On SnI reactions

Benzene rings have a dramatic effect on SnI reaction rates. This depends on the position of the ring relative to the leaving group. Consider the following reactions. 

Table 10.2 Some 2° deuterium isotope effects mostly on SnI reactions (a) Acetolyses of deuterated cyclopentyl tosylates at 50 °Ca...

While increasing anion solvation by protic solvents has an accelerating effect on SnI reactions as described above, it is often a decelerating factor in Sn2 reactions. Thus, reaction (5-103) between (iodomethyl)benzene and radioactively labeled sodium iodide in acetone is clearly decelerated by the addition of protic solvents such as water, ethanol or phenol, as demonstrated in Fig. 5-16 [266]. 

What about solvent Do solvents have the same effect in S l reactions that they have in 8 2 reactions The answer is both yes and no. Yes, solvents have a large effect on SnI reactions, but no, the reasons for the effects are not the same. Solvent effects in the S 2 reaction are due largely to stabilization or destabilization of the nucleophile reSolvent effects in the S -l reaction, however, are due largely to stabilization or destabilization of the transition state. 

The rates of Sn2 reactions correlate well with relative nucleophilicities, because the nucleophile is intimately involved in the rate-determining step. In SnI reactions, the nucleophile is involved after the rate-determining step. Furthermore, the product ratios observed for Sn 1 reactions, when more than one nucleophile is present, do not correlate very well with relative nucleophilicities. This is because reactions with very unstable intermediates, such as carbenium ions, are not selective (see the reactivity-selectivity principle in Chapter 7). They occur at close to diffusion controlled rates. Therefore, in the following discussion, little needs to be said about the influence of the nucleophile on SnI reactions. Instead, our focus is on Sn2 reactions. 

D Solvent Effects on SnI Reactions The Ionizing Ability of the Solvent... 

The effects on SnI reactions of the four variables—substrate, leaving group, nucleophile, and solvent—are summarized in the following statements ... 

Functional group transfonrrations that rely on substitution by the SnI mechanism are not as generally applicable as those of the Sn2 type. Hindered substrates are prone to elimination, and reanangement is possible when carbocation intennediates are involved. Only in cases in which elimination is impossible are SnI reactions used for functional group transfonnations. 

For each reaction, plot energy (vertical axis) vs. the number of the structure in the overall sequence (horizontal axis). Do reactions that share the same mechanistic label also share similar reaction energy diagrams How many barriers separate the reactants and products in an Sn2 reaction In an SnI reaction Based on your observations, draw a step-by-step mechanism for each reaction using curved arrows () to show electron movements. The drawing for each step should show the reactants and products for that step and curved arrows needed for that step only. Do not draw transition states, and do not combine arrows for different steps. 

When a molecule has in an allylic position a nucleofuge capable of giving the SnI reaction, it is possible for the nucleophile to attack at the y position instead of the a position. This is called the SnI mechanism and has been demonstrated on 2-buten-l-ol and 3-buten-2-ol, both of which gave 100% allylic rearrangement when treated... 

For some tertiary substrates, the rate of SnI reactions is greatly increased by the relief of B strain in the formation of the carbocation (see p. 366). Except where B strain is involved, P branching has little effect on the SnI mechanism, except that carbocations with P branching undergo rearrangements readily. Of course, isobutyl and neopentyl are primary substrates, and for this reason they react very slowly by the SnI mechanism, but not more slowly than the corresponding ethyl or propyl compounds. 

No matter how produced, RN2 are usually too unstable to be isolable, reacting presumably by the SnI or Sn2 mechanism. Actually, the exact mechanisms are in doubt because the rate laws, stereochemistry, and products have proved difficult to interpret. If there are free carbocations, they should give the same ratio of substitution to elimination to rearrangements, and so on, as carbocations generated in other SnI reactions, but they often do not. Hot carbocations (unsolvated and/or chemically activated) that can hold their configuration have been postulated, as have ion pairs, in which OH (or OAc , etc., depending on how the diazonium ion is generated) is the coun-... 

The SnI reactions do not proceed at bridgehead carbons in [2.2.1] bicyclic systems (p. 397) because planar carbocations cannot form at these carbons. However, carbanions not stabilized by resonance are probably not planar SeI reactions should readily occur with this type of substrate. This is the case. Indeed, the question of carbanion stracture is intimately tied into the problem of the stereochemistry of the SeI reaction. If a carbanion is planar, racemization should occur. If it is pyramidal and can hold its structure, the result should be retention of configuration. On the other hand, even a pyramidal carbanion will give racemization if it cannot hold its structure, that is, if there is pyramidal inversion as with amines (p. 129). Unfortunately, the only carbanions that can be studied easily are those stabilized by resonance, which makes them planar, as expected (p. 233). For simple alkyl carbanions, the main approach to determining structure has been to study the stereochemistry of SeI reactions rather than the other way around. What is found is almost always racemization. Whether this is caused by planar carbanions or by oscillating pyramidal carbanions is not known. In either case, racemization occurs whenever a carbanion is completely free or is symmetrically solvated. 

