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What causes a reaction involving a carbonyl group to diverge from typical addition reaction to a subsitution reaction?
when a heteroatom or chlorine is attached to the carbonyl group
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Basic conditions of a reaction favor what type of nucleophile?
a strong nucleophile
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Acidic conditions of a reaction favor what type of nucleophile?
Weak nucleophile
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In acidic conditions, what event allows the nucleophile to attach to the carbonyl group?
the c=O is protonated to become +c-O-H. The weak nucleophile can attach to the cationic carbon.
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The effects that control reaction rate?
- steric effects
- inductive effects
- resonance effects
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How do you produce an acyl chloride?
carboxylic acid with SOCl2 (thionyl chloride) or PCl3
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The importance of an acyl chloride?
The chlorine acts as a good leaving group providing the basis needed to synthesize many compounds.
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Preperation of anyhydrides
- any carboxylic acid with and acyl chloride
- in pyridine (the lone pair off the N group removes the H of the -OH)
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to make an ester
acyl chloride with an alcohol in pyridine
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what is the role of pyridine in ester synthesis?
the pyridine remove a H off the intermediate (once the lone pair of the ROH group attack the carbonyl)
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another way to prepare an ester?
carboxylic acid reacts with an alcohol. This requires the presence of an acid.
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what is a lactone?
cyclic ester, a product of intramolecular esterification when a carboxyl and a hydrox group are on the same molecule.
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carbonyl (c=o) + H20
- geminal diol (hydrate)
- 2 OH groups now present on the carbonyl carbon
- in acidic or basic conditions
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an aldehyde in the presence of one mol of alcohol
hemiacetal (OR)CH(OH)
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addition of an aldehyde + (excess) alcohol
acetal (OR)2CHR
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ketone + one mole of alcohol
hemiketal
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ketone + excess alcohol
ketal
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A hemiacetal has one ______ and one _____ functional groups attached to reacted carbonyl
- OR and an OH group.
- in exess alcohol the OH group becomes an OR group as well
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in words describe how a hemiketal is made
the carbonyl group is reacted, the double bonded oxygen becomes protonated from an alchol producing a formal charge of +1. Through resonance the double bond breaks to restore the charge on the oxygen and the carbon gains + charge. The alcohol (ethanol) has a lone pair of electron on the oxygen that are attracted to the cationic carbon and performs a back-side attack. The conjugate base produced from the original reaction removes a proton (H) from the alcohol group to restore the oxygens charge.
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what makes a good protecting group?
acetals and ketals
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how do we remove a acetal protecting group?
acid hydrolysis (HCl + H20)
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carbonyl + cyanide = ?
- produces an -OH group and CN (triple bonded) group to the carbon
- a cyanohydrin
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HCN in presence of carbonyl =
- no reaction
- it is a poor nucleophile but can be converted to CN- in the presence oh OH-
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wanting to perform addition of cyanide to a carbonyl?
HCN in the presence of NaCN or KCN
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decribe the addition of cyanide to a carbonyl group
figure out how to get CN-, its a good nucleophile. The nucleophile attacks the slightly positive carbon and gives the double bonded oxygen a single bond plus a lone pair (3) with a negative charge. The oxygen steals a (H) from HCN to make an alcohol group.
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Primary amines add to carbonyl to produce
- imines
- the nitrogen maintains the double bond and rids of 2 H to produce a C=N-R and HOH
- the reaction favors the reactants because C=O is a stronger bond. Remove HOH as it is produced to shift eq. to the products.
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seconday amines react with carbonyls to produce
- enamines
- a single bond is formed to the N from the carbon but beta to the amine forms a double bond (removes a H) where a single bond once was
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how do you reduce an imine?
- add H2/Ni
- reduces C=NR to C-NRH
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The wittig reaction reacts carbonyl to produce ______
- all C=O to C=C
- produces mixtures of cis and trans products
- requires the formation of an ylide
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what is an ylide?
