Neighboring Group Participation

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Neighboring Group Participation

Introduction: For nucleophilic substitution reactions, neighboring group participation is defined as the introduction of a new reaction intermediate by a substituent that bonds to the reaction center. For such substitutions, neighboring group participation occurs primarily in the form of intramolecular nucleophilic attack, followed by intermolecular substitution (Figure 1).

Figure 1. Neighboring group participation in bimolecular nucleophilic substitution.

The result of this participation is the formation of a substituted product with retention of configuration, as opposed to inversion of configuration, which is typically associated with the SN2 mechanism.Hence, the mechanism of the reaction is changed.[1,2,3] In addition to affecting the stereochemical outcome of a reaction, neighboring groups can also affect the rate of reaction. If a neighboring group affects a reaction in such a way that the rate of the reaction is increased, that neighboring group is said to provide anchimeric assistance.3 The background reaction used to determine if the neighboring group is rate enhancing is usually the analogous reaction in the absence of the neighboring group. Groups: Neighboring group participation has been observed for a wide variety of substituents. In this section, a number of different examples of neighboring group participation will be presented. These examples are presented to give a general flavor of the types of groups that are usually good neighboring

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group participants. In addition to a general overview, the individual characteristics of the examples will be addressed. b-halogens (one carbon removed from the leaving group) are a very basic example of neighboring group participants, forming cyclic halonium ions with the reacting center, as shown in Figure 2. Ions of this type are known for chlorine, bromine, and iodine. Cyclic ions of this type are formed stereospecifically with inversion of configuration.2

Figure 2. Formation of a cyclic iodonium intermediate.

Similarly, sulfides, amines, alcohols, and ethers can be effective neighboring group participants. Like the halogens, these groups add stereospecifically to the reaction center.Unlike halogens, these groups do not have to be in the b-position in order to act as a neighboring group, and can therefore form cyclic intermediates of varying ring sizes (Figure 3), the kinetics of which will be discussed later. These groups almost always provide anchimeric assistance, in addition to the aforementioned retention of configuration of the products.2

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Figure 3. Amines, sulfides, ethers, and alcohols as participating neighboring groups. X=leaving group.

b-acetoxy substituents are also known to be neighboring participants, forming five-membered cyclic species by bonding through the carbonyl carbon (Figure 4).4 The existence of the acetoxonium ion (2) shown in Figure 4 has been supported by trapping experiments in ethanol to give 4.5 These trapping experiments were important in showing that the reaction was not proceeding by a classical SN1 mechanism. The reaction to produce 3 proceeds with inversion of configuration, once again yielding an overall retention of configuration.

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Figure 4. The Acetoxy group as a neighboring group participant.

In addition to substituents with lone pairs of electrons, p-bonded systems have been shown to be participating neighboring groups. b-phenyl groups form phenonium ions by donation of p-electrons (Figure 5). The phenonium ion intermediate has been supported by the stereochemistry of the final substitution products.6 The final product, after migration, like all of the previous examples, has an inverted configuration only.

Figure 5. The phenyl group as a neighboring group.

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Neighboring group participation has also been demonstrated for non-conjugated p-systems. Perhaps the most famous example of p-bond neighboring group participation is that of anti-7-norbornenyl derivatives. These derivatives were believed to participate via a bishomoaromatic p-orbital interaction (Figure 6).7 Though this interaction invokes a molecular orbital explanation (as opposed to the nucleophilic nature of the neighboring groups in previous examples), the same retention of configuration is observed in substitution products as seen with previous examples. In other words, one observes only anti-substitution with respect to the double bond.

Figure 6. Stabilization of the norbornenyl cation through p-orbital interaction.

Supporting evidence for this type of cation versus a rapidly equilibrating structure was provided by Gassman et al., who substituted one methyl group onto the double bond and showed a significant rate increase (13.3 times greater than the unsubstituted reaction) for a similar substitution reaction.When they substituted a second methyl group onto the double bond, the rate increase was almost as large as that for the first substitution (148 times greater than the unsubstituted reaction).8 Hence, the stabilization of the carbocation is
dependent on both carbons in the double bond. If the structure of the carbocation were rapidly equilibrating between the two double bonded carbons, adding the second methyl group would have shown no rate increase.

