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ORGO LAB > Lidocaine Synthesis (Multi-step synthesis) > Flashcards

Lidocaine Synthesis (Multi-step synthesis) Flashcards

1
Q

How many reactive groups does
alpha-chloroacetylchloride have?

A

TWO

–> Acyl chloride group (chloride bonded to a carbonyl group)
–> Primary alkyl chloride group

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2
Q

How does the fact that alpha-chloroacetylchloride has TWO reactive groups impact which step of lidocaine synthesis must come first?

A

Due to the two reactive groups, the reaction with alpha-chloroacetylchloride and 2,6-dimethylaniline must come FIRST! –> Substitution reaction will occur on the acyl chloride (what we want!)

If the reaction of alpha-chloroacetylchloride and diethylamine were to take place first, this addition would also occur to the LEFT (on the acyl chloride!) which is NOT what we want as lidocaine contains the diethylamine group on the RIGHT of the carbonyl group!

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3
Q

What is the first step reaction in the synthesis of lidocaine?

A

2,6-dimethylaniline + alpha-chloroacetylchloride (in the presence of acetic acid) =
alpha-chloro-2,6-dimethylacetanilide

+ HCl gas!

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4
Q

What is the second step reaction in the synthesis of lidocaine?

A

alpha-chloro-2,6-dimethylacetanilide + diethylamine (in toluene + HEATED) = lidocaine

And some HCl gas

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5
Q

In the overall lidocaine synthesis what are the electrophilic sites and what are the major nucleophiles?

A

Two electrophilic sites on the alpha-chloroacetylchloride (Carbonyl carbon and primary chloride carbon)

Two nucleophiles = 2,6-dimethylaniline + diethylamine

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6
Q

What (experimentally) gives us clues about the relative reactivities of electrophilic sites?

A

The TIME and AMOUNT OF HEAT needed for the reaction of a nucleophile and a given electrophilic site

The longer/higher temperature requirements, the less reactive the electrophilic site

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7
Q

Which site is more electrophilic of the following?

–> Acyl chloride
–> Alkyl chloride

How do we know?

A

ACYL CHLORIDE is a much more reactive electrophilic site!

If you react acyl chloride with water, the substitution reaction occurs instantaneously at ROOM temp whereas if you react an alkyl chloride with water, the reaction requires heat and takes a LONG TIME!

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8
Q

Reactions involving acyl chlorides must be carried out in…

A

DRY glassware!
Will react with any water present!

–> Absolutely no water should be present as water will react rapidly with the acyl chloride group to produce unwanted products!

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9
Q

What is the intermediate in the multistep synthesis of lidocaine?

A

alpha-chloro-2,6-dimethylacetanilide

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10
Q

Why is the first reaction in lidocaine synthesis carried out in acetic acid?

A

Used a solvent to solubilize the reactants (2,6-dimethylaniline and alpha-chloroacetylchloride)

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11
Q

Acidity of 2,6-dimethylaniline

A

It’s a BASE!

–> The NH2 group has a free lone pair to become NH3 by accepting a proton!

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12
Q

Upon first look at lidocaine synthesis, what LOOKS like it could be a potential issue in the first reaction?

A

The use of acetic acid as a solvent when one of the reactants is a BASE!! (makes it seem like they would react with each other to produce unwanted products)

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13
Q

Why is it not a problem to use acetic acid as the solvent in step 1 of lidocaine synthesis?

A

Because acetic acid is WEAKER than the conjugate acid the acid/base reaction would produce!

–> The reaction of 2,6-dimethylacetinillide (base) and acetic acid will produce a conjugate acid that is STRONGER than the original acid! (NOT FAVORED)

–> Therefore, equilibrium will lie to the LEFT (towards the reactants side) and that will result in no byproducts forming (since the reaction essentially will not occur)

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14
Q

In acid/base reactions, equilibrium ALWAYS lies to the side with…

A

The WEAKER acid!

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15
Q

As the first step reaction occurs, how does equilibrium change to further hinder the acid/base reaction with acetic acid?

A

As the first reaction progresses, the reactants (2,6-dimethylaniline and alpha-chloroacylchloride) will get more depleted

= In the acid base reaction with acetic acid, as 2,6-dimethylaniline conc. decreases, equilibrium is pushed further to the LEFT = further hinders reaction with acetic acid!

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16
Q

What is the GAS byproduct of the first step reaction in lidocaine synthesis?

Why/how is it produced?

A

HCl GAS!!!!

When the aniline reacts with the acyl chloride, the nitrogen of the NH2 group from the aniline forms a new bond to carbon = gains a (+) charge

–> This (+) charge then gets attacked by the free chloride ions (that were displaced due to the substitution reaction) = H+ release from the nitrogen

Deprotonation = H+ + Cl- = HCL GAS

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17
Q

Why must the first step of lidocaine synthesis occur in the hood?

A

Because HCL GAS is produced!