- PH3P- CH2
- (+)-(-)
- reacts with carbonyl to make PH3P=O
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Will a ketone attached to a phenyl group (benzene) undergoe a Wittig Reaction?
no. The ketone is stabilized in the pi system. Only aldehydes undergoe this kind of reaction.
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reduction of a ketone via hydrogenation produces first and secondary alcohols.
What 2 reactions can accomplish this?
- metal-hydride reactions
- catalytic hydrogenation - reduces all C=O and C=C
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name 2 metal hydrides used to reduce the C=O group
LiAlH4 and NaBH4
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the solvents used for metal-hydride reaction?
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Grignard reaction
formaldehyde produces?
1' alcohols
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Grignard reactions
aldehydes produce?
2' alcohols
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Grignard reactions
Ketone produce?
3' alcohols
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How would you prepare 3-phenyl-3-pentanol using a Grignard synthesis?
- Method 1 – react 3-pentanone with phenylmagnesium bromide in diethyl ether followed by workup with acidified water
- Method 2 – react ethyl phenyl ketone with ethylmagnesium bromide in diethyl ether followed by workup with acidified water
- Method 3 – involves benzoic acid and two moles of ethylmagnesium bromide and belongs in the next module.
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a grignard reagant reacts with carbon dioxide to produce?
a carboxylic acid attached to the R group of the grignard reagant
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when a carbonyl group is conjugated with a C=C addition of the nucleophile can occur in 2 ways. Explain
- The nucleophile can add to the carbonyl group (1,2-addition) or add to the C=C (1,4-addition) becuase the conjugation allows a partial positive on either carbon
- the reaction is also dependant on the nucleophile
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1,2-addition occurs when a conjugated pi system reacts with 3 different things. What are these?
- reactive Nu
- LiAlH4
- Grignard reagent
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1,4-addition occursw when a conjugated pi system reacts with 4 different things. What are they?
- weak nucleophile
- CN-
- organcuprates
- amines
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Does NaBH4 react with a conjugated carbonyl by 1,2-addition or 1,4-addition mechanisms?
reacts to form a mixture
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Organocuprate reactions
2RLi + CuI → R2CuLi + LiI
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make a carboxylic acid from amide?
- in acid
- or in base followed by acid
- similar to ester hydrolysis
- biproduct is ammonia
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describe the preperation of CA from amide in basic conditions.
The base (in H2O) backside attacks the carbonyl group(addition) forcing a pi bond to break adding a lone pair on the oxygen. Next, (elimination) the double bond re-establishes and NH2- leaves. The base steals a proton from the OH group on the carbonyl (deprotonation). A proton is regained from H20 to restore then carboxylic acid.
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notes on preparation of CA from Nitriles
- can be in acid or base (in HOH)
- reaction is known as hydrolysis
- good way to turn an alkyl halide into an acid and useful in synthesis
- -CN to CA
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a hydride can reduce amides and nitriles to _________
amines
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hrdride nucleophiles can reduce esters,acyl halides. amhydrides and CA to _________
alcohols
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special nucleophile hydrides can reduce acyl halides and anhydrides to_____
aldehydes
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special nucleophile halides can reduce esters, CA's and nitriles to ________
aldehydes
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how can a C(=O)-NH2 (amide) be reduced to an CH2-NH2
(rid the C=O to CH2)
- 1) LiAlH4 in ether
- 2) water
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Nitriles (C triple bond N) can be reduced to CH2-NH2. How?
note: can also been done using catalytic hydrogenation
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______ is the hydride nucleophile that will not reduce esters or acids. only ____ reduces these compounds.
NaBH4
LiAl4 reduces everything
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what are the steps to reduce an acyl compound (esters,qcyl halides, anhydrides, CAs) to alcohols?
- 1)LiAl4, ether
- 2) H2O/H30+
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when an intermediate of acyl reduction is an aldehyde...how can we top the reaction from further reducing the aldehyde?
- 1)use bulky hydride -- LiAlH(OtBu)3
- 2) HOH
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