SN2 Mechanism Backside Attack

Waiden inversion typicaiiy resuits in inversion of configuration 

Introduction to Strategies for Organic Synthesis, First Edition. Laurie S. Starkey. 2012 John Wiley Sons, Inc. Published 2012 by John Wiley Sons, Inc. 

Another interesting example of an inversion reaction is the Mitsunobu reaction, which displaces a hydroxyl with a carboxylate group. Reaction of a chiral alcohol with triphenylphosphine and diethyl azodicarboxylate (PhsP, DEAD) in the presence of a carboxylic acid results in the formation of a good leaving group followed by the Sn2 replacement of that group by the carboxylate nucleophile to give an ester product with an inverted stereochemistry. 

---

Int-A leads to the product A, when the bromonium ion is attacked by bromide at the more substituted, and therefore more electrophilic carbon with an Sn2 mechanism (backside attack results in trans bromines). The same mechanism gives rise to product B from Int-B. Since the intermediates are formed in unequal amounts, the diastereomeric products are also expected to be formed in unequal amounts. 

In reaction (a), cyanide ion, CN , is a good nucleophile (Table 6-7), and acetone is a polar aprotic solvent, a combination that favors the Sn2 mechanism. Backside attack occurs, leading to inversion at the site of displacement (see Figure 6-4). 

Backside attack of the nucleophile suggests an Sn2 mechanism, but attack at the more substituted carbon suggests an S l mechanism. To explain these results, the mechanism of nucleophilic attack is thought to be somewhere in between Sis l and Sis 2. 

Sn2 stands for substitution nucleophilic bimolecular. The lUPAC designation (p. 384) is AnDn- In this mechanism there is backside attack The nucleophile approaches the substrate from a position 180° away from the leaving group. The reaction is a one-step process with no intermediate (see, however, pp. 392-393 and 400). The C—Y bond is formed as the C—X bond is broken ... 

C X bond, but not from B because only the has such an orbital. If the intermediate is in conformation B, the OR may leave (if X has a lone-pair orbital in the proper position) rather than X. This factor is called stereoelectwnic control Of course, there is free rotation in acyclic intermediates, and many conformations are possible, but some are preferred, and cleavage reactions may take place faster than rotation, so stereoelectronic control can be a factor in some situations. Much evidence has been presented for this concept. More generally, the term stereoelectronic effects refers to any case in which orbital position requirements affect the course of a reaction. The backside attack in the Sn2 mechanism is an example of a stereoelectronic effect. 

When a sulfonate ester possessing this type of chirality was converted to a sulfone with a Grignard reagent (10-129), inversion of configuration was found. This is not incompatible with an intermediate such as 147 but it is also in good accord with an Sn2 like mechanism with backside attack. 

Ladhams-Zieba (2004) has demonstrated that university students working on reaction mechanisms in organic chemistry also operate on the drawings on the page, rather than on what they represent. She asked 18 second year university students to predict and draw the product species most likely to be produced from the substitution reaction of hydroxide ion into 2 bromobutane, represented as in Fig. 1.13(a). Ten of them drew the inverted substitution product that you might expect from backside attack in an Sn2 reaction (Fig. 1.13(b)). 

Figure 7. Top The formation of heterodimer 6-7 from softballs 6 6 and 7-7. Bottom Two SN2-like window" mechanisms for guest exchange in the softballs. Attack in an approximate 90°C angle between incoming and leaving guest is favored over backside attack energetically - only ten instead of twelve hydrogen bonds are broken - and entropically - statistically, there are four ways to open two vicinal windows, but only two ways to open windows opposite to each other.

Many theories have been put forward to explain the mechanism of inversion. According to the accepted Hugles, Ingold theory aliphatic nucleophilic substitution reactions occur eigher by SN2 or SN1 mechanism. In the SN2 mechanism the backside attack reduces electrostatic repulsion in the transition state to a minimum when the leaving meleophile leaves the asymmetric carbon, naturally an inversion of configuration occurs at the central carbon atom. 

The fluorines in fluorinated C60 can be displaced by a variety of nucleophiles. Furthermore, fluorinated C60 derivatives are likely to be synthetically useful because they are both more reactive, and more soluble than other halogenated derivatives (Taylor et al. 19925). They thus react readily with water, which negates their use as lubricants (Taylor et al. 1992 a). Mass spectrometry indicates that the products contain numerous hydroxy groups and epoxide links (probably from elimination of either HF or H20 from adjacent groups). An addition-elimination mechanism is probably involved since the normal SN2 process is ruled out because backside attack (Taylor et al. 19926) is impossible. 

The 1° alkyl tosylate and the strong, unhindered nucleophile both favor substitution by an Sn2 mechanism, which proceeds by backside attack, resulting in inversion of configuration at the stereogenic center. 

Although backside attack of the nucleophile suggests that this reaction follows an Sn2 mechanism, the regioselectivity of the reaction with unsymmetrical epoxides does not. 

A third mechanism for substitution at C(sp3)-X bonds under basic conditions, elimination-addition, is occasionally seen. The stereochemical outcome of the substitution reaction shown in the figure tells us that a direct Sn2 substitution is not occurring. Two sequential Sn2 reactions would explain the retention of stereochemistry, but the problem with this explanation is that backside attack of MeO- on the extremely hindered top face of the bromide is simply not reasonable. The SrnI mechanism can also be ruled out, as the first-row, localized nucleophile MeO- and the 2° alkyl halide are unlikely substrates for such a mechanism. 

The SnV(7 mechanism is a logical analogue of the Sn2 reaction at saturated carbon that occurs via backside attack of the nucleophile, but it has long been rejected as a feasible pathway on the basis of steric considerations and of early theoretical calculations on a rather crude model system. However, quite recently definite examples of a reactions have been found, and recent theoretical studies show that the SnVo- as well as the SnVtt mechanism is feasible. If imbalance of bond formation and bond cleavage occurs, the dissociative extreme of... 

Even though 1°, the neopentyl carbon is hindered to backside attack, so SN2 cannot occur easily. Instead, an SN1 mechanism occurs, with rearrangement. 

Another way of looking at this, which explains why anti-elimination is preferred from the antiperiplanar conformation, is that the electron pair from the breaking C—H bond displaces the bromide anion by backside attack. This keeps the incoming electrons and the outgoing electrons as far apart as possible. Just as backside attack by a nucleophile is favoured in the Sn2 mechanism, so backside displacement of the leaving group is favoured in the E2 elimination... 

While the retrosynthesis of a thioether should still take into consideration the more favorable, less hindered Sn2 mechanism, it is possible to do a backside attack of RS on a secondary alkyl halide to synthesize a sterically crowded thioether. A symmetrical thioether or cyclic ether can be prepared via sequential Sn2 displacements of two halides with sodium sulfide (Na2S). 

---