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Aromatic Synthesis (3) – Sulfonyl Blocking Groups
Last updated: October 17th, 2022 |
The Sulfonyl Blocking-Group Strategy For Synthesis of Aromatic Molecules
Or, how to just get the “ortho” product without any para- .
Table of Contents
- Why do para products tend to be favored over ortho- products?
- How Do You Get Just The ortho- Product?
- The Sulfonyl “Blocking Group” Strategy
- The Sulfonyl Blocking Group Strategy In Action
- Combining Sulfonyl Blocking Groups With Polarity Reversal
- Two Practice Problems
- Summary: Sulfonyl Blocking Groups
- Notes
1. I Just Want The ORTHO- Product, Thank You
Question: Just how selective are ortho- para, directors for the ortho- and para- products, respectively?
There are two ortho positions and one para. All else being equal, we’d expect a ratio of about 2:1 favoring the ortho.
Is that what we get? No.
In reality, most electrophilic aromatic substitutions give a ratio of products slightly favoring para over ortho. A 60:40 ratio is typical.
Why the preference for para?
Steric effects, mostly. The ortho- positions are adjacent to the substituent, which can block the path of the electrophile. The para- position is therefore more accessible for the electrophile to attack.
This 60:40 ratio is just a rough number, and depends on the particular substituent. To really drive products to the para-, use a really bulky group like t-butyl. This gives para products almost exclusively.
2. How Do You Get Just The ortho- Product?
This preference for the para– product can be annoying. What if we just want the ortho– product?
Sorry, not an option. At least: not yet. There aren’t any reactions we’ve learned that are selective for the ortho– product. So getting to the ortho- in one step, without ever having to separate it from the para-, just isn’t possible with the knowledge we have.
But, as often happens in organic chemistry, there IS a work-around. Here it is.
What if we take advantage of the natural preference for para- substitution, and install a group that can be reversibly added to an aromatic ring? This blocks the para position, which means that any subsequent reaction must go onto the ortho position.
Then we remove the blocking group, and voila! we have our ortho- substituted product exclusively.
3. The Sulfonyl “Blocking Group” Strategy
Have we seen any substituents that can be installed reversibly on benzene?
Yes. There are two: sulfonyl (SO3H) and t-butyl.
Here, we’ll mostly cover sulfonyl. (If you just can’t get enough of this topic – completely understandable! – I’ll cover t-butyl in the endnotes.)
Let’s review sulfonation:
- In the forward direction, treating an aromatic ring with heat, SO3 and acid, puts SO3H on the ring. [Note 1]
- To remove SO3H, we just heat the aromatic ring with strong acid (e.g. H2SO4), which eventually loses gaseous SO3.
Here,. the aromatic ring is protonated at the carbon bearing the SO3H. [Note 2] In the re-aromatization event, SO3 is lost instead of H+. Once gaseous SO3 boils off, it’s not coming back.
4. Using SO3H As A Blocking Group
Let’s show a simple example of this blocking group strategy in action, beginning with methoxybenzene (“anisole”) toward the goal of synthesizing ortho-bromoanisole.
- Step 1 is to install the SO3H with SO3 and strong acid, which will go (mostly) to the para position.
- Step 2 is to install the desired substituent (bromine) on the ortho position.
- Step 3 is to remove SO3H with strong acid and heat, giving us our ortho- substituted product.
And there we go. After removal of the sulfonyl, we’re left with only ortho-bromoanisole.
Hooray!
5. Combining Blocking Sulfonyl Groups With “Polarity Reversal”
We can combine this blocking group strategy with the “polarity reversal” and “order of operations” strategies we learned earlier.
For example: how could we use this to make o-methyl aniline (aka o-toluidine)?
- We saw that we can’t form C-NH2 bonds directly through electrophilic aromatic substitution, but we can form C-NO2 and reduce to the NH2. This means we need to install NO2 on the ortho position.
- This results in the following order of operations: 1) sulfonylation, 2) nitration, 3) removal of SO3H using strong acid and heat, and 4) reduction of NO2 to NH2 using a reductant like zinc and acid (Zn/HCl).
