The leaving groups

The better the leaving group, the faster the rate of both SN1 and SN2 reactions (as C-X bond cleavage is involved in both of the ratedetermining steps). The best leaving groups are those that form stable neutral molecules or stable anions, which are weakly basic. The less basic the anion, the more stable (or less reactive) the anion. 

All of these reactions are nucleophilic substitutions and have the same overall result— replacement of the leaving group by the nucleophile, regardless of the identity or charge of the nucleophile. To draw any nucleophilic substitution product  

Problem 7.8 identify the nucleophile and leaving group and draw the products of each reaction. 

Problem 7.9 Draw the product of nucleophilic substitution with each neutral nucleophile. When the initial substitution product can lose a proton to form a neutral product, draw that product as well. 

Nucleophilic substitution occurs with leaving groups that are weak bases. 

For example, H2O is a better leaving group than OH because H2O is a weaker base. Moreover, the periodic trends in basicity can now be used to identify periodic trends in leaving group ability  

CPC (cetylpyridinium chloride), an antiseptic found in throat lozenges and mouthwash, is synthesized by the following reaction. Draw the stmcture of CPC. 

Cepacol throat lozenges and Crest Pro-Health Mouth Rinse contain the antiseptic CPC, which is prepared by nucleophilic substitution (Problem 7.11). 

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Similar fragmentations to produce S-cyclodecen-l-ones and 1,6-cyclodecadienes have employed l-tosyloxy-4a-decalols and 5-mesyloxy-l-decalyl boranes as educts. The ringfusing carbon-carbon bond was smoothly cleaved and new n-bonds were thereby formed in the macrocycle (P.S. Wharton, 1965 J.A. Marshall, 1966). The mechanism of these reactions is probably E2, and the positions of the leaving groups determine the stereochemistry of the olefinic product. 

Two different access routes are used, whether the leaving group is carried on thiazolium derivatives such as anilinovinyl (method A), acetanilidovinyl (method B), formyl methylene, or thioformylmethylene or on the ketomethylene compound (method C). The use of acid anhydride together with pyridine has been patented (method E). 

When 5-halogeno-2-nitrothiazole reacts with methoxide ion. the leaving group is the nitro group in position 2, following Scheme 17 (86). 

Because adjacent bonds are eclipsed when the H—C—C—X unit is syn coplanar a transition state with this geometry is less stable than one that has an anti coplanar rela tionship between the proton and the leaving group... 

Use curved arrows to show the bonding changes in the reaction of CIS 4 tert butylcyclohexyl bromide with potassium tert butoxide Be sure your drawing correctly represents the spatial relationship between the leaving group and the proton that is lost... 

Because the carbon-halogen bond breaks m the slow step the rate of the reaction depends on the leaving group Alkyl iodides have the weakest carbon-halogen bond and are the most reactive alkyl fluorides have the strongest carbon-halogen bond and are the least reactive... 

What IS the structure of the transition state m an 8 2 reaction s In particular what is the spatial arrangement of the nucleophile m relation to the leaving group as reactants pass through the transition state on their way to products ... 

Two stereochemical possibilities present themselves In the pathway shown in Fig ure 8 la the nucleophile simply assumes the position occupied by the leaving group It attacks the substrate at the same face from which the leaving group departs This is called front side displacement or substitution with retention of configuration... 

In a second possibility illustrated in Figure 8 Ih the nucleophile attacks the sub state from the side opposite the bond to the leaving group This is called back side dis placement or substitution with inversion of configuration... 

FIGURE 8 1 Two contrast mg stereochemical pathways for substitution of a leaving group (red) by a nucleophile (blue) In (a) the nucleophile attacks carbon at the same side from which the leaving group departs In (b) nude ophilic attack occurs at the side opposite the bond to the leaving group... 

Once past the transition state the leaving group is expelled and carbon becomes tetracoordmate its hybridization returning to sp ... 

Stretching then breaking of the bond to the leaving group Formation of a bond to the nucleophile from the opposite side of the bond that is broken... 

We saw m Section 8 2 that the rate of nucleophilic substitution depends strongly on the leaving group—alkyl iodides are the most reactive alkyl fluorides the least In the next section we 11 see that the structure of the alkyl group can have an even greater effect... 

FIGURE 8 8 Inversion of configuration predomi nates in SnI reactions because one face of the car bocation is shielded by the leaving group (red)... 

As crowding at the carbon that bears the leaving group decreases the rate of nude ophilic attack by the Lewis base increases A low level of steric hindrance to approach of the nucleophile is one of the special circumstances that permit substitution to pre dominate and primary alkyl halides react with alkoxide bases by an 8 2 mechanism m preference to E2... 

The reactions of alcohols with hydrogen halides to give alkyl halides (Chapter 4) are nucleophilic substitution reactions of alkyloxonium ions m which water is the leaving group Primary alcohols react by an 8 2 like displacement of water from the alkyloxonium ion by halide Sec ondary and tertiary alcohols give alkyloxonium ions which form carbo cations m an S l like process Rearrangements are possible with secondary alcohols and substitution takes place with predominant but not complete inversion of configuration... 

Next in what amounts to an intramolecular Williamson ether synthesis the alkoxide oxygen attacks the carbon that bears the halide leaving group giving an epoxide As m other nucleophilic substitutions the nucleophile approaches carbon from the side oppo site the bond to the leaving group... 

Once It was established that hydroxide ion attacks the carbonyl group in basic ester hydrolysis the next question to be addressed concerned whether the reaction is concerted or involves a tetrahedral intermediate In a concerted reaction the bond to the leaving group breaks at the same time that hydroxide ion attacks the carbonyl... 

These results rule out substitution by addition-elimination because that mechanism requires the nucleophile to attach itself to the carbon from which the leaving group departs... 

The carbon that bears the leaving group and a carbon ortho to it become equiva lent m the benzyne intermediate Thus when chlorobenzene 1 is the substrate the ammo group may be introduced with equal likelihood at either position... 

Nucleophilic aromatic substitution by the elimination-addition mecha nism can lead to substitution on the same carbon that bore the leaving group or on an adjacent carbon... 

Cycloalkene (Section 5 1) A cyclic hydrocarbon characterized by a double bond between two of the nng carbons Cycloalkyne (Section 9 4) A cyclic hydrocarbon characterized by a tnple bond between two of the nng carbons Cyclohexadienyl anion (Section 23 6) The key intermediate in nucleophilic aromatic substitution by the addition-elimination mechanism It is represented by the general structure shown where Y is the nucleophile and X is the leaving group... 

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