SN1 Reaction

11 Key excerpts on "SN1 Reaction"

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  eBook - ePub

  Essentials of Organic Chemistry

  For Students of Pharmacy, Medicinal Chemistry and Biological Chemistry

  • Paul M. Dewick(Author)
  • 2013(Publication Date)
  • Wiley

    (Publisher)

  6

  Nucleophilic reactions: nucleophilic substitution

  As the term suggests, a substitution reaction is one in which one group is substituted for another. For nucleophilic substitution, the reagent is a suitable nucleophile and it displaces a leaving group. As we study the reactions further, we shall see that mechanistically related competing reactions, eliminations and rearrangements, also need to be considered.

  6.1 The SN 2 reaction: bimolecular nucleophilic substitution

  The abbreviation SN 2 conveys the information ‘substitution–nucleophilic–bimolecular’. The reaction is essentially the displacement of one group, a leaving group, by another group, a nucleophile. It is a bimolecular reaction, since kinetic data indicate that two species are involved in the rate-determining step:

  where Nu is the nucleophile, RL the substrate containing the leaving group L, and k is the rate constant.

  In general terms, the reaction can be represented as below

  Differences in electronegativities (see Section 2.7) between carbon and the leaving group atom lead to bond polarity. This confers a partial positive charge on the carbon and facilitates attack of the nucleophile. As the nucleophile electrons are used to make a new bond to the carbon, electrons must be transferred away to a suitable acceptor in order to maintain carbon’s octet. The suitable acceptor is the electronegative leaving group.

  The nucleophile attacks from the side opposite the leaving group – electrostatic repulsion prevents attack in the region of the leaving group. This results in an inversion process for the other groups on the carbon centre under attack, rather like an umbrella turning inside out in a violent gust of wind. The process is concerted, i.e. the bond to the incoming nucleophile is made at the same time as the bond to the leaving group is being broken. As a consequence, the mechanism involves a high-energy transition state in which both nucleophile and leaving group are partially bonded, the Nu–C–L bonding is linear, and the three groups X, Y, and Z around carbon are in a planar array. This is the natural arrangement to minimize steric interactions if we wish to position five groups around an atom, and will involve three sp 2 orbitals and a p orbital as shown. The p orbital is used for the partial bonding; note that we cannot have five full bonds to a carbon atom. The energy profile for the reaction (Figure 6.1

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  Organic Chemistry

  • David R. Klein(Author)
  • 2021(Publication Date)
  • Wiley

    (Publisher)

  • When a solvent molecule functions as the attacking nucleo- phile, the resulting S N 1 process is called solvolysis. • Unimolecular elimination reactions are called E1 reactions. • S N 1 processes are favored by polar protic solvents. • S N 1 and E1 processes are observed for tertiary alkyl halides, as well as allylic and benzylic halides. • When the α position is a chiral center, an S N 1 reaction gives nearly a racemic mixture. In practice, there is generally a slight prefer- ence for inversion over retention of configuration, as a result of the effect of ion pairs. REVIEW OF CONCEPTS AND VOCABULARY Tertiary Substrates An alcohol An alkene (Zaitsev product) An alkyl halide NaOH TsCl, py conc.H 2 SO 4 HBr Br OH OTs t-BuOK NaOH An alkyl tosylate An alkene (Hofmann product) H 2 O t-BuOK 346 CHAPTER 7 Alkyl Halides: Nucleophilic Substitution and Elimination Reactions SKILLBUILDER REVIEW 7.1 DRAWING THE PRODUCT OF AN S N 2 PROCESS Replace the LG with the Nuc, and draw inversion of configuration. OH OH Br Br + + − − Try Problems 7.3, 7.4, 7.53, 7.54 7.2 DRAWING THE TRANSITION STATE OF AN S N 2 PROCESS EXAMPLE Draw the transition state of the following process. STEP 1 Identify the nucleophile and the leaving group. STEP 2 Draw a carbon atom with the Nuc and LG on either side. Use δ– symbols to indicate partial charges. STEP 3 Draw the three groups attached to the carbon atom. Place brackets and the symbol indicating a transition state. Cl NaSH SH NaCl Cl SH Leaving group Nucleophile C Cl HS Bond Forming Bond Breaking C Cl HS CH 3 H H + δ– δ– δ– δ– − Try Problems 7.5, 7.6, 7.50 7.3 PREDICTING THE REGIOCHEMICAL OUTCOME OF AN E2 REACTION STEP 1 Identify all β positions bearing protons. STEP 2 Draw all possible regiochemical outcomes. STEP 3 Identify the Zaitsev and Hofmann products. STEP 4 Analyze the base to determine which product predominates.