In type A, the adduct loses water (or, in the case of addition to C=NH, ammonia, etc.), and the net result of the reaction is the substitution of C=Y for C=0 (or C= NH, etc.). In type B, there is a rapid substitution, and the OH (or NH2, etc.) is replaced by another group Z, which is often another YH moiety. This substitution is in most cases nucleophilic, since Y usually has an unshared pair and SnI reactions occur very well on this type of compound (see p. 434), even when the leaving group is as poor as OH or NH2. In this chapter, we shall classify reactions according to what is initially adding to the carbon-hetero multiple bond, even if subsequent reactions take place so rapidly that it is not possible to isolate the initial adduct. 

Effect of Solvent on Elimination versus Substitution. Increasing polarity of solvent favors Sn2 reactions at the expense of E2. In the classical example, alcoholic KOH is used to effect elimination, while the more polar aqueous KOH is used for substitution. Charge-dispersal discussions, similar to those on page 450, only partially explain this. In most solvents, SnI reactions are favored over El. The El reactions compete best in polar solvents that are poor nucleophiles, especially dipolar aprotic solvents" A study made in the gas phase, where there is no solvent, has shown that when 1-bromopropane reacts with MeO only elimination takes place no substitution even with this primary substrate." ... 

There will be many times in the second half of this course when you will be trying to determine which way a reaction will proceed from two possible outcomes. Many times, you will choose one outcome, because the other outcome has steric problems to overcome (the geometry of the molecules does not permit the reactive sites to get close together). In fact, you will learn to make decisions like this as soon as you learn your first reactions Sn2 versus SnI reactions. Now that we know why geometry is so important, we need to brush up on some basic concepts. 

Finally we learned that if we analyze the first factor (substrate), we will find two effects at play electroiucs and sterics. We saw that Sn2 reactions require primary or secondary substrates because of sterics—it is too crowded for the nucleophile to attack a tertiary substrate. On the other hand, SnI reactions did not have a problem with sterics, but electronics was a bigger issue. Tertiary was the best, because the alkyl groups were needed to stabilize the carbocation. 

For now, let s consider the effect of the substrate on the rate of an El process. The rate is fonnd to be very sensitive to the nature of the starting aUcyl halide, with tertiary halides reacting more readily than secondary halides and primary halides generally do not nndergo El reactions. This trend is identical to the trend we saw for SnI reactions, and the reason for the trend is the same as well. Specihcally, the rate-determining step of the mechanism involves formation of a carbocation intermediate, so the rate of the reaction will be dependent on the stability of the carbocation (recall that tertiary carbocations are more stable than secondary carbocations). 

Substitutions are very common synthetic reactions by their very nature they produce at least two products, one of which is commonly not wanted. As a simple example 2-chloro-2-methylpropane can be prepared in high yield by simply mixing 2-methylpropan-2-ol with concentrated hydrochloric acid (Scheme 1.10). Here the hydroxyl group on the alcohol is substituted by a chloride group in a facile SnI reaction. Whilst the byproduct in this particular reaction is only water it does reduce the atom economy to 83%. 

Phosphate esters have a variety of mechanistic paths for hydrolysis. Both C-O and P-0 cleavage are possible depending on the situation. A phosphate monoanion is a reasonable leaving group for nucleophilic substitution at carbon and so 8 2 or SnI reactions of neutral phosphate esters are well known. PO cleavage can occur by associative (by way of a pentacoordinate intermediate), dissociative (by way of a metaphosphate species), or concerted (avoiding both of these intermediates) mechanisms. 

GH Theory was originally developed to describe chemical reactions in solution involving a classical nuclear solute reactive coordinate x. The identity of x will depend of course on the reaction type, i.e., it will be a separation coordinate in an SnI unimolecular ionization and an asymmetric stretch in anSN2 displacement reaction. To begin our considerations, we can picture a reaction free energy profile in the solute reactive coordinate x calculated via the potential of mean force Geq(x) -the system free energy when the system is equilibrated at each fixed value of x, which would be the output of e.g. equilibrium Monte Carlo or Molecular Dynamics calculations [25] or equilibrium integral equation methods [26], Attention then focusses on the barrier top in this profile, located at x. ... 

This reaction proceeds via the transition state illustrated in Fig. 10.2. An Sn2 reaction (second order nucleophilic substitution) in the rate limiting step involves the attack of the nucleophilic reagent on the rear of the (usually carbon) atom to which the leaving group is attached. The rate is thus proportional to both the concentration of nucleophile and substrate and is therefore second order. On the other hand, in an SnI reaction the rate limiting step ordinarily involves the first order formation of an active intermediate (a carbonium ion or partial carbonium ion, for example,) followed by a much more rapid conversion to product. A sampling of a and 3 2° deuterium isotope effects on some SnI and Sn2 solvolysis reactions (i.e. a reaction between the substrate and the solvent medium) is shown in Table 10.2. The... 

The first-order nature of this reaction reminds us that rate-limiting hydroxide attack on tcrt-butylbromide is not a feature of this SnI reaction. 

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