Neighboring Group Participation

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Neighboring Group Participation

Neighboring group participation - unseen cyclizations and their effect on reactions at sites withneighboring electron-rich groups: Yamada, K.; Sakata, S.; Yoshimura, Y. "Synthesis of Novel Iso-4'-thionucleosides Using the Mitsunobu Reaction".J. Org. Chem. 1998, 63, 6891-6899.

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 isincreased, 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

hboring Group Participation http://euch6f.chem.emory.edu/neighbo

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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 formcyclic 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 trappingexperiments 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 ofanti-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 byGassman et al., who substituted one methyl group onto the double bond and showed a significant rateincrease (13.3 times greater than the unsubstituted reaction) for a similar substitution reaction.When theysubstituted 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 isdependent 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 firstexperimental 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 explainthis observation, Winstein applied the same concept (Figure 8) that describes the addition of a halogen to anolefin, that is, the existence of a bridging halonium ion

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

that stabilizes the developing positive charge on the neighboring carbon. Displacement of the protonatedhydroxyl followed by the consequent introduction of bromide ion produces a net retention of the originalconfiguration of the starting bromohydrin. The starting meso-bromohydrin yields meso-2,3-dibromobutanebecause the bridged ion presents two homotopic electrophilic sites. On the other hand, each one of theoptically pure bromohydrins produces racemic final product due to the fact that the resulting bromoniumcation 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 extendedstereochemical control over displacement reactions which can be potentially utilized to achieve particularsynthetic 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 of9, when stoppedbefore 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 ofthis result lies in the fact that the intimate ion pair can, in principle, destroy the stereochemical information ofthe starting material if the bridged intermediate has some degree of asymmetry (i.e. if it is enantiotopic ordiastereotopic). 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 accelerationis 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 rateincrease between five and fifty-fold with respect to the background reaction is necessary. A straightforwardmeasure of anchimeric assistance is the ratio of the rate of the assisted process (k

D) 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 anda 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 arguedthat the rate determining step for the acetolysis of10 is the formation of the carbocation at the 7 position afterloss of tosylate. A hypothetical stabilization of the intermediate would produce an acceleration of the reactionrate by lowering of the activation energy of the rate determining step. This is what is observed when aneighboring 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 besmaller 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 Rate Relative to Formation of 3-Member Ring

3 14 0.0145 8336 147 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 memberrings. This study focused on measuring the rates of formation of the salts (the salts were the final products ofthe reaction). Different bond angle strain (sulfur accommodates smaller bond angles) explains this marked

difference2.

Ring Size Rate Relative to Formation of 3-Member Ring

3 14 0.00535 0.2




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6 0.0177 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 todisplace a leaving group without stereochemical inversion at the electrophilic carbon. A recent example of

the use of this strategy is shown in the synthesis of6 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 thatis obtained by treating 13 with DAST (diethyl amino sulfur trifluoride). Intermediate A is obtained afteractivation of the hydroxyl group by DAST, which is then displaced by one of the carbonyl functions on theuracyl 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 C

2symmetrical 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 anintermediate episulfonium cation. Ring opening of this structure would produce either15 or16 depending onthe regioselectivity of the reaction.

Figure 13.Experimental results.

In practice, treatment of17 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 cationicepisulfonium 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 tointroduce 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 byHIV.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, andretention 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. NOEexperiments were used to determine the stereochemistry of the reaction center.Irradiation of H-2 of21benhanced 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 % Yield b/a Ratio (21b/21a)

THF 29 1.1Benzene 34 0.8CH3CN 21 6

CH2Cl2 22 1.2

DMF trace ------

Table 3. Solvent, product yield, and isomeric ratio for Mitsunobu reaction.15




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Discussion:

Yamada et al. wanted to synthesize the b-isomer (21b) by taking advantage of neighboringgroup 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 theisomeric 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 SN

2 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 neighboringgroup 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 strongnucleophiles were used, only direct substitution was observed.This is because the rate of direct substitutionis 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 oftrans-2-Acetoxycyclohexylp-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 ofSubstituted 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 theQuaternizedN3-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 of2, 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 asan unexpected product. Propose a mechanism for this conversion.




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Neighboring Group Participation

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