisobutylaluminum hydride (DIBAH) O 1. DIBAH, toluene, -78 °C
R C OR + 2. H3O
Ketone: Ozonolysis of alkenes yields ketones if one of the unsaturated carbon atoms is disubstituted (see Section 7.8) R H 1. O3 C C + 2. Zn/H3O R H 45 19.2 Preparation of Aldehydes and Ketones
Ketone: Friedel–Crafts acylation of an aromatic ring with an acid chloride in the presence of AlCl3 catalyst (see Section 16.4)
Ketone: Hydration of terminal alkynes in the presence of Hg2+ catalyst (Section 8.5)
46 Complete the following reactions
Prepare the following product form the appropriate alcohol:
Structure of Arrow/Rxn Structure of Product Name of Alcohol Conditions Product pentanal
A.
2-hexanone
B.
47 Complete the following reactions
O C. O 1. DIBAH, toluene, -78 °C C H CO C (CH ) CH 3 2 4 3 + H (CH2)4CH3 2. H3O
H CH2CH3 H CH2CH3 1. O3 C O O C C C + + D. 2. Zn/H3O H CH3 H CH3
O O AlCl3 E. C + Cl C CH2CH3 Heat CH2CH3
+ H O O F. 3 H3C C CH H3C C CH3 48 HgSO4 19.3 Oxidation of Aldehydes and Ketones Ketones are usually unreactive towards oxidation. This reactivity is consequence of structure. Aldehydes have a –CHO proton that can be removed during oxidation, but ketones do not. Ketones are inert to most oxidizing agents, but undergo a slow cleavage reaction when treated with
hot alkaline KMnO4. Reaction is practical for cleaving symmetrical ketones
49 19.3 Oxidation of Aldehydes and Ketones Aldehydes are oxidized to the corresponding carboxylic acid.
50 19.3 Oxidation of Aldehydes and Ketones Tollens’ reagent (qualitative test for aldehydes): One of the simplest methods for oxidizing an aldehyde is to use silver ion, Ag+, in dilute ammonia. As the oxidation proceeds, a shiny mirror of silver metal is deposited on the walls of the reaction flask.
51 Other Oxidation reactions of Aldehydes Jones oxidation: Jones reagent:
CrO3, H2SO4, acetone
Benedicts Reagent Oxidation (qualitative test for aldehydes). A red precipitate of Cu2O forms to detect the presence of an aldehyde functional group in a sample of unknown.
2+ - - RCHO + 2 Cu + 5 OH RCOO + Cu2O(s) + 3 H2O blue red solution ppt 52 Predict the product(s) for the following
A. O Tollens O Ag+ Ag C + C + (s) CH2 H solution CH2 OH
B. O Jones O reagent OH
C. O + 2 Cu2+ + 5 OH- No Reaction
53 19.4 Nucleophilic Addition Reactions of Aldehydes and Ketones
The most common reaction of aldehydes and ketones is the nucleophilic addition reaction. The nucleophile (:Nu or :Nu-) adds to the electrophilic carbon of the carbonyl group from a direction approximately 45 to the plane of the carbonyl group. At the same time, rehybridization of the carbonyl carbon from sp2 to sp3 occurs.
General Mechanism for negative nucleophiles
54 Nucleophiles
Nucleophiles can be negatively charged ( :Nu) or neutral ( :Nu) at the reaction site The overall charge on the nucleophilic species is not considered
55 19.5 Electrophilicity of Aldehydes and Ketones
Aldehydes are generally more reactive than ketones in nucleophilic addition reactions for steric and electronic reasons.
Aldehyde C=O is more polarized than ketone C=O As in carbocations, more alkyl groups stabilize positive (+) character Ketone has more alkyl groups, stabilizing the C=O carbon inductively
56 19.6 Nucleophilic Addition of H2O: Hydration Aldehydes and ketones react with water to yield 1,1-diols (geminal (gem) diols) Hydration is reversible: a gem diol can eliminate water The reaction is slow in pure water but is catalyzed by both acids and bases. Equilibrium generally favors the carbonyl compound over hydrate General reaction of hydration of an aldehyde or ketone
57 Relative Energies
Equilibrium generally favors the carbonyl compound over hydrate for steric reasons Acetone in water is 99.9% ketone form 0.1% acetone hydrate
Exception: simple aldehydes In water, formaldehyde consists is 99.9% hydrate
58 Addition of H-Y to C=O
Reaction of C=O with H-Y, where Y is electronegative, gives an addition product (“adduct”) Formation is readily reversible. The reaction shifts to the left when Y is
OCH3, OH, Br, Cl, HSO4 59 19.7 Nucleophilic Addition of HCN: Cyanohydrin Formation Aldehydes and unhindered ketones react with HCN to yield cyanohydrins, RCH(OH)CN Addition of HCN is reversible and base-catalyzed, generating nucleophilic cyanide ion, CN
Mechanism
60 Uses of Cyanohydrins
Cyanohydrin formation is useful because of further chemistry that can be carried out.
The nitrile group (CN) can be reduced with LiAlH4 to yield a primary amine (RCH2NH2) Can be hydrolyzed by hot acid to yield a carboxylic acid
61 19.8 Nucleophilic Addition of Grignard Reagents and Hydride Reagents: Alcohol Formation
Treatment of aldehydes or ketones with Grignard reagents yields an alcohol (17.6) Unlike the nucleophilic additions of HOH and HCN, these are NOT reversible because the carbanion group is too poor of a leaving group.