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  Carbocation Chemistry

  Applications in Organic Synthesis

  • Jie Jack Li(Author)
  • 2016(Publication Date)
  • CRC Press

    (Publisher)

  2 Nucleophilic Aliphatic Substitution SN 1 Yu Feng, Safiyyah Forbes, and Jie Jack Li

  CONTENTS

  2.1 Introduction 2.2 π-Activated Alcohols: Brønsted Acids 2.3 π-Activated Alcohols: Lewis Acids 2.4 Alkylation of Aldehydes and Ketones 2.5 Glycosylation 2.6 Friedel–Crafts Alkylation and Acylation 2.7 Electrophilic Fluorination Using Fluoronium Ion

  2.8 Miscellaneous SN 1-Related Reactions

  References

  2.1 INTRODUCTION

  In organic chemistry, nucleophilic substitution is a fundamental catalog of reactions involving the addition of a nucleophile to an electrophilic atom or ion. When such substitution takes place at a tetrahedral or sp3 carbon, it is termed as a nucleophilic aliphatic substitution. There are two major mechanisms for nucleophilic substitutions: SN 1 reaction and SN 2 reaction. In such, S stands for substitution, N stands for nucleophilic, and the number indicates the kinetic order of the reaction. So SN 1 reaction is a first-order nucleophilic substitution which means the rate of the reaction depends only on the concentration of substrate (Equation 2.1 ).

  Rate = k

  [ S ]

      (2.1)

  The mechanism for the reaction is described in Scheme 2.1 , and the corresponding energy level changes have been depicted in Figure 2.1 . This pathway is a multistep process: (1) slow loss of the leaving group (LG) to generate a carbocation intermediate and (2) rapid attack of a nucleophile on the electrophilic intermediate to form a new δ bond. In SN 1 reaction, the rate-determining step is the first elementary step (loss of the LG to form the intermediate carbocation), which means the more reactive the LG, the faster reaction rate. The carbocation is a real-life positive ion with a limited lifetime and thus is not just a transition state. Bulky groups attached help stabilize the charge on the carbocation via distribution of charge and resonance. Polar solvents which stabilize carbocation can also favor the SN

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  Organic Chemistry

  • T. W. Graham Solomons, Craig B. Fryhle, Scott A. Snyder(Authors)
  • 2022(Publication Date)
  • Wiley

    (Publisher)

  6.10 A Mechanism for the S N 1 Reaction 261 Furthermore, these results indicate that the transition state govern- ing the rate of reaction involves only molecules of tert-butyl chloride, and not water or hydroxide ions. The reaction is said to be unimolecular (first-order) in the rate-determining step, and we call it an S N 1 reaction (substitution, nucleophilic, unimolecular). In Chapter 7 we shall see that elimination reactions can compete with S N 1 reactions, leading to the formation of alkenes, but in the case of the conditions used above for the experiments with tert-butyl chloride (moderate temperature and dilute base), S N 1 is the dominant process. How can we explain an S N 1 reaction in terms of a mechanism? To do so, we shall need to consider the possibility that the mechanism involves more than one step. But what kind of kinetic results should we expect from a multistep reaction? Let us consider this point further. 6.9A Multistep Reactions and the Rate-Determining Step • If a reaction takes place in a series of steps, and if one step is intrinsi- cally slower than all the others, then the rate of the overall reaction will be essentially the same as the rate of this slow step. This slow step, consequently, is called the rate-limiting step or the rate-determining step. Consider a multistep reaction such as the following: Reactant ⟶ intermediate 1 ⟶ intermediate 2 ⟶ product Step 1 Step 2 Step 3 When we say that the first step in this example is intrinsically slow, we mean that the rate con- stant for step 1 is very much smaller than the rate constant for step 2 or for step 3. That is, k 1 << k 2 or k 3 . When we say that steps 2 and 3 are fast, we mean that because their rate constants are larger, they could (in theory) take place rapidly if the concentrations of the two intermediates ever became high. In actuality, the concentrations of the intermediates are always very small because of the slowness of step 1.