- (it’s probably best to leave the reduction until the end; NH2, being basic, will interfere with the de-blocking step)
While this is one way to do it, it’s not the only way. There’s always an element of choose-your-own-adventure in synthesis.
6. Two Practice Problems
Why not try some of your own? Here’s a few examples to practice with using this strategy:
7. Summary: Sulfonyl Blocking Groups
When you need the ortho- and only the ortho-, a blocking group strategy like this one is a useful trick to have in your toolbox.
Having covered some synthetic strategies, it’s likely worth our time to devote a whole post just to worked examples. That will come next!
Notes
Related Articles
- Electrophilic Aromatic Substitutions (2) – Nitration and Sulfonation
- EAS Reactions (3) – Friedel-Crafts Acylation and Friedel-Crafts Alkylation
- Understanding Ortho, Para, and Meta Directors
- Electrophilic Aromatic Substitution – The Mechanism
- Electrophilic Aromatic Substitutions (1) – Halogenation of Benzene
- Aromatic Reactions and Synthesis Practice (MOC Membership)
- Aromatic Synthesis (1) – “Order Of Operations”
- Synthesis of Benzene Derivatives (2) – Polarity Reversal
- Synthesis (7): Reaction Map of Benzene and Related Aromatic Compounds
Note 1. This will not occur with 100% selectivity for the para position; there will be some ortho- product as well, and it will need to be separated out at some point. So in one sense we are just switching the step at which we have to separate out the undesired product.
Note 2. In contrast to ortho-, meta-, or para-, the carbon attached to the substituent is referred to as the ipso– carbon.
t-Butyl As A Blocking Group
To be brutally frank, the sulfonyl strategy doesn’t get a ton of use in modern organic chemistry. One of the problems is that the resulting sulfonic acid groups are quite polar, and this can present its share of problems with isolation and purification. Ask anyone who’s done ion-exchange chromatography about how much they like concentrating their aqueous fractions. Yeah, no.
A different tack is to employ t-butyl groups as blocking groups. The t-butyl groups are nice and greasy – perfect for flash chromatography.
First, let’s review. How are t-butyl groups installed and removed again?
Installation is via Friedel-Crafts alkylation. We can use either t-BuCl with AlCl3 or 2-methylpropene with strong acid.
Removal of the t-butyl group is achieved by heating with an excess of aluminum chloride (AlCl3) using benzene as solvent. (This also happens to remove the methyl group from anisole as well). These are not exactly mild conditions, which limits the scope of the reaction somewhat a lot, but… onward.
t-Butyl as a Blocking Group: In Action
Here’s an example of this blocking group being used toward the synthesis of a 2-hydroxy benzophenone derivative. Starting with anisole (methoxybenzene), the t-butyl group is added to the para position. Next, a Friedel-Crafts acylation results in exclusive formation of the ortho– product. Finally, removal of the t-butyl with AlCl3 and benzene results in the final product.
Notice that this also pops off the methyl ether – not an easy thing to do! Mild, these conditions are not.
So how does the removal of the t-butyl group happen?
The reaction probably begins by protonating the ring with trace acid (e.g. HCl) present either in AlCl3 or from reaction of AlCl3 with trace water. Protonation of the ring at the para position can then set up re-aromatization not by loss of H+, but by loss of the t-butyl cation. The t-butyl cation is then quickly deprotonated to give 2-methylpropene (“isobutylene”) in an E1 reaction. To stop the isobutylene from Friedel-Crafting back to the para– position, benzene (or toluene) is used as solvent (or co-solvent), which eventually results in formation of t-butylbenzene.
This method does occasionally see use in synthesis. For example, in the synthesis of some resveratrol derivatives, Hou et. al. were trying to dimerize a stilbene derivative. To cut down on the number of potential products, they found it useful to block two positions of a phenol with t-butyl groups, which were later removed using AlCl3, nitromethane, and toluene. Reference here.
For more on the synthesis, check out Classics in Total Synthesis, volume 3 (Nicolaou and Chen) Chapter 20. And while you’re there, don’t miss chapter 23!
