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Year 2 Organic > Retrosynthesis > Flashcards

Retrosynthesis Flashcards

1
Q

What is retrosynthesis?

A

Retrosynthesis, also known as the disconnection approach, is a process for devising a synthetic route to a target molecule by working backwards from that molecule

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2
Q

How does retrosynthesis take place?

A

By breaking the molecule down into simpler fragments, these fragments are broken down further in to even more simple fragments etc, until we work back to fragments that are commercially available

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3
Q

How does retrosynthesis work with complex molecules?

A

With complex molecules we can use retrosynthesis to come up with many possible ways of trying to make them, there is not just one right answer

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4
Q

What is important about retrosynthesis with complex molecules?

A

When we have several possible synthetic routes we need to determine which is the best, the one with fewest steps, best yield, economic factors, costs of products and energy considerations, considerations of waste

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5
Q

What a good bond to break in a ketone?

A

A good bond to disconnect is the C-C bond between the carbons that are alpha and beta to the ketone, we show which bond we are disconnecting with a wiggly line

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6
Q

What needs to be considered when a bond is disconnected?

A

When we disconnect a bond w need to consider what happens to the electrons in that bond, the electrons could go to one of the fragments or the other

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7
Q

What are the two possibilities of fragments called?

A

Synthons

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8
Q

What are synthons?

A

Synthons are not real compounds, the are hypothetical compounds that would react together to form the desired bond if they existed

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9
Q

What needs to be considered with synthons?

A

Once we have determined possible pairs of synthons, we have to consider if there are any real compounds that would react the same way

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10
Q

Why can’t a primary carbocation exist as a synthon?

A

Too high energy and too unstable

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11
Q

Real life equivalent of a primary alkyl cation?

A

A real life equivalent would be the corresponding alkyl halide eg an alkyl bromide and this would react by an SN2 mechanism

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12
Q

What would the real life equivalent for a carbanion at the alpha position of a carbonyl?

A

The corresponding enolate, formed by deprotonation of that carbonyl

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13
Q

How are enolates normally generated?

A

Enolates are normally generated by deprotonation of the corresponding carbonyl

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14
Q

What is important about the base for generating an enolate?

A

The correct selection of the base for deprotonation is crucial to achieve a high concentration of the desired enolate, eg EtO- is only a good base for those substrates which are substantially more acidic than EtOH (pKa = 18)

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15
Q

What are the typical bases used in generation of enolates?

A

Alkoxides (usually with Na as the couterion), alkali metal hydrides (NaH, KH), alkali metal amides (NaNH2, KNH2)

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16
Q

What amides are especially useful in generation of enolates?

A

Particularly useful amides are those derived by deprotonation secondary amines, namely lithium diisoproplyamide (LDA), and lithium hexamehyldisilazide (LHMDS)

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17
Q

Why are these amides especially useful in generation of enolates?

A

These are soluble in inert solvents such as THF, and are hindered and therefore non nucleophilic, strong bases

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18
Q

Relation which bases and pKa?

A

Higher the pKa the stronger the base

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19
Q

What is the problem with alkyllithiums?

A

They are very strong bases, they are commercially available but are not often used for enolate formation as they are also good nucleophiles, which leads to side reactions

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20
Q

Picking a base for generating an enolate?

A

Pick a base with the same pKa or bigger

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21
Q

Why are dicarbonyls easy to deprotonate?

A

Dicarbonyl species unusually easy to deprotonate, more resonance so more stable, so after deprotonation anion of this is very stable, the more stable anion is easier it’ll be to deprotonate

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22
Q

What is the rate of alkylation of enolates dependent on?

A

The rate of alkylation of enolates is very solvent dependent

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23
Q

Whats important about polar aprotic solvents in the alkylation of enolates?

A

Polar aprotic solvents such as DMF, DMSO, HMPA are good cation solvates and therefore leave a naked, reactive anion

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24
Q

Whats important about polar solvents in the alkylation of enolates?

A

Polar solvents such as THF and DME are still able to coordinate cations but with a smaller charge separation generating less reactive enolates

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25
Q

When does C alkylation occur?

A

Small cations such as Li+ bind tightly to oxygen promoting C alkylation

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26
Q

Why does O alkylation occur?

A

Larger cations such as K+ favour O alkylation

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27
Q

What affects C and O alkylation?

A

The choice of alkylation agent is important

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28
Q

Alkylating agent for O alkylation?

A

Oxygen derived leading groups promote O alkylation

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29
Q

Alkylating agent for C alkylation?

A

For C alkylation use halides ie iodides or bromides

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30
Q

What is OTs?

