Problem+13

//(C) Miguel E. Alonso Amelot - 2016//


**Before you start**

===You may wish to learn that Cyclopropanes (cps) are unique in many senses and thus open to surprising reactions and odd mechanisms. When two or more cps are fused as this particular reaction illustrates (Scheme 0), things go a bit over the edge [Meijere et al., 2006]. Strain energy is just one driving force, of course, the best example of which is the failed synthesis of the long sought perfect tetrahedron, or tetrahedrane. The synthetic challenge was undertaken by several people since the 70’s and 80’s with great ingenuity.===

===There was some manner of success as far as //substituted tetrahedrane// (e.g. **3**)//.// (Please take due note that I have depicted tetrahedrane in Scheme 1 using the same point of view of starting material **1** of Scheme 0. To clear things a bit I ignored the southern portion of the molecule and other distracting substituents on cps and adding just one C-C bond to complete tetrahedrane). Despite efforts to zero in on tetrahedrane, the parent hydrocarbon remaines elusive [For a delightful review about polyhedrane synthesis and a bit of Greel philosophy, read Prof Leo Paquete’s paper (1982)- see ref list below. Yes, there was excellent chemistry then]===

===The first synthesis of a tetrahedrane relative was achieved by means of the low temperature photolysis of dilithium acetylide (**4**). The oddly looking tetralithiotetrahedrane (**5**) with a Li atom on every carbon (suggesting a tetracarbanion) was characterized as the direct product of this photolysis but stubbornly resisted the obvious alkylation with methyl iodide or protonation to tetrahedrane. Theoretical calculations put **5** at an energy minimum although above **6**. But the activation energy barrier between them cannot be surmounted without the reaction going astray. Other experiments showed tetrahedrane to be an unstable intermediate in reaction conditions required for its synthesis.=== ===The tetrakis-(trimethylsilyl)-tetrahedrane and several other substituted tetrahedranes have been obtained in a flask. Interestingly, this compound was stable up to 300 ºC. Theoretical calculations (B3LYP/6-31G(d) level for those among you who are familiar with this terminology) determined that the bulky substituents stabilize tetrahedrane by 76.6 kcal mol-1, a remarkable result considering that benzene is stabilized by 60 kcal mol-1 by aromatization.===

=SCHEME 1=

=== This does not mean that the C-Li bond is totally unreactive in cps. In can perfectly well undergo alkylation against carbon electrophiles in a S N 2 fashion, something to keep in mind while solving problem 13 and others. Scheme 2 portrays an example of a double alkylation reaction [Stulgies et al. 2005]. Importantly, this sequence shows you two important principles: ===

2.- This C-Li bond has enough carbanion character to perform as a nucleophile, as in **7**→ **8**
===The reaction is conceptually simple (SN2 and intramolecular SN2 in tandem) in spite of the confusion created by the apparently twisted structure. ===

SCHEME 2


===**Hint # 1**: As one counts the number of carbons in **1** and **2**, one realizes that there is one more carbon in **2**. Where from? MeBr of course, you would be quick to assert since there is no other carbon source around. Well, not exactly. MeLi is there too, an excellent Nu with two halide sites to attack in **1**. So, what is MeBr for? One cannot say much at this point except that we either have MeBr (requiring an anion derived from 1) adding this methyl as electrophile, or MeLi (requiring a leaving group to introduce this Me. Keep in mind that in highly strained systems like fused cps, cleaving a C-C bond via an SN2 attack of Me(-) from MeLi is another manner of adding a Me.===

===To follow this lead, let us tag carbons first in 2 and then pinpoint a given carbon, usually the predictably less likely to undergo any transformation, in 1 and 2. Build the rest of carbon tags from there. Let’s draw a line as a time out call while you elaborate further the reaction in Scheme 0 from these suggestions.===


 * SOLVING THE PROBLEM: A FIRST ATTEMPT (PLAN A)**

===Perhaps it is a lot easier to earmark carbons in 2 and look fr those carbons in 1 rather than the contrary. The hope is to identify new bonds and those that get cleaved, in addition to the identity of the new methyl group we expect in **2**.===

SCHEME 3


**As far as translating these numbers to** ** 1, ** **one gets a helpful handle in the methylene string C** **5** **-C** **6** **-C** **7** **, (red circles in Scheme 3) assuming that these methylenes are the least prone to react.** ===Then, there’s C1 next to C7 and C8 just beyond if one follows the principle of the least number of C-C bond changes (see my book shown in the home page of this wiki to know more about this). This implies a reductive elimination of Cl with simultaneous C-C bond cleavage in the vicinal cp to account for the terminal C=C. At least in principle.===

Turning our attention to the western end of **2**, one may be able to spot C4, C3 and methyl C10 without much trouble (green oval)
===Only C2 and C9 were left out. Being a methyl, the latter is bound to be the extra methyl incorporated at some intermediary stage from **1** to **2**, whereas C2 might as well be the C-Br unit of **2**, but it is perhaps to soon to be sure. If not, other carbons may also have been tagged the wrong way but again, we cannot say much.===