00 General Chemistry Review
01 Bonding, Structure, and Resonance
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08 Substitution Reactions
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09 Elimination Reactions
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10 Rearrangements
11 SN1/SN2/E1/E2 Decision
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12 Alkene Reactions
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- Palladium on Carbon (Pd/C) for Catalytic Hydrogenation of Alkenes
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- A Fourth Alkene Addition Pattern - Free Radical Addition
- Alkene Reactions: Ozonolysis
- Summary: Three Key Families Of Alkene Reaction Mechanisms
- Synthesis (4) - Alkene Reaction Map, Including Alkyl Halide Reactions
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13 Alkyne Reactions
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- Alkyne Reactions - The "Concerted" Pathway
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14 Alcohols, Epoxides and Ethers
- Alcohols - Nomenclature and Properties
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15 Organometallics
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16 Spectroscopy
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17 Dienes and MO Theory
- What To Expect In Organic Chemistry 2
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- s-cis and s-trans
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18 Aromaticity
- Introduction To Aromaticity
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19 Reactions of Aromatic Molecules
- Electrophilic Aromatic Substitution: Introduction
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- Electrophilic Aromatic Substitution - The Mechanism
- Ortho-, Para- and Meta- Directors in Electrophilic Aromatic Substitution
- Understanding Ortho, Para, and Meta Directors
- Why are halogens ortho- para- directors?
- Disubstituted Benzenes: The Strongest Electron-Donor "Wins"
- Electrophilic Aromatic Substitutions (1) - Halogenation of Benzene
- Electrophilic Aromatic Substitutions (2) - Nitration and Sulfonation
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- Intramolecular Friedel-Crafts Reactions
- Nucleophilic Aromatic Substitution (NAS)
- Nucleophilic Aromatic Substitution (2) - The Benzyne Mechanism
- Reactions on the "Benzylic" Carbon: Bromination And Oxidation
- The Wolff-Kishner, Clemmensen, And Other Carbonyl Reductions
- More Reactions on the Aromatic Sidechain: Reduction of Nitro Groups and the Baeyer Villiger
- Aromatic Synthesis (1) - "Order Of Operations"
- Synthesis of Benzene Derivatives (2) - Polarity Reversal
- Aromatic Synthesis (3) - Sulfonyl Blocking Groups
- Birch Reduction
- Synthesis (7): Reaction Map of Benzene and Related Aromatic Compounds
- Aromatic Reactions and Synthesis Practice
- Electrophilic Aromatic Substitution Practice Problems
20 Aldehydes and Ketones
- What's The Alpha Carbon In Carbonyl Compounds?
- Nucleophilic Addition To Carbonyls
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- Sodium Borohydride (NaBH4) Reduction of Aldehydes and Ketones
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- Wittig Reaction
- Hydrates, Hemiacetals, and Acetals
- Imines - Properties, Formation, Reactions, and Mechanisms
- All About Enamines
- Breaking Down Carbonyl Reaction Mechanisms: Reactions of Anionic Nucleophiles (Part 2)
- Aldehydes Ketones Reaction Practice
21 Carboxylic Acid Derivatives
- Nucleophilic Acyl Substitution (With Negatively Charged Nucleophiles)
- Addition-Elimination Mechanisms With Neutral Nucleophiles (Including Acid Catalysis)
- Basic Hydrolysis of Esters - Saponification
- Transesterification
- Proton Transfer
- Fischer Esterification - Carboxylic Acid to Ester Under Acidic Conditions
- Lithium Aluminum Hydride (LiAlH4) For Reduction of Carboxylic Acid Derivatives
- LiAlH[Ot-Bu]3 For The Reduction of Acid Halides To Aldehydes
- Di-isobutyl Aluminum Hydride (DIBAL) For The Partial Reduction of Esters and Nitriles
- Amide Hydrolysis
- Thionyl Chloride (SOCl2)
- Diazomethane (CH2N2)
- Carbonyl Chemistry: Learn Six Mechanisms For the Price Of One
- Making Music With Mechanisms (PADPED)
- Carboxylic Acid Derivatives Practice Questions
22 Enols and Enolates
- Keto-Enol Tautomerism
- Enolates - Formation, Stability, and Simple Reactions
- Kinetic Versus Thermodynamic Enolates
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- Claisen Condensation and Dieckmann Condensation
- Decarboxylation
- The Malonic Ester and Acetoacetic Ester Synthesis
- The Michael Addition Reaction and Conjugate Addition
- The Robinson Annulation
- Haloform Reaction
- The Hell–Volhard–Zelinsky Reaction
- Enols and Enolates Practice Quizzes
23 Amines
- The Amide Functional Group: Properties, Synthesis, and Nomenclature
- Basicity of Amines And pKaH
- 5 Key Basicity Trends of Amines
- The Mesomeric Effect And Aromatic Amines
- Nucleophilicity of Amines
- Alkylation of Amines (Sucks!)