A

OTs is the shorthand for a para tolunesulfonate or ‘tosylate’, sultanates are leaving groups that can be synthesised in 1 step from the corresponding alcohol

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31
Q

When is regioselective deprotonation important?

A

In non symmetrical ketones the question of which proton is removed is very important

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32
Q

When does the kinetic enolate form?

A

The kinetic enolate is the fastest formed enolate usually formed by the removal of the least hindered proton

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33
Q

What are conditions for forming the kinetic enolate?

A

Good conditions for this involve adding the ketone to an excess of a strong hindered base eg LDA at low temperature -78 degreesC, this avoids an equilibrium being set up

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34
Q

What are conditions for forming the thermodynamic enolate?

A

The thermondynamic enolate can be formed by adding a strong base to the ketone often at room temperature or above to form the more substituted enolate, allows an equilibrium to be set up, the thing that there will be the most of is the most stable hence why thermodynamic enolate is present

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35
Q

Why is the thermodynamic enolate more stable?

A

Stabilities effect of the methyl group on the C=C, it is more substituted and therefore the alkene is more stable

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36
Q

How is an equilibrium set up in the thermodynamic enolate?

A

The pKa of the base and the proton on the methyl group are similar so can be protonated and deprotonated again and hence an equilibrium can be set up

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37
Q

How selective is the kinetic enolate?

A

99:1 K/T, therefore it is very selective

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38
Q

How selective is the thermodynamic enolate?

A

22:78 K/T, so not quite as selective

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39
Q

How does enolate trapping work?

A

Mixtures of kinetic and thermodynamic enolates can be trapped as stable derivatives and then separated

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40
Q

How can enolates be trapped?

A

A particualelry useful way of trapping enolates is to prepare silyl Enols ethers (also known as enol silanes) these are generated by trapping the enolate mixture with a trialklysilyl chloride, the most common is trimethylsilyl chloride (TMS-Cl)

41
Q

How can the resultant enol silanes be isolated?

A

The resultant enol silanes can be isolated and separated by distillation treatment with methyl lithium regenerates the enolate

42
Q

What is another method of achieving deprotonation at a specific position?

A

An alternative method to achieve deprotonation at a specific position is to introduce an activating group that increases the acidity of the desired proton, this is usually achieved by the introduction of a further EWG such as an ester, after alkylation the activating group can be removed by hydrolysis and then decarboxylation

43
Q

Where is the hydrogen atom locates in a beta-ketoacid?

A

In the beta-ketoacid the hydrogen is located between the two carbonyl due to intramolecular H bonding, at high temperature a pericyclic reactions occurs, extruding CO2 and forming the enol of the final product, this tautomerises to the ketone

44
Q

Why can there be problems with the direct alkylation of ketone?

A

Problems such as double alkylation and self condensation

45
Q

How can the problem with direct alkylation of ketones be avoided?

A

One solution is to use enamines, enols can react with themselves whereas enamines can’t

46
Q

What are enamines?

A

These can be considered as the nitrogen analogues of enols

47
Q

How are enamines formed?

A

By the reaction of a secondary amine with a carbonyl compound in the presence of an acid catalyst, pyrrolidine and morpholine are commonly used amines

48
Q

How do enamines react?

A

Enamines are nucleophilic at the beta position, they react with alkyl halides and can then be hydrolysed to regenerate the carbonyl compound

49
Q

What are the advantages to using enamines?

A

No base is used so no self condensation occurs
Monoalkylation is usually observed (the intermediate mono alkylenamines are unreactive towards further reaction)
Alkylation of unsymmetrical ketones is regioselective the major enamine is less substituted (steric inhibition of resonance)

50
Q

Where is the most thermodynamically acidic proton at the enolate of the alpha beta unsaturated ketone?

A

The most thermodynamically acidic proton is at the thermodynamically stable anion

51
Q

Where are the three nucleophilic sites on the enolate of the alpha beta unsaturated ketone?

A

The enolate has three potentially nucleophilic sites - the oxygen atom, the alpha and gamma carbons

52
Q

Where does kinetic alkylation take place on the enolate of the alpha beta unsaturated ketone?

A

Kinetic alkylation (ie fastest) takes place at the alpha positions, the most kinetically acidic proton is at the alpha position

53
Q

What is the real life equivalent of the cation to alpha to a ketone synthon?

A

The real life equivalent of the cation to alpha to a ketone synthon is an alpha halo ketone - these undergo nucleophilic displacement in a particularly facile manner

54
Q

How are Grignard reagents formed?

A

They are formed from the corresponding alkyl or aryl halide and magnesium metal

55
Q

How do Grignard reagents react?

A

Grignard reagents act as a carbon nucleophile and react with many different electrophiles for example they react with aldehydes and ketones to give the corresponding alcohols

56
Q

What does aldehyde plus Grignard reagent make?