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18
Q

What is the effect of HCl gas production on byproduct formation in the first step of lidocaine synthesis?

A

Most of the HCl gas will dissipate, however, some of it won’t and will react with the aniline reactant to produce an anilinium chloride SALT

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19
Q

Why is the production of anilinium chloride salt a problem in lidocaine synthesis?

A

Because it is insoluble in water (just like the dimethylacetinilide intermediate we want to isolate for the second step!

–> Creates a problem as without altering something about the solubility, we would not be able to isolate the dimethylacetinilide! Any extract would be contaminated with the salt!

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20
Q

2,6-dimethylaniline solubility in WATER

A

GOOD: will dissolve in water!

(Due to the amine grp which has hydrogen bonding!)

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21
Q

alpha-chloroacetylchloride solubility in WATER

A

GOOD: will dissolve in water!

(Gets converted to an acid as it reacts with water which is soluble in water!)

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22
Q

Alpha-chloro-2,6-dimethylacetinilide solubility in WATER

A

INSOLUBLE in water!

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23
Q

2,6-dimethylanilinium chloride solubility in WATER

A

INSOLUBLE in water!

Remember! This is an unwanted byproduct formed by reaction of HCl w/ the reactant aniline!

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24
Q

How do we overcome the issue of HCl reacting to form the anilinium salt preventing the isolation of the intermediate product (alpha-chloro-2,6-dimethylacetinilide)?

A

By treating the reaction product mixture with SODIUM ACETATE (NaOAc)

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25
Q

What does sodium acetate do to anilinium salts?

A

It REPLACES the Cl(-) grp in the salt with an ACETATE grp (-) which is SOLUBLE in water!

(the replaced Cl- then reacts with the Na+ from the sodium acetate to form NaCl

–> Results in the anilinium salt becoming SOLUBLE in water!

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26
Q

Procedure steps for first reaction of lidocaine synthesis:

A

1) Measure out 2,6-dimethylaniline
2) Dissolve in acetic acid
3) Add in the alpha-chloroacetylchloride (HCl is produced)
4) Add in aqueous sodium acetate (aqueous to provide water for the aqueous layer formation)

5) alpha-chloro-2,6-dimethylacetinilide will PRECIPITATE out of solution

6) Collect precipitate by vacuum filtration

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27
Q

What type of molecule is alpha-chloro-2,6-dimethylacetanilide?

What does this mean about its acidity/basicity?

A

An amine!

It is BASIC!

28
Q

What type of reaction is the second step in lidocaine synthesis?

A

Substitution RXN

–> SN2!

29
Q

What is the general mechanism for the second step reaction of lidocaine synthesis?

A

Lone pair on the nitrogen of the diethylamine attacks the primary chloride carbon atom, forming a bond between the chloride carbon and the diethylamine while simultaneously breaking the carbon to Cl bond

= A lidocaine SALT (= ACIDIC) (has a + charge due to the nitrogen from the diethylamine acquiring a new bond!

ANOTHER diethylamine molecule (a base!) will then come in and DEPROTONATE the lidocaine salt to give LIDOCAINE in its neutral form!

–> Produces side product of dimethylanilinium chloride salt

30
Q

What is the molar ration of alpha-chloro-2,6-dimethylacetanilide to diethylamine to give 100% lidocaine product?

A

1:2

–> We need TWO molecules of diethylamine for every ONE dimethylacetanilide molecule to produce ONE lidocaine molecule

31
Q

For the second step reaction of lidocaine synthesis:

A _________ molar excess of diethylamine is needed but we used a __________ molar excess. Why did we do this?

A

TWO molar excess is needed

We used a THREE molar excess

–> To prevent the reaction of lidocaine with the dimethylacetanilide reactant!

32
Q

In the second reaction of lidocaine synthesis, what could act as a nucleophile for the primary alkyl chloride?

A

Diethylamine (what we want to react)

AND LIDOCAINE (what we DONT want to react!)

–> Diethylamine and lidocaine compete as nucleophiles!

33
Q

What is the purpose of each mole of diethylamine in the second reaction of lidocaine synthesis?

A

First mole: Reacts to give lidocaine salt
Second mole: Deprotonates salt to give lidocaine
Third mole: Makes sure there’s enough diethylamine to OUTCOMPETE lidocaine as a nucleophile (prevents lidocaine from reacting with the reactant!)

34
Q

After the reflux of the second reaction in lidocaine synthesis what does the RBF contain?

A

1) Lidocaine
2) Diethylaminium Salt
3) Unreacted starting materials
4) Toluene

(No water! We introduce the water during the washing step)

35
Q

How was lidocaine extracted after it was synthesized?

A

Through two rounds of liquid-liquid extraction:

1) Washing of the organic layer with water (lidocaine remains in organic layer)

2) HCl mediated extraction (protonates lidocaine = salt! –> Gives lidocaine charge so it moves to AQ layer)

–> Then react this salt with NaOH to reform lidocaine + precipitate it out of soln.