 * //MOVING FORWARD FROM THIS PLAN A.//**

===1.- Activation of **1** by MeLi takes place in the spirit of MeLi acting as a Nu on a halide. We have two to chose from; Br and Cl. While Br is more reactive, Cl is more exposed (on a primary C) and is not part of **2** anyway. The organolithium or C(-) equivalent should create the terminal C=C bond we are after.===

===Plan A as described should move along self-explanatory Scheme 4. Take due note that **1** contains a 6-membered ring (red bonds) reminiscent of the cyclohexyl unit of **2**. All one needs is to cleave the cp C-C bond facing the observer (heavy black line).===

SCHEME 4


=== The reaction sequence seems devoid of serious error or unsound chemical reasoning. If anything at all looks out of the ordinary is transient structure ** 12 **. Mind, however, that bromine can expand its valence shell (fluorine would not be able to do this but all other halogens would) and can accommodate the additional C-Br bonding electrons, developing a (-) charge, of course. Bromine is electronegative and large enough to support this charge. This is equivalent to a [1,2]-Br suprafacial shift, the anion way (why should it be always the topic bromonium ion involved?). Be reminded that restrictions of the Woodward-Hoffmann rules, which would allow this shift for anions in an impossible antarafacial manner, do not apply to third row elements such as bromine and heavier ones. ===

===There is one difficulty, though. As shown, Scheme 4 should yield only one stereoisomer of **2**. But authors Alber & Szeimies contend that a mixture of enantiomers is obtained as shown in Scheme 0. Thus, the suprafacial bromide shift, which furnishes one stereoisomer only, must be superseded by another pathway allowing the two stereoisomers or at least the opposite one in competition with the sequence of Scheme 4.===

A SECOND OPTION. PLAN B
===At this point in the problem, let us see what authors Alber & Szeimies propose. A different mechanism, of course, one based on the earlier discovery of the reaction by Wiberg and coworkers years before [Wiberg et al., 1993] (Scheme 5). In this particular case the intermediate was trapped with benzenethiol. A shed of inspiration for the mechanism can be found in Scheme 2 above.===

SCHEME 5


===The mechanism of this reaction, quite a challenge by itself, is worth the effort as there is fascinating and novel (at that time) cp-chemistry in it. For your perusal, Scheme 6 shows the answer. Once you have understood it, you can now apply part of this mechanism to explain **1 →** **2**. It only takes replacing benzenethiol for MeLi as nucleophile acting on the bridgehead carbon of the preposterously strained tricycle[2.2.0.0] pentane (**19**). ===

===For those of you who still need a pull, the bottom part of Scheme 6 depicts this mechanism In a non-radical manner as applied to **1.** It will be instructive if you spare some time to check Wiberg 1993 JACS paper for interesting details. ===

SCHEME 6
 

===There is one remaining problem, a serious one: In the end product of this sequence (**2**), preferred by authors of this paper, the angular methyl (marked in red in Scheme 6, bottom) is beta, above the plane of the ring rather than alpha. There is no way to epimerize this quaternary carbon. Authors offer no comment. Take note that scheme 4 does give the correct stereoisomer save for the enantiomeric form of C3 (at C-Br in **2**). ===

WHAT HAVE YOU LEARNED HERE?
===It is always a good idea to jot down what you harvest from solving each problem. This is personal endeavor as it goes with whatever each problem solver knows about good chemistry. Here are just a couple of suggestions: ===


 * 1) ===1. Fused cyclopropanes are perfectly feasible structures. Complex cage-type compounds including two or more cps have been synthesized successfully ===
 * 2) ===2. Certain C-H bonds in fused cps, particularly angular protons, can be activated as anions or as C-Li derivatives, open to alkylation reactions ===
 * 3) ===3. These anions or Li equivalents are capable of intramolecular reactions adding more cps to the fused system. ===
 * 4) ===4. Ring strain is extreme. Small temperature changes, as low as 5 ºC (e.g. from -55 to -50 ºC), can rigger ring opening, usually homolytic, to give diradical intermediates. These intermediates may be degenerate energetically with the parent fused cp system (e.g. **19** ** D ****<span style="font-family: Arial,sans-serif;"> 20 **<span style="font-family: Arial,sans-serif;">, but more reactive as shown in Scheme 6 with thiophenol in the radical sense. ===
 * 5) ===<span style="font-family: Arial,sans-serif;">5. Some mechanisms involving oligofused cps defy classical principles of carbon chemistry. The true fact is that the MO and FOMO (frontier orbital MO) theories and theoretical treatment of fused cps are not yet mature enough to give as clear a picture as larger carbocycles. ===

===<span style="font-family: Arial,sans-serif; font-size: 11pt;">Finally, most problems in reaction mechanisms allow more than one solution, as we have shown here once again. Self complacency after just one solution is not a good idea if one wants to put wits on the fray and become a successful researcher in the future. ===

<span style="font-family: Arial,sans-serif; font-size: 11pt;">Prof. M. E. Alonso-Amelot - 2016