A

Gives secondary alcohol

57
Q

What does ketone plus Grignard reagent make?

A

Gives tertiary alcohol

58
Q

Why are Grignards more often used than corresponding alkyllithiums?

A

Grignard reagents are much more commonly used as carbon nucleophiles than the corresponding alkyllithiums as these are very basic which often leads to side reactions

59
Q

What are alkyllithiums normally used as?

A

Alkyllithiums are mainly just used as strong irreversible bases

60
Q

What are Grignard reagents normally used for in retrosynthesis?

A

They give a method for disconnecting the C-C bond next to the secondary or tertiary alcohol, Grignard reagents are also useful for opening strained rings

61
Q

What is a problem with the alpha halo ketone?

A

The alpha halo ketone is an ambient electrophile, a nucleophile can react with it in more than one place - since the nucleophile (ie the Grignard reagent) could attack in more than one place we need to know about the selectivity of the nucleophilic carbon species

62
Q

What is the selectivity of the Grignard reagent?

A

The Grignard reagent will attack the ketone in preference to the alpha carbon, so a Grignard is not a good choice of real life reagent for the alpha halo ketone

63
Q

What type of nucleophilic carbon species is a Grignard reagent?

A

A Grignard is a hard nucleophilic carbon species, which are small and highly charged with electrostatic interactions, so it reacts with the carbonyl carbon as this is the harder electrophilic site

64
Q

What are soft nucleophilic carbon species?

A

Soft nucleophiles are likely to be found further down the group on the periodic table with orbital overlap, some soft carbon nucleophiles would also be useful, as they would show complementary reactivity to Grignards

65
Q

What is a softer kind of organometallic nucleophile?

A

An organocopper reagent or “cuprate”

66
Q

How are cuprates made?

A

Unlike Grignard reagents they aren’t made by directly combining copper metal with an alkyl or aryl halide instead we take an organometallic reagent that we have pre formed (eg a Grignard or an organolithium) and carry out a transmetallation ie swapping one metal for another

67
Q

What is used in the transmetallation to form a cuprate?

A

Various copper (I) salts can be used for the transmetallation: Cl, Br, I, CN etc

68
Q

How can the structure of the curate be derived?

A

In the case of the cuprate derived from a Grignard reagent this has been written as R-Cu as the precise structure is ill defined, the structure of the cuprate derived from two equivalents of organolithium is better defined

69
Q

Where do cuprates react on a molecule?

A

Generally speaking curates do not react with carbonyls directly at the carbonyl carbon as this carbon is too hard an electrophile

70
Q

What is the one exception where cuprate will react directly at the carbonyl carbon?

A

Acid chlorides, a cuprate will react with an acid chloride once displacing the chloride

71
Q

How is an acid chloride made?

A

Acid chlorides can be made by reacting the corresponding carboxylic acid with thionyl chloride or with oxalyl chloride/DMF

72
Q

What is important about the solvent when making an acid chloride?

A

Usually a polar parotid solvent used but actually gets involved in the reaction mechanism

73
Q

What do cuprates do in retrosynthesis?

A

The reaction between cuprates and acid chlorides gives us more options in terms of which bond to disconnect when undertaking retrosynthesis
Cuprates are very good at conjugate addition to alpha beta unsaturated carbonyl systems ie 1, 4-addition, (Grignard effect 1, 2-addition)

74
Q

When can organocopper be used catalytically?

A

When you use an organocopper species derived from a Grignard you can use the copper catalytically

75
Q

What bond does conjugate addition technology allow us to break?

A

Conjugate additions allows us to disconnect a third bond - the one between the beta and gamma carbons

76
Q

What other molecules undergo conjugate addition?

A

Heteroatom nucleophiles can undergo conjugate addition toe nones - this is a powerful method for C-X bond formation

77
Q

What ring system can cuprates open?

A

Just like Grignard reagents can be used to open epoxides, cuprates can be used to open aziridines (the nitrogen equivalent of epoxides)

78
Q

In the case of cuprate mediated aziridine opening the reaction does not work well is R2 = H so how do you get round this if you want R2 to be H?

A

The solution is to use a R2 substituent on the nitrogen that you can remove after the cuprate has been added. In general installing a functional group in a molecule temporarily to allow a particle reaction to be carried out (and the removing that group) is called using a protecting group, various protecting groups can be used to protect an aziridine nitrogen prior to the ring opening with a cuprate

79
Q

Boc as a protecting group?

A

Not appropriate in acidic conditions since it comes off when you don’t want it to

80
Q

How does dissolving metal reduction remove Ts group?