Structural and Reactivity Features: Despite the fact that neighboring group participation can result in a rate increase, the first experimental evidence that pointed out its existence was the unexpected stereochemical outcome of the reaction of hydrobromic acid with a number of bromohydrins9 (Figure 7). Essentially what

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Figure 7. Winstein's Results

was expected to be an SN2 process which occurs with inversion of stereochemistry yielded products where the nucleophile seemed to have retained the original configuration of the leaving group. In order to explain this observation, Winstein applied the same concept (Figure 8) that describes the addition of a halogen to an olefin, that is, the existence of a bridging halonium ion

Figure 8. Bromonium ion hypothesis to account for the observed stereochemistry of the dibromobutane products.

that stabilizes the developing positive charge on the neighboring carbon. Displacement of the protonated hydroxyl followed by the consequent introduction of bromide ion produces a net retention of the original configuration of the starting bromohydrin. The starting meso-bromohydrin yields meso-2,3-dibromobutane because the bridged ion presents two homotopic electrophilic sites. On the other hand, each one of the optically pure bromohydrins produces racemic final product due to the fact that the resulting bromonium cation can be opened at two enantiotopic sites. If the bridged intermediate has two diastereotopic electrophilic sites, then products where the neighboring group has migrated from its original site will be formed6,10.

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Figure 9. Rearrangements of neighboring groups.

Therefore, a noteworthy characteristic of neighboring group participation is an extended stereochemical control over displacement reactions which can be potentially utilized to achieve particular synthetic targets. An interesting structural feature that results after the neighboring group has displaced the leaving group is the intimate ion pair that results. Cram11 observed that the acetolysis of 9, when stopped before completion, yielded racemic starting material (Figure 10), a fact which proves that, once the ion pair is formed it recombines at a faster rate than the solvent can interact with it (krecom/ksolv = 4). The relevance of this result lies in the fact that the intimate ion pair can, in principle, destroy the stereochemical information of the starting material if the bridged intermediate has some degree of asymmetry (i.e. if it is enantiotopic or diastereotopic). Apart from the less subtle stereochemical effect, neighboring group participation

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Figure 10.Cram's Experiment.

can be responsible for the rate acceleration of chemical processes (anchimeric assistance) as compared to background reaction where this effect is not present as stated previously. The amount of kinetic acceleration is dependent on the system of interest and on the proximity of the neighboring group to the leaving group. However, in order to discern if neighboring group is participating through anchimeric assistance, a rate increase between five and fifty-fold with respect to the background reaction is necessary. A straightforward measure of anchimeric assistance is the ratio of the rate of the assisted process (kD) over the rate of the solvolysis reaction (ks) without a participating neighboring group12. The energetic reasons that provoke anchimeric assistance are both of a thermodynamic and a kinetic nature. An example of the former is the comparison of the

Figure 11.Anchimeric assistance in the anti-7-norbornenyl tosylate system.

relative rates of solvolysis of 7-norbornyl tosylate (10) and anti-7-norbornenyl tosylate (11). It can be argued that the rate determining step for the acetolysis of 10 is the formation of the carbocation at the 7 position after loss of tosylate. A hypothetical stabilization of the intermediate would produce an acceleration of the reaction rate by lowering of the activation energy of the rate determining step. This is what is observed when a neighboring group in the form of a double bond is introduced in the molecule and, therefore, 11 is solvolyzed 1011 times faster that the saturated analog1. Because neighboring group participation can be understood by the formation of a cyclic

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intermediate, the ring size of the intermediate formed will affect whether anchimeric assistance is provided or not. Therefore, if the formation of the intermediate is faster than the competing direct displacement or the capture of the carbocation by the nucleophile, then, the intermediate will be stabilized and the rate increased. This implies that the size of the ring formed will be directly responsible for the amount of anchimeric assistance of the neighboring group. In other words, stabilization by the neighboring group (thermodynamic acceleration of the reaction) will only happen if the ring closure is faster (kinetic factor) than solvolysis. It is also important to note that the entropy of activation of an intramolecular process is almost always going to be smaller than that of an intermolecular process. Interestingly enough, the rate of ring closure seems to depend on the nature of the neighboring group. As Tables 1 and 2 indicate, five member cyclic ammonium salts

Ring Size 3 4 5 6 7

Rate Relative to Formation of 3-Member Ring 1 0.014 833 14 0.027

Table 1: Rates of formation of cyclic ammonium salts in water at 25 C.

form more readily than any other ring size, whereas sulfonium salts seem to prefer forming three member rings. This study focused on measuring the rates of formation of the salts (the salts were the final products of the reaction). Different bond angle strain (sulfur accommodates smaller bond angles) explains this marked difference2.

Ring Size 3 4 5

Rate Relative to Formation of 3-Member Ring 1 0.0053 0.2

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6 7

0.017 0.0096

Table 2: Rate of formation of cyclic sulfonium salts in 20% auqeous dioxane at 100o C.

One of the most obvious uses of neighboring group participation comes at hand when one wishes to displace a leaving group without stereochemical inversion at the electrophilic carbon. A recent example of the use of this strategy is shown in the synthesis of 6 by Marquez et al13.

