Chem 345 Reaction Sheets:
Acetal formation
O cat. H2SO4 O
OH O
Mechanism: O cat. H2SO4
OH
Summary (Key words): Acetals are made under acidic conditions, so no basic compounds can be used in the mechanism. The mechanism consists of hemiacetal formation followed by an SN1 reaction. The carbonyl oxygen is lost as water. Acetals are useful to protect ketones and aldehydes from nucleophiles such as Grignards. Acetal formation is reversible.
Chem 345 Reaction Sheets:
Acetal Cleavage
cat. H2SO4
O OH O H2O HO O
Mechanism: cat. H2SO4
O O H2O
Summary (Key words): Acetals are cleaved by acid and water. The carbonyl oxygen comes from water. Acetals are useful to protect ketones and aldehydes from nucleophiles such as Grignards. All steps in the mechanism are reversible.
Chem 345 Reaction Sheets:
Imine Formation
cat. H2SO4 O N
NH2
Mechanism: cat. H2SO4 O
NH2
Summary (Key words): If a strong acid is used, then it must be catalytic. It is not necessary for the carbonyl before the amine attacks. Reaction generates water. All steps are reversible.
Chem 345 Reaction Sheets:
Imine Hydrolysis
cat. H2SO4
N O H2O NH2
Mechanism: cat. H2SO4 N H2O
Summary (Key words): Imines are slightly basic. It is not necessary for there to be an acid catalyst. Imines are water sensitive and are readily converted to carbonyls. All steps are reversible.
Chem 345 Reaction Sheets:
Cyanohydrin Formation
AcOH, KCN CN O or cat. NaOH, HCN racemic
OH
Mechanisms: O AcOH, KCN
cat. NaOH, HCN O
Summary (Key words): Reaction is reversible. Cyanohydrins are base sensitive. Cyanide is a good nucleophile. It attacks the carbonyl directly.
Chem 345 Reaction Sheets:
Cyanohydrin cleavage
OH cat. NaOH O
CN racemic
Mechanism:
OH cat. NaOH
CN racemic
Summary (Key words): All steps reversible. Cyanohydrins are base sensitive.
Chem 345 Reaction Sheets:
Reduction of a ketone with sodium borohydride
O
NaBH4 EtOH OH
Mechanism:
O
NaBH4 EtOH
Summary (Key words): Addition of the hydride to carbonyl is irreversible. The hydrogen that attacks the carbonyl carbon comes from sodium borohydride. The proton that adds to the oxygen comes from the alcohol solvent. Sodium borohydride is basic. It can also deprotonate OH’s (cyanohydrins, hemiacetals) Chem 345 Reaction Sheets:
Reaction of a ketone with a Grignard Reagent
O
1.) MeMgBr, Et2O + OH 2.) H3O
Mechanism:
O
1.) MeMgBr, Et2O + 2.) H3O
Preparation of a Grignard Reagent: Mg
O MeBr MeMgBr
Summary (Key words): Addition of the carbon group to the carbonyl is irreversible. Always a two step procedure. Grignards are really strong bases. It will react with acidic hydrogens very quickly. This includes OH’s on cyanohydrins or hemiacetals.
Chem 345 Reaction Sheets:
Fisher Esterification
O O cat. H2SO4
OH O
OH
Mechanism: O
cat. H2SO4 OH
OH
Summary (Key words): All steps are reversible. This reaction will not work with tertiary alcohols. This reaction is acid catalyzed only. Base will not work.
Chem 345 Reaction Sheets:
Acid catalyzed hydrolysis of an ester
O
O cat. H2SO4 OMe OH MeOH H2O
Mechanism: O
cat. H2SO4 OMe
H2O
Summary (Key words): All Steps are reversible. If the ester is a tertiary ester, a different mechanism will likely take place. This reaction is acid catalyzed only. Base will not work.
Chem 345 Reaction Sheets:
Saponification
O
1.) NaOH O + 2.) H3O OMe OH MeOH
Mechanism: O
1.) NaOH + 2.) H3O OMe
Summary (Key words): This contains an irreversible step. Deprotonation of the carboxylic acid by the alkoxide that is generated. You need one equivalent of sodium hydroxide, ie: catalytic base will not work.