36
Q

For organic compounds with oxygen and nitrogen in them, what structural component determines their solubility in water?

A

4 carbons or less = SOLUBLE in H2O

Greater than 4 carbons = INSOLUBLE in H2O

37
Q

Upon the first extraction step (after first wash) of lidocaine, in which layer do all RBF contents end up in?

A

Toluene (organic) layer =
LIDOCAINE + (unreacted materials) diethylamine + alpha-chloro-2,6-dimethylacetanilide

Water (aqueous) layer =
diethylaminium salt + diethylamine

38
Q

What is the problem with diethylamine solubility?

A

Problem = soluble in BOTH the organic and aqueous layers

–> Prevents isolation of lidocaine by extraction

39
Q

How was the dual solubility of diethylamine combatted?

A

Through the properties of its solubility itself!

–> Diethylamine is soluble in BOTH water and toluene BUT, it does have a greater affinity for water!

= We can wash the organic layer multiple times with water to get most of the diethylamine out!

40
Q

How to determine amount of a substance that can be extracted from a mixture using a certain volume of solvent

A

Utilizing K!

41
Q

With each wash of the organic layer, what percentage of diethylamine remains in the organic layer and what percentage goes into the aqueous layer?

A

40% remains in the organic layer

60% goes into the aqueous layer!

42
Q

After each wash of the organic layer, how much diethylamine is left in the organic layer?

A

First wash = 40% left

Second wash = (40% of 40%) = 16% left

Third wash = (40% of 16%) = 6% left

Fourth wash = (40% of 6%) 2% left

43
Q

After the water washes, what was used to extract lidocaine from the organic layer?

A

HCl !!!!

44
Q

Is lidocaine an acid or base?

A

a base!!!

45
Q

Why did we extract lidocaine from the organic layer with HCl?

A

Because lidocaine is a base, so to get it out of the organic layer, we need to make it charged (and therefore soluble in water)

–> To give it a charge, we PROTONATE it!!!! (why we use HCl, an acid, to extract!)

46
Q

After extraction of lidocaine with HCl, how did we get lidocaine back?

A

By reacting with a base! (NaOH)

= deprotonates the lidocaine salt to return it to its neutral, lidocaine, state

47
Q

Upon basification of lidocaine salt, what occurs to the solution?

A

The solution becomes HETEROgenous!

–> Lidocaine precipitates out of solution because it is NOT soluble in water!

48
Q

How did we collect lidocaine after extraction?

A

Vacuum filtration!!!

49
Q

When calculating theoretical yield of lidocaine, what is the limiting reagent?

A

Could be one of two:

2,6-demethylaniline

alpha-chloroacetylchloride

–> Both are from the first reaction! And both are in a 1:1 ratio to lidocaine!

50
Q

Emulsion

A

Mixtures of tiny droplets of one liquid dispersed in another

51
Q

What is the problem with emulsions?

A

Once formed, they are very hard to separate!

52
Q

During the washing of the organic layer, during which step is the risk of generating an emulsion the greatest?

A

In the FIRST wash!

53
Q

If an emulsion forms during the washing stage, what should be done?

A

Add more toluene

54
Q

What is the structure of
2,6-dimethylaniline?

A

Benzene with two methyl groups and one amine substituent

55
Q

What is the structure of
alpha-chloroacetylchloride?

A

Carbonyl grp with two grps attached to the alpha carbon:

1) Chloride
2) Alkyl chloride –> (-CH2Cl)

56
Q

What is the structure of
alpha-chloro-2,6-diethylacetanilide?

A

2,6-diethylaniline bonded to alpha-chloroacetylchloride

–> Bond occurs between the nitrogen and carbonyl carbon

57
Q

What is the structure of
diethylamine?

A

Two ethyl groups bonded to an NH group

58
Q

What is the structure of
lidocaine?

A

Trisub. benzene (2 methyl grps + 1 NH grp)

–>NH grp is bonded to a carbonyl grp with a substituent consisting of a CH2 bonded to a diethyl NH grp

59
Q
A

2,6-dimethylaniline

60
Q
A

alpha-chloroacetylchloride

61
Q
A

alpha-chloro-2,6-diethylacetanilide

62
Q
A

diethylamine

63
Q
A

lidocaine

64
Q

What is this? What causes this to form?

A

This is a multi-alkylated product in which lidocaine has reacted with alpha-chloro-2,6-diethylacetanilide

–> This product forms when there is not enough diethylamine to compete with lidocaine for the nucleophilic attack of alpha-chloro-2,6-diethylacetanilide during the second reaction in lidocaine synthesis

65
Q

What is this? What will happen to this molecule?

A

This is the molecule formed by substitution reaction of diethylamine and alpha-chloro-2,6-diethylacetanilide

–> This molecule will get DEPROTONATED by a SECOND molecule of diethylamine to yield lidocaine!

ORGO LAB (15 decks)

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