62 Hydride Addition
Convert C=O to CH-OH
LiAlH4 and NaBH4 react as donors of hydride ion Protonation after addition yields the alcohol
63 19.9 Nucleophilic Addition of Amines: Imine and Enamine Formation
RNH2 adds to C=O to form imines, R2C=NR (after loss of HOH)
R2NH yields enamines, R2NCR=CR2 (after loss of HOH) (ene + amine = unsaturated amine)
64 19.10 Nucleophilic Addition of Hydrazine: The Wolff–Kishner Reaction
Treatment of an aldehyde or ketone with
hydrazine, H2NNH2 and KOH converts the compound to an alkane
O H NNH C 2 2 CH3 H + N + H O KOH 2 2 65 19.11 Nucleophilic Addition of Alcohols: Acetal Formation
Ketone/aldehyde an acetal
Two equivalents of ROH in the presence of an acid
catalyst add to C=O to yield acetals, R2C(OR)2 Acetals can serve as protecting groups for aldehydes and ketones These can be called ketals if derived from a ketone
66 Formation of Acetals
CH OH, OH O 3 CH3OH, OR + ROH + H catalyst H+ catalyst C R' C R" R' C R" + H O R' R" 2 OR OR hemiacetal acetal
Alcohols are weak nucleophiles but acid promotes addition forming the conjugate acid of C=O Addition yields a hydroxy ether, called a hemiacetal (reversible); further reaction can occur Protonation of the OH and loss of water leads to an + oxonium ion, R2C=OR to which a second alcohol adds to form the acetal
67 19.12 Nucleophilic Addition of Phosphorus Ylides: The Wittig Reaction
The sequence converts C=O is to C=C A phosphorus ylide adds to an aldehyde or ketone to yield a dipolar intermediate called a betaine The intermediate spontaneously decomposes through a four-membered ring to yield alkene and triphenylphosphine oxide, (Ph)3P=O Formation of the ylide is shown below
68 Mechanism of the Wittig Reaction
- + + O P (Ph)3 O P (Ph) 3 - C C C C R' R R' R
O P(Ph)3 R' C C C C + (Ph)3P=O R' R R
69 Uses of the Wittig Reaction
Can be used for monosubstituted, disubstituted, and trisubstituted alkenes but not tetrasubstituted alkenes The reaction yields a pure alkene of known structure
For comparison, addition of CH3MgBr to cyclohexanone and dehydration with, yields a mixture of two alkenes
70 19.13 The Cannizzaro Reaction: Biological Reductions
The reaction takes place by nucleophilic addition and has few practical applications. The adduct of an aldehyde and OH can transfer hydride ion to another aldehyde C=O resulting in a simultaneous oxidation and reduction (disproportionation)
Which product was oxidized and was reduced? 71 19.14 Conjugate Nucleophilic Addition to ,b- Unsaturated Aldehydes and Ketones
A nucleophile can add to the C=C double bond of an ,b- unsaturated aldehyde or ketone (conjugate addition, or 1,4 addition) The initial product is a resonance- stabilized enolate ion, which is then protonated 72 Conjugate Addition of Amines
Primary and secondary amines add to ,b-unsaturated aldehydes and ketones to yield b-amino aldehydes and ketones
73 Conjugate Addition of Alkyl Groups: Organocopper Reactions
Reaction of an ,b-unsaturated ketone (no aldehydes) with a lithium diorganocopper reagent
Diorganocopper (Gilman) reagents from by reaction of 1 equivalent of cuprous iodide and 2 equivalents of organolithium
74 Mechanism of Alkyl Conjugate Addition
1, 2, 3 alkyl, aryl and alkenyl groups react but not alkynyl groups (C≡C) Conjugate nucleophilic addition of a diorganocopper anion, R2Cu , an enone Transfer of an R group and elimination of a neutral organocopper species, RCu
75 19.15 Biological Nucleophilic Addition Reactions One of the pathways that amino acids are made is from nucleophilic addition of an amine to -keto acids.
76 19.16 Spectroscopy of Aldehydes and Ketones Infrared Spectroscopy Aldehydes and ketones show a strong C=O peak 1660 to 1770 cm1 Aldehydes show two characteristic C–H absorptions in the 2720 to 2820 cm1 range.
77 C=O Peak Position in the IR Spectrum
The precise position of the peak reveals the exact nature of the carbonyl group
78 NMR Spectra of Aldehydes
Aldehyde proton signals are at 10 in 1H NMR - distinctive spin–spin coupling with protons on the neighboring carbon, J 3 Hz
Hydrogens on the carbon next to a carbonyl group absorb near 2.0-2.3 δ.
Methyl ketone protons absorb at 2.1 δ 79 13C NMR of C=O
C=O signal is at 190 to 215 No other kinds of carbons absorb in this range
80 Mass Spectrometry – McLafferty Rearrangement Some aliphatic aldehydes and ketones undergo McLafferty rearrangement. A hydrogen on the carbon is transferred to the carbonyl oxygen, the bond between the α carbon and the β carbon is broken, and a neutral alkene fragment is produced The remaining cation radical is detected.
81 Mass Spectroscopy: -Cleavage
Cleavage of the bond between the carbonyl group and the carbon Yields a neutral radical and an oxygen-containing cation
82