- Reductive Amination
- The Gabriel Synthesis
- Some Reactions of Azides
- The Hofmann Elimination
- The Hofmann and Curtius Rearrangements
- The Cope Elimination
- Protecting Groups for Amines - Carbamates
- The Strecker Synthesis of Amino Acids
- Introduction to Peptide Synthesis
- Reactions of Diazonium Salts: Sandmeyer and Related Reactions
- Amine Practice Questions
24 Carbohydrates
- D and L Notation For Sugars
- Pyranoses and Furanoses: Ring-Chain Tautomerism In Sugars
- What is Mutarotation?
- Reducing Sugars
- The Big Damn Post Of Carbohydrate-Related Chemistry Definitions
- The Haworth Projection
- Converting a Fischer Projection To A Haworth (And Vice Versa)
- Reactions of Sugars: Glycosylation and Protection
- The Ruff Degradation and Kiliani-Fischer Synthesis
- Isoelectric Points of Amino Acids (and How To Calculate Them)
- Carbohydrates Practice
- Amino Acid Quizzes
25 Fun and Miscellaneous
- A Gallery of Some Interesting Molecules From Nature
- Screw Organic Chemistry, I'm Just Going To Write About Cats
- On Cats, Part 1: Conformations and Configurations
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- On Cats, Part 4: Enantiocats
- On Cats, Part 6: Stereocenters
- Organic Chemistry Is Shit
- The Organic Chemistry Behind "The Pill"
- Maybe they should call them, "Formal Wins" ?
- Why Do Organic Chemists Use Kilocalories?
- The Principle of Least Effort
- Organic Chemistry GIFS - Resonance Forms
- Reproducibility In Organic Chemistry
- What Holds The Nucleus Together?
- How Reactions Are Like Music
- Organic Chemistry and the New MCAT
26 Organic Chemistry Tips and Tricks
- Common Mistakes: Formal Charges Can Mislead
- Partial Charges Give Clues About Electron Flow
- Draw The Ugly Version First
- Organic Chemistry Study Tips: Learn the Trends
- The 8 Types of Arrows In Organic Chemistry, Explained
- Top 10 Skills To Master Before An Organic Chemistry 2 Final
- Common Mistakes with Carbonyls: Carboxylic Acids... Are Acids!
- Planning Organic Synthesis With "Reaction Maps"
- Alkene Addition Pattern #1: The "Carbocation Pathway"
- Alkene Addition Pattern #2: The "Three-Membered Ring" Pathway
- Alkene Addition Pattern #3: The "Concerted" Pathway
- Number Your Carbons!
- The 4 Major Classes of Reactions in Org 1
- How (and why) electrons flow
- Grossman's Rule
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When you convert anisole to phenole you put 2 arrow between them but I think only arrow will be present bacause when anisole react with HCl then 1st protonation occur on oxygen then Cl- attack on sigma star orbit of C-O bond and formation of phenol and methyl chloride.Then why you put 2 arrow plss say
only one*
The purpose of the two arrows is just to show that the reaction eventually converts to phenol, without going into details on the mechanism. If I had to draw it out, as you suggest, the first arrow would be protonation of the anisole oxygen, and the second would be attack at the sigma star with Cl- .
Another nifty example of dealkylation is the formation of meta products following long reaction times/higher temps during poly-alkylation: https://en.wikipedia.org/wiki/Friedel%E2%80%93Crafts_reaction#Friedel%E2%80%93Crafts_dealkylation . The wikipedia page does say “needs citation” but I think I recall reading it in March’s advanced organic.
I have yet to meet a student I tutor who has actually needed to know this fun fact. So I fear to breath a word of it, because drawing a meta product for alkylation would get zero points on 99.9% of exams!