Figure 11.Marquez's Work.

The key fluorine atom at the 2' and 3' position is introduced by opening a very reactive anhydride that is obtained by treating 13 with DAST (diethyl amino sulfur trifluoride). Intermediate A is obtained after activation of the hydroxyl group by DAST, which is then displaced by one of the carbonyl functions on the uracyl moiety. Another recent example of this type of strategy comes from the work of Le Merrer et al14. The authors were interested in effecting a ring contraction on the C2 symmetrical 14 to form 15. Their

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Figure 12. Episulfonium strategy for ring contraction.

final strategy was based on the idea that the sulfur would displace the activated hydroxyl yielding an intermediate episulfonium cation. Ring opening of this structure would produce either 15 or 16 depending on the regioselectivity of the reaction.

Figure 13.Experimental results.

In practice, treatment of 17 with PPh3/CBr4 produced exclusively the desired tetrahydrothiopyran 18 in 45% yield. An 80% yield of the desired six-member ring 19 was obtained when Mitsunobu conditions (DEAD, benzoic acid) were employed. The observed products strongly suggest the intermediacy of a cationic episulfonium intermediate.

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Results: Synthesis of Novel Iso-4-thionucleosides Using the Mitsunobu Reaction In the case study by Yamada, Sakata, and Yoshimura15, the Mitsunobu reaction was used to introduce 6-chloropurine into the 2-position of 20.

Figure 14. Synthesis of Iso-4-thionucleoside.

The reaction was carried out at room temperature in various solvents. The resulting iso-4-thionucleoside (21) is thought to be a potential pharmaceutical effective against HIV. It is known that some nucleoside analogs can inhibit reverse transcriptase coded by HIV.15 b-Isonucleosides are among these analogs. For SN2-type reactions, inversion of configuration occurs at the reaction site (Product 21a, Figure 15). However, because of the participating sulfur atom, 23 is an important intermediate, and retention of configuration results (21b, 24).

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Figure 15.Possible reaction pathways of Mitsunobu reaction.

A mixture of diastereomers 21a and 21b were synthesized in poor yield. However, the thietane product (24) was not observed. It was found that using acetonitrile as a solvent produced primarily the b-isomer. NOE experiments were used to determine the stereochemistry of the reaction center.Irradiation of H-2 of 21b enhanced the H-4 by 6.5%, while irradiation of H-3 of the same compound enhanced H-8 by 2.7%.

Figure 16. NOE data for 21b.

Peak integrations calculated by 1H NMR were compared to determine the isomeric ratios of the products.

Solvent THF Benzene CH3CN CH2Cl2 DMF

% Yield 29 34 21 22 trace

b/a Ratio (21b/21a) 1.1 0.8 6 1.2 -----15

Table 3. Solvent, product yield, and isomeric ratio for Mitsunobu reaction.

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Discussion: Yamada et al. wanted to synthesize the b-isomer (21b) by taking advantage of neighboring group participation. In a previous paper, the same reaction was tried, but diphenylphosphoryl azide was used as the nucleophile (same mechanism as in Figure 15, except Nu- = N3-).16In this reaction, however, only the SN2 product was obtained, because the substitution reaction was faster than the formation of the episulfonium cation.This is due to the ring strain that is produced upon the formation of the intermediate. The reason why the Yamada et al. were able to synthesize 21b in the case study was because 6-chloropurine is a weak nucleophile, slowing the rate of bimolecular substitution. Also, the thietane product 24 was not formed because it is less thermodynamically stable than 21b. Another peculiarity about the case study reaction was the effect of solvent polarity on the isomeric ratio of products. In nonpolar solvents, thea-isomer was the predominant product. However, in more polar solvents the isomeric ratio favors the b-isomer. In acetonitrile, the b-isomer was obtained in the greatest yield. Polar solvents increase the formation of the b-isomer because they help stabilize the episulfonium cation intermediate (23). This stabilization favors sulfur to act as a participating neighboring group. Conclusion: Neighboring group participation is a useful tool for synthetic chemists.In SN2 reactions, retention of configuration of the reaction center can be obtained instead of the expected inversion of configuration.Also, if the neighboring group helps stabilize the intermediate produced in the rate determining step, rate acceleration occurs (anchimeric assistance). Many nucleophilic substituents are able to participate in this way. Examples of these substituents include b-halogens, sulfides, amines, alcohols, ethers, and p-bonded systems. In the case study, the effects of solvent polarity on the competition between neighboring group participation and SN2 direct substitution were addressed. It was observed that polar solvents increased neighboring group participation. Use of polar solvents seemed to help stabilized the cyclic cation intermediate.Also, the strength of the nucleophile was found to affect the reaction outcome. When strong nucleophiles were used, only direct substitution was observed.This is because the rate of direct substitution is greater than the rate of episulfonium cation formation. References: 1.Capon, B. Neighboring Group Participation. Q. Rev. Chem. Soc. 1964, 18, 45-111. 2.Miller, B. Advanced Organic Chemistry: Reactions and Mechanisms. Prentice Hall: Upper Saddle River, NJ, 1998. 3.Capon, B.; McManus, S. P.Neighboring Group Participation. Vol. 1.Plenum Press: New York and