A

Dissolving metal reduction passes an electron to naphthalene which reduces it which is the reactive reductant so passes another electron onto the nitrogen-sulfur bond (reductive cleavage) sodium mercury amalgam can be used as well, this is effective at removing the Ts group

81
Q

What is the conditions for removing the protecting group?

A

Orthogonal conditions - in the context of protecting groups this mean you want each one to be removed under different reaction conditions than the others

82
Q

What is important about protecting groups?

A

For each functional group many different protecting groups have been developed each of which is stable to different conditions and is removed by different conditions

83
Q

What is important about complicated synthesis and protecting groups?

A

If you are carrying out a very complex synthesis you may need several different types of protecting group for different parts of the molecules - ideally you want these protecting groups to be orthogonal

84
Q

Why are protecting groups useful?

A

Protecting groups are very useful in that they allow you to use disconnections that would not work otherwise they greatly expand the synthetic toolkit

85
Q

What is a problem with protecting groups?

A

Every protecting group you use will add at least two steps to the synthesis (one to introduce it and one to remove it) and as these steps are unlikely both to have yield of 100% this will inevitable reduce the overall yield for your synthesis

86
Q

What is the most common strategy for protecting groups?

A

The most common strategy for protecting alcohols is use of silyl ethers

87
Q

How can silyl ethers be formed?

A

These can be formed from the alcohols by using the corresponding silyl chloride (the more steric bulk around the silicon the more stable the silyl ether)

88
Q

How are silyl ethers removed?

A

Silyl ethers are stale to most reaction conditions but are removed by treatment with acid or with a source of fluoride (Si-F is a very strong bond) - using several different silyl ethers in the same molecule can allow for their selective removal

89
Q

What protecting group can be used for alcohols?

A

A different protecting groups strategy for alcohols is the use of tetrahydropyranyl ether (THP ether) these are installed under acid catalysis and removed the same way (it is an equilibrium), as THP ethers can be cleaved by acid but not by fluoride they can be seen as orthogonal to silyl ethers

90
Q

What is the most common way of protecting aldehydes and ketones?

A

The most common way of protecting an aldehyde is to use an acetal and to protect a ketone is a ketal, these are formed by treating the carbonyl in question with a diol and catalytic acid

91
Q

Why is water needed to be removed in the formation of acetals and ketals?

A

As the reaction is an equilibrium it is important to remove the water that is formed with a Dean Stark strap to drive the equilibrium to the right, in order to remove these protecting groups we need to drive the equilibrium to the left so we need to deliberately add lots of water

92
Q

How can the reaction be used to protect a diol?

A

If you look at the reaction the other way round it can also be used to protect a diol, this time we are adding an aldehyde or ketone, commonly acetone or benzaldehyde

93
Q

What is an example of where protecting groups are necessary?

A

In the formation of Grignard reagents that would not be accessible otherwise, if we disconnect the molecules to two synthons the electrophile is ok but the Grignard is not viable if we try to form it it will instantly react with itself as there is an electrophilic ketone elsewhere in the same molecules, the solution is to use a metal protecting group - in the protected compound the former ketone carbon is no longer electrophilic so we can from the Grignard reagent without any problems carry out the additions into the aldehyde then remove the protecting group

94
Q

How else do protecting groups allow access to Grignard reagents?

A

Protecting groups can allow access to Grignard reagents containing masked alcohols, we have disconnected adjacent to one of the alcohols giving a cationic synthon which correspond to a ketone and an anionic synthon corresponding to an unstable Grignard reagent, the problem is that the Grignard reagent is a strong base as well as a strong nucleophile and there is an acidic proton elsewhere in the molecule on the -OH, so it will deprotonate itself and the Grignard reagent will be quenches

95
Q

What are the two retrosynthetic steps?

A

A retrosynthetic step can either be a bond disconnection or a functional group interconversion

96
Q

When is an interconversion used?

A

When both pairs of synthons have problems such as no real life equivalent or selectivity issues

97
Q

What FGI can be used to make a ketone from the alcohol?

A

We can make the ketone from the alcohol by oxidation so we can disconnect the alcohol instead, this maps on to the use of an epoxide and gives us two valid, compatible real life reagents, PCC is pyridinium chlorochromate which is an oxidising agent

98
Q

What are possible oxidising agents?

A

The most powerful is Jones reagent, whereas PCC and PDC are milder reagents that have solubility in organic solvents, all these reagents will oxidise a secondary alcohol to a ketone, in the case of a primary alcohols PCC and PDC will oxidise it once to an aldehyde whereas the Jones reagent will oxidise it further to a carboxylic acid

99
Q

What is a problem with chromium (VI) reagents?

A

They are all toxic and carcinogenic and the waste is expensive to dispose of

Year 2 Organic (1 decks)

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