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  Reactions of Aromatic Compounds

  • R.G. Compton, C.H. Bamford, C.F.H. Tipper†, R.G. Compton, C.H. Bamford, C.F.H. Tipper†(Authors)
  • 1972(Publication Date)
  • Elsevier Science

    (Publisher)

  Chapter 2 Nucleophilic Aromatic Substitution: the SN2 Mechanism S . D. ROSS 1. Introduction Nucleophilic aromatic substitution has been the subject of frequent and ex- tensive reviews'-''. The data on reaction rates, reaction products, substituent ef- fects, salt effects, etc. are all readily available and need not be reassembled here. In spite of this abundance of both data and discussion, some questions of mechanism remain incompletely resolved. Our knowledge of mechanism is most sophisticated for the S,2 nucleophilic displacements, where the reactive agent is an electron donor, where the leaving group is a halogen ion or some other group capable of some stability as an anion, and where the activation is due to electron-withdrawing substituents, suitably positioned in the aromatic substrate. The most widely accepted mechanism for this category of reactions is one involving an intermediate complex, formed by addition of the nucleophile to the carbon atom undergoing substitution and converting that carbon atom to one with its substituents arranged in a tetrahedral configuration. The best evidence for this interpretation comes from studies of reaction rates, and, in particular, from the observation of the effects of basic catalysts on the rates of reactions with selected substrates and selected nucleophiles. It is regrettable that the evidence afforded by reaction kinetics is rarely, if ever, uniquely consistent with a single mechanism or a single explanation. The results for nucleophilic aromatic substitution reactions are no exception. Legitimate questions can be raised with respect to the extent to which observations made on a particular system permit generalization to other systems. Even for the specific systems studied points of detail arise, and choices have to be made where alterna- tives are possible. Every such choice introduces an element of uncertainty and imposes a limitation on the extent to which the reaction mechanism is, in fact, known.

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  eBook - PDF

  Reaction Mechanisms in Organic Chemistry

  • Metin Balcı(Author)
  • 2021(Publication Date)
  • Wiley-VCH

    (Publisher)

  However, the situation is somewhat dif- ferent in S N 2 ′ reactions. The nucleophile approaches the double bond on the side from which the leaving group departs, which is called a syn-attack. In such an attack, double-bond electrons open backward to remove the X-group. Thus, the electron density is increased at the back of the leaving group. Substitution occurs by the attack of electrons on the car- bon atom to which the leaving group is bonded. If the nucleophile attacks the double bond from the opposite direction (anti-attack), the electron density will increase at the side of the leaving group, which will not be suitable for a substitution reaction. 74 2 Nucleophilic Substitution Reaction C CH C X Nu syn-attack C HC C Nu The syn-attack can be nicely demonstrated in cyclic structures. In the example given below, the nucleophile attacks the molecule from the side of the leaving group and removes benzoate [19]. C(CH 3 ) 3 O O Ph N H C(CH 3 ) 3 N 2.3.4 Internal Nucleophilic Substitution Reaction, S N i In the previous sections, we have discussed S N 1 and S N 2 mechanisms. S N 2 reactions proceed through the formation of a transition state, resulting in configuration inversion of the product. There are still other reactions whose stereochemical outcome cannot be explained by S N 1 or S N 2 mechanisms. In some nucleophilic substitution reactions, although the reaction molecularity is bimolecular, retention of the configuration is observed instead of inversion. These and similar reactions are often observed by the reaction of chiral alcohol with thionyl chloride to give the corresponding alkyl halide. In the first step, the oxygen atom of alcohol attacks the sulfur atom of thionyl chloride and removes one of the chlorine atoms attached to the sulfur atom to form alkyl chlorosulfite, which can be isolated. At this stage, there is no configurational change at the chiral carbon atom as the nucleophilic substitution reaction takes place on the sulfur atom.

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  Organic Chemistry

  • David R. Klein(Author)
  • 2016(Publication Date)
  • Wiley

    (Publisher)

  • S N 2 reactions proceed via inversion of configuration, because the nucleophile can only attack from the back side. Review of Concepts and Vocabulary 333 • S N 2 reactions cannot be performed with tertiary alkyl halides. • An S N 2 process will generally not occur if there are three sub- stituents at a β position. SECTION 7.4 • There are many factors that contribute to nucleophilