Baldwin Rules
I recently had a revelation about the targets I’m trying to synthesize. While I’m surprised no one (in our group) ever picked up on the possibility, it occurred to me that the compounds I’m preparing could cyclize given the surrounding functionality. As such, I went crawling through my old physical organic notes and started rereading the section on Baldwin’s rules. However, this concept is not to be confused with the Baldwin Hypothesis—formulated by a couple of theatre geeks at Assumption (myself included)—which states that the incorporation of any Baldwin brother into a movie or television series (other than Alec) will devalue the overall premise or plot ten-fold (case in point, the X-Files).
Rather (to the uninitiated), Baldwin’s rules/suggestions are guidelines governing the tendency for substrates to cyclize based off of thermodynamic and electronic considerations. In other words, there are certain conditions (functional groups, orbital geometry, electron flow) that will cause a substrate to cyclize if given the opportunity—sufficient reactivity. In the mid to late 70’s, Jack Baldwin and co-workers published observations from intramolecular conjugate additions of oxygen nucleophiles resulting in cyclizations (J. Org. Chem.1977, 42, 3846-3852). Ultimately they concluded the following:
“There are substantial differences in the ease of nucleophilic ring closures, strongly dependent on ring size, geometry of reacting terminus, and the endo or exo nature of the reactions.”
March’s Advanced Organic Chemistry 6th edition (specifically p. 306) does a good job outlining the basic guidelines of such a phenomenon. The suggestions for cyclization are spelled out for sp (digonal), sp2 (trigonal) and sp3 (tetrahedral) hybrids based on the flow of electrons—in the ring (endo) or outside the ring (exo). Specifically (for you underpaid, overworked grad students):
Tetrahedral systems: 3—7-exo-tet cyclizations are favored whereas 5—6-endo-tet are not.
Trigonal systems: 3—7-exo and 6—7-endo-trig are favored whereas 3—5-endo-trig are not.
Digonal systems: 5—7-exo and 3—7-endo-dig are favored whereas 3—4-exo-dig are not.
Of course, with any physical organic concept, there are exceptions to this rule (see: J. Am. Chem. Soc. 1985, 107, 1778-1781; Tetrahedron Letters 1985, 26, 4455-4458; Science1993, 259, 490-493; Chemical Communications 2007, 2698-2700). The common thread in the entirety of Baldwin’s suggestions is proper alignment of the orbitals (geometrically) in the transition state. If the orbitals cannot align, the system has less of a chance to undergo cyclization (Alder had a fantastic set of notes that adequately bridges the gap between electronics and synthesis; Baldwin’s rules are ~1/2 down the page).
As in many cases, the challenge lies not in utility but, rather, in control. Often, this implies altering functional groups (sorry Phil Barran) or limiting your synthetic route or (my personal favorite) coming up with a brand-new, creative way to skin the proverbial cat. My next endeavor: a search for a Mitsunobu inversion-type reaction that generates less waste than the common method. Any suggestions?
P.S. This server (though free) is beginning to annoy me. Font colors are spontaneously changing, images are difficult to upload (I had a great graphic to insert into this post), and it tends to crash at odd hours (it screwed up Safari–my browser to all you PC people–last night). As such, I might be switching in the near future. I apologize for any inconveniences. Go Sox.