Chem 345 Reaction Sheets:
Alkylation of a carboxylate
O
O K2CO3 OH O
Br
Mechanism: O
K2CO3 OH
Br
Summary (Key words): Two step process: acid-base to create a good nucleophile followed by an SN2 reaction. Works best when the alpha carbon is Me or primary. Gives a mixture when the alpha carbon is tertiary due to competing E2 reaction.
Chem 345 Reaction Sheets:
Reaction of a ketone with a Wittig Reagent
O PPh3
Mechanism:
O PPh3
Preparation of a Wittig Reagent:
1.) PPh3 2.) KOtBu Br PPh3
Summary (Key words): Formation of the four member ring may be one step or two steps. The resulting alkene can be mono, di, or tri substituted. Tetra substituted alkenes are typically too hindered to form via a Wittig reaction. If two diastereomers is possible, you can get either E or Z depending on the structure of the Wittig reagent and the base used to form it. (You get to choose which diastereomer you get as the major product in Chem 345). Real life on the other hand… Chem 345 Reaction Sheets:
Acid chloride formation
O O
SOCl2 OH Cl
Mechanism: O
SOCl2 OH
Summary (Key words): Reaction is an irreversible reaction. Acid Chlorides are very reactive compounds. In synthesis type problems, once you make it, use it in the next step. Thionyl chloride will also change normal alcohols in chlorides via an SN1 or SN2 mechanism depending on the alcohol.
Chem 345 Reaction Sheets:
Transesterification
O O NaOEt OMe O EtOH
Mechanism: O
NaOEt OMe EtOH
Summary (Key words): The entire reaction is reversible. Base can be catalytic. Works best if the base matches the solvent ie: NaOEt/EtOH or NaOMe/MeOH. Base cannot be hydroxide. Hydroxide leads to saponification. Chem 345 Reaction Sheets:
Cleavage of a tertiary ester
O O HCl O Cl OH
Mechanism: O
HCl O
Summary (Key words): This is just an SN1 reaction. All steps reversible. If sulfuric acid is used, the mechanism switches to an E1 reaction.
Chem 345 Reaction Sheets:
Reaction of an acid chloride with an alcohol
O
O EtOH Cl O
NEt3
Mechanism: O
EtOH Cl
NEt3
Summary (Key words): Irreversible reaction. You need a tertiary amine or pyridine if the alcohol is tertiary. It does not hurt to include an tertiary amine or pyridine with every alcohol
Chem 345 Reaction Sheets:
Formation of a 2-aminonitrile
O NH NH4Cl 2 KCN CN racemic
Mechanism: O
NH4Cl KCN
Summary (Key words): All arrows reversible. Form the imine first, otherwise you cannot get rid of the OH.
Chem 345 Reaction Sheets:
Reaction of an acid chloride with an amine
O
O MeNH2 Cl N H NEt3
Mechanism: O
MeNH2 Cl
NEt3
Summary (Key words): Irreversible reaction. Either an excess of amine or a sacrificial amine such as triethyl amine must be present otherwise poor yields (less than 50%) occur.
Chem 345 Reaction Sheets:
Hydrolysis of an amide
O
O H2SO4 N OH
H2O
Mechanism: O
H2SO4 N
H2O
Summary (Key words): Very slow process. Often needs heat. Amides are not very reactive to nucleophilic attack. Under acidic conditions, so strong bases such as negative nitrogens and negative oxygens should be avoided.
Chem 345 Reaction Sheets:
Carbodiimide coupling
O DCC O MeNH OH 2 N H NEt3
Mechanism: Structure of DCC: O DCC
MeNH2 N OH C N
NEt3
Summary (Key words): Driving force of the reaction is the formation of the urea. This is a more mild way of generating amides than acid chlorides. Make sure that there is only one carboxylic acid and one amine present, otherwise protecting groups must be used. Chem 345 Reaction Sheets:
Amine Protection/Deprotection
FmocCl NH NEt3 NH NH2 NH2 Fmoc
BocCl NEt3 HCl NH NH2 NH3 Boc
H2 ZCl Pd NEt3 NH NH2 NH2 Z
Draw out the full structures of the protected amines in the boxes below:
NH NH NH
Fmoc Boc Z
O O O O N O NH H N O H
Summary (Key words): These protecting groups are orthogonal to one another. You can deprotect one independently of the others.
