Handout: This is intended to help with complex diagrams, and to guide you to appropriate sections of textbooks, but there is no "hidden agenda" – if you have good lecture notes, you can pass this course without consulting these references.

"Organic Chemistry", K. P. C. Vollhardt and N. E. Schore, 3^rd Edition, 1998.

"Pericyclic Reactions" I. Fleming, Oxford Chemistry Primers, 1999.

References are given in bold italics, e.g. V&S 123 or F 45. Diagrams equivalent to those in these books will also be used as far as possible. Other complex diagrams are reproduced in these notes.

These lectures go beyond these texts at some points, so the following excellent advanced general textbook is sometimes referred to:-

Several strategies for making particular ring sizes are conceivable:-

The last three are useful for making difficult-sized rings, and will be discussed only briefly.

Two main factors affect the ease of ring closure (V&S 349, C&S A163-5, see also C. Willis and M. Wills, "Organic Synthesis" Oxford Chemistry Primers, 1995, page 24):-

A third factor - the proper alignment of orbitals in the reaction significantly affects the ease of ring-closure in a few cases (see Baldwin’s rules below).

Ring strain per methylene group from V&S 132, Table 4-2 is plotted below:

Molecular mechanics breaks strain down into several factors; see your "Introduction to Molecular Modelling" Computing for Chemists Workshop.

From the interaction of these strain effects with the entropy factor, it is found that 5-membered rings are usually formed most easily, followed by 6- and 3-membered. When favourable ring sizes are involved, ring closure reactions are often easier than similar intermolecular reactions (see S. Warren "Organic Synthesis: the Disconnection Approach", Wiley, 1982, page 54, and especially Ch. 29, page 240 for an interesting comment).

3-Membered rings are both opened and closed more easily than expected, while 4-membered rings are opened and closed surprisingly slowly - the causes of these effects is still not completely understood.

In a number of cases quantitative comparison of ring closure (intramolecular) and intermolecular reactions have been made. The ratio of rates is a molarity:-

Effective molarity (EM) = kintra/kinter (units of EM are mol/litre)

EM values range from 10³ (impossible as a real molarity of course!) for 5-membered rings to less than 10^-3 for 8- and 9-membered rings (this means that you would have to work at concentrations of less that 10^-3 M for cyclisation to compete with polymerisation).

Baldwin's Rules (C&S A165, see also "Stereoelectronic Effects", A. J. Kirby, Oxford Chemistry Primer, 1996, page 27-8.).

The important principle behind Baldwin’s rules is that the proper geometry for the transition state must be attainable if the reaction is to take place. Thus in an S_N2 reaction, the entering and leaving groups must be in line, and this can't occur in a small ring. The favoured direction of attack on an sp² (trigonal) carbon is from above the plane of the attached groups but not quite perpendicular. This is difficult when the double bond is inside a small ring (endo).

The only case which is important is that 5-endo-trig reactions are disfavoured but 5-exo-trig are OK.

Preparation of manxane from bicyclo[3.3.1]nonan-9-one. The ring expansion steps were ketone plus diazomethane reactions (C&S B504).

Preparation of cubane. The ring contraction step is known as a Favorskii reaction (C&S B506).

Leonard's synthesis of manxine shows how a molecule consisting entirely of 8-membered rings can be achieved from a precursor with easy-to-make 5-membered rings. In the second example below, hydroboration of a double bond, followed by addition of hydroxide, leads to a fragmentation of a bicyclic compound to create a 10-membered ring.

Most common reactions can occur intramolecularly so as to give ring closure. Try looking up "Ring-closure reactions" in the Index of Vollhardt and Schore and see how many there are!

S_N2 reactions.

Oxacyclopropanes (epoxides ) are readily formed from compounds containing the C(OH)-C(X) functionality (V&S 350).

Bromolactone formation (2nd year experiment; see also C&S B181).

S_N2 reactions can also be used for carbocycle formation. E. g. diethyl malonate with a ,w -dihaloalkanes and sodium ethoxide.

This is a particularly important reaction for carbohydrates (V&S 743-747, 1074)

Intramolecular Aldol-type reactions (V&S 796, 805)

Intramolecular ester (Claisen) condensations are called Dieckmann condensations. These are only useful for 5- and 6-membered rings (V&S 1041).

The Robinson annulation (2nd year experiment; see also V&S 807, 1049) is a Michael reaction, followed by an aldol condensation.

In the acyloin reaction, diesters reacts with sodium in hydrocarbon solvents. Best results are obtained in the presence of Me₃SiCl. N.B. This is a reduction, not a condensation reaction like the Dieckmann. The reaction works quite well for 4-membered and, especially, medium to large rings, probably because the cyclisation step occurs at the metal surface. The McMurry reaction is a related reductive coupling of diketones. Ring closing metathesis is a recently-developed reaction involving metallocarbene intermediates. Oxidative coupling of alkynes is another way to make large rings, which was used in the classic synthesis of annulenes. In a few cases, ring closing reactions can be done around a template; thus 18-crown-6 formation occurs efficiently around a potassium ion.