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London, 1976. 4.Winstein, S.; Hanson, C.; Grunwald, E. The Role of Neighboring Groups in Replacement Reactions.X. Kinetics of Solvolysis of trans-2-Acetoxycyclohexyl p-Toluenesulfonate. J. Am. Chem. Soc. 1948, 70, 812-816 5.Winstein, S.; Buckles, R. E.The Role of Neighboring Groups in Replacement Reactions. VI.Cyclohexene ethyl orthoacetate. J. Am. Chem. Soc. 1943, 65, 613-618. 6.Heck, R.; Winstein, S.Neighboring Carbon and Hydrogen.XXIX. r-s Analysis of Acetolysis of Substituted Neophyl Arylsulfonates. J. Am. Chem. Soc. 1957, 79, 3432-3438. 7.Brookhart, M.; Diaz, A.; Winstein, S. Structure of the Nonclassical 7-Norbornenyl Cation. J. Am. Chem. Soc. 1966, 88, 3135-3136. 8.Gassman, P. G.; Patton, D. S.Evidence for the Symmetrical Nature of the 7-Norbornenyl Cation. J. Am. Chem. Soc. 1969, 91, 2160-2162. 9.Winstein, S.; Lucas, H. J.Retention of Configuration in the Reaction of the 3-Bromo-2-butanols with Hydrogen Bromide. J. Am. Chem. Soc. 1939, 61, 1576-1581. 10.Fuson, R. C.; Zirkle, C. L.Ring Enlargement by Rearrangement of the 1,2-Aminochloralkyl group; Rearrangement of 1-ethyl-2-chloromethyl pyrolidine to 1-ethyl-2-chloro piperidine. J. Am. Chem. Soc. 1948, 70, 2760-2765. 11.Cram, D. J. Studies in Stereochemistry. V. Phenonium Sulfate Ion-Pairs as Intermediates in the Intramolecular Rearrangements and Solvolysis Reactions that Occur in the 3-Phenyl-2-butanol System. J. Am. Chem. Soc. 1952, 74, 2129-2137. 12.Winstein, S.; Shatanovsky, M.; Norton, C.; Woodward, R. B. 7-Norbornenyl and 7-Norbornnyl Cations. J. Am. Chem. Soc. 1955, 77, 4183-4184. 13.Jeong, L. S.; Nicklaus, M. C.; George, C.; Marquez, V. E. Facile Fluorination of Deoxy-4-thipyrimidine Nucleosides with Down Hydroxyl Groups.Retention of Configuration After Fluoride Opening of the Quaternized N3-MEM Anhydronucleosides. Tetrahedron Lett. 1994, 35, 7573-7576. 14.Fuzier, M.; Merrer, Y. L.; Depezay, J. Thiosugars From D-Mannitol. Tetrahedron Lett. 1995, 36, 6443-6446. 15.Yamada, K.; Sakata, S.; Yoshimura, Y. Synthesis of Novel Iso-4-thionucleosides Using the Mitsunobu Reaction. J. Org. Chem. 1998, 63, 6891-6899. 16.Yoshimura, Y.; Kitano, K.; Satoh, H.; Watanabe, M.; Miura, S.; Sakata, S.; Sasaki, T.; Matsuda, A. A Novel Synthesis of 2-Modified 2-Deoxy-4-thiocytidines from D-Glucose. J. Org. Chem.1997, 62, 3140-3152. Questions: 1. Nagano and Akita (Tetrahedron Lett. 1998, 39,8109-8112) observed an unexpected product outcome when treating 1 with SiO2 in hexanes. Propose a reasonable mechanism for the formation of 2, draw out the key intermediate and explain the selectivity of the reaction.

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Answer: The observed product distribution can be rationalized through the intermediacy of a phenonium ion (3), resulting from the neighboring group participation of the electron rich phenyl group. After hydrolysis of the ester, the observed g lactone (2) forms preferentially to the d lactone (4) due to the expected attack of the carboxylate on the more stable secondary carbocation.

2. Popsavin et al (Tetrahedron Lett. 1999, 40, 3629-3632) treated 1 with lithium benzoate and obtained 2 as an unexpected product. Propose a mechanism for this conversion.

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Answer:

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