Chem 345 Reaction Sheets:
Reaction of a Grignard with an Ester
O
OH
O 1.) MeMgBr, Et2O + 2.) H3O
Mechanism: O
O 1.) MeMgBr, Et2O + 2.) H3O
How do you make a Grignard? Grignards are made by adding Mg and ether to an organohalide.
Summary (Key words): The carbon-carbon bond formation step is irreversible. Grignards and organolithiums react multiple times with an ester to form an alchol. You cannot stop at the ketone. It does not matter if you use an excess of the ester, the ketone will not be the major product, because ketones are much more reactive than esters.
Chem 345 Reaction Sheets:
Reaction of a Grignard with Carbon Dioxide
O
1.) MeMgBr, Et2O CO 2.) H O+ 2 3 OH
Mechanism: 1.) MeMgBr, Et2O + CO2 2.) H3O
Summary (Key words): The carbon-carbon bond formation step is irreversible. Grignards are not reactive enough to react with a carboxylate regardless of how much Grignard reagent is used.
Chem 345 Reaction Sheets:
Reaction of an organolithium with carbon dioxide
O 1.) 1.0 eq. MeLi 1.) excess MeLi O O O CO2 OH 2.) H O+ + 3 2.) H3O
Mechanisms:
1.) 1.0 eq. MeLi O CO2 + 2.) H3O
1.) excess MeLi O CO2 + 2.) H3O
Two ways to make an organolithium: Organolithiums are made by adding Li and ether to an organohalide or by adding BuLi and ether to an organohalide.
Summary (Key words): Organolithiums are more reactive than Grignard reagents. They are capable of reacting with carboxylates while Grignards cannot. Other than that, organolithiums typically do everything Grignards do. The carbon-carbon bond formation step is irreversible. Chem 345 Reaction Sheets:
Reaction of an organolithium with a carboxylic acid
O O 1.) excess MeLi OH O
+ 2.) H3O
Mechanism: O
1.) excess MeLi OH O
+ 2.) H3O
Summary (Key words): Organolithiums are more reactive than Grignard reagents. They are capable of reacting with carboxylates while Grignards cannot. Other than that, organolithiums typically do everything Grignards do. If one equivalent of organolithium is used, then the reaction stops at the carboxylate. The carbon-carbon bond formation step is irreversible.
Chem 345 Reaction Sheets:
Reduction of a ketone/aldehyde with LAH
O 1.) LiAlH4
O OH
+ 2.) H3O
Mechanism: O 1.) LiAlH4
O
+ 2.) H3O
Summary (Key words): The abbreviated sodium borohydride mechanism cannot be used because the proton source and the hydride source are not present at the same time. Lithium aluminum hydride is strongly basic and reacts vigorously with acidic protons. Addition of the hydride to the carbonyl is irreversible. Chem 345 Reaction Sheets:
Reduction of an ester with LAH
O
1.) LiAlH4 OMe O OH MeOH
+ 2.) H3O
Mechanism: O
1.) LiAlH4 OMe O
2.) H O+ 3
Summary (Key words): The abbreviated sodium borohydride mechanism cannot be used because the proton source and the hydride source are not present at the same time. Lithium aluminum hydride is strongly basic and reacts vigorously with acidic protons. Addition of the hydride to the carbonyl is irreversible. Since aldehydes are more reactive than esters, you cannot stop at the aldehyde intermediate. Chem 345 Reaction Sheets:
Reaction of a nitrile with a Grignard
CN O
1.) MeMgBr, Et2O + 2.) H3O
Mechanism: CN
1.) MeMgBr, Et2O + 2.) H3O
Summary (Key words): Grignards and organolithiums add once to nitriles. Neither is strong enough to react with a deprotonated imine to form a nitrogen with a -2 charge. The carbon-carbon bond formation step is irreversible.
Chem 345 Reaction Sheets:
Acid mediated hydrolysis of a nitrile
CN O H2SO4 H2O OH
Mechanism:
CN H2SO4 H2O
Summary (Key words): All steps technically reversible. Since nitriles are more reactive to nucleophiles than primary amides, it is possible to stop at the primary amide.
Chem 345 Reaction Sheets:
Reduction of an amide with LAH
O 1.) LiAlH4
O NH NH + 2.) H3O
Mechanism: O 1.) LiAlH4
O NH 2.) H O+ 3
Summary (Key words): Addition of hydride to carbonyl is irreversible. The product is an amine.