Common Blind Spot: Intramolecular Reactions

Intramolecular Reactions

So I bought a belt today (pleather, 75 cents at the Goodwill).  and decided to show it off. This is me putting it together.

This is what it looks like now:

At this point you’re probably saying WTF: that’s not what a belt is supposed to look like when you put it together. That’s because I linked it together with my other belt.

I say: broaden your horizons of how nucleophiles and electrophiles can meet.

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Here’s a typical reaction you meet early on in Org 2. Formation of an ether through the addition of an oxygen nucleophile to an alkyl halide. This is the Williamson ether synthesis. (See post: The Williamson Ether Synthesis)

Makes some sense, right? Nucleophile, electrophile: give the product.

Here’s the same reaction. Exactly the same. But a lot of students I talk to will look twice at it the first time they see it,  not quite sure what to do.

Different example: the Friedel Crafts acylation between aromatic rings and acyl halides.

Then, here’s the exact same reaction. Common result: hesitation. What happens?

Last example: formation of esters from alcohols and carboxylic acids. The Fischer esterification. Once people see this, they usually find it straightforward.

But then hand them this reaction, and it’s a stumper.

What do all of these reactions have in common?

When the nucleophile and electrophile are on the same molecule, they form RINGS.

Because you’re probably used to seeing linear molecules – not chains – it looks weird.  But if you think about it, you’re already familiar with an example of this:

Notes

(Advanced) References and Further Reading

Control of intra- vs. inter-molecular reactions is commonly done by dilution. The former are favored at very low concentrations (high dilution), to minimize the probability of the molecule reacting with another molecule of itself.

1. Ring closure reactions of bifunctional chain molecules
   Gabriello Illuminati and Luigi Mandolini
   Accounts of Chemical Research 1981, 14 (4), 95-102
   DOI: 1021/ar00064a001
   Fig. 1 in this paper shows that the intramolecular formation of 5- and 6-membered rings is especially favored relative to other ring sizes.
2. Ring-closure reactions. 22. Kinetics of cyclization of diethyl (.omega.-bromoalkyl)malonates in the range of 4- to 21-membered rings. Role of ring strain
   Maria Antonietta Casadei, Carlo Galli, and Luigi Mandolini
   Journal of the American Chemical Society 1984, 106 (4), 1051-1056
   DOI: 1021/ja00316a039
   Figure 1 in this paper also plots the relationship between ring size and rate of intramolecular cyclization, with a pronounced global maximum for 5-membered rings. The authors state that cyclizations for 9-11 membered rings “should be run at concentrations of less than 10^-6 M in order to proceed free from polymerization!”.
3. Ring-closure reactions. 7. Kinetics and activation parameters of lactone formation in the range of 3- to 23-membered rings
   Carlo Galli, Gabriello Illuminati, Luigi Mandolini, and Pasquale Tamborra
   Journal of the American Chemical Society 1977, 99 (8), 2591-2597
   DOI: 1021/ja00450a031
   Esterification can also take place intramolecularly to give lactones, and as to be expected, 5-membered rings are the most favored, followed by 4 and 6, then 7, then other ring sizes (see Table I).
4. Ring-closure reactions. 11. The activation parameters for the formation of four- to six-membered lactones from .omega.-bromoalkanoate ions. The role of the entropy factor in small- and common-ring formation
   Luigi Mandolini
   Journal of the American Chemical Society 1978, 100 (2), 550-554
   DOI: 1021/ja00470a032
   As shown in Fig. 2, DS^‡ values for intramolecular cyclizations are fairly negative and of the same magnitude as DH^‡ values, which is why it can be difficult to favor intramolecular reactions for large rings.
5. Cyclization and polymerization of .omega.-(bromoalkyl)dimethylamines
   DeLos F. DeTar and Walter Brooks
   The Journal of Organic Chemistry 1978, 43 (11), 2245-2248
   DOI: 1021/jo00405a033
6. Quantitative evaluation of steric effects in SN2 ring closure reactions
   DeLos F. DeTar and Narender P. Luthra
   Journal of the American Chemical Society 1980, 102 (13), 4505-4512
   DOI: 1021/ja00533a033
   Cyclic amines can also be formed via intramolecular reactions and are subject to the same principles – 5- and 6-membered rings form fastest.
7. Neighboring Group Participation by Carbonyl Oxygen
   J. Pasto and M. P. Serve
   Journal of the American Chemical Society 1965, 87 (7), 1515-1521
   DOI: 10.1021/ja01085a019
   In this case, a carbonyl oxygen can aid with leaving group departure and form a cyclic ether, which is especially favored if a 5- or 6-membered ring is formed.
8. Rules for Ring Closure
   Jack E. Baldwin
   Chem. Soc. Chem. Comm. 1976, 734-736
   DOI: 10.1039/C39760000734
   An advanced topic, this introduces ‘Baldwin’s rules for ring closure’, which allows one to predict whether a particular intramolecular ring-closing reaction is favorable based on ring size, the hybridization of the carbon atom at the reaction site, and the relationship (exocyclic or endocyclic) of the reacting bond to the forming ring. These rules are based on empirical observations of ring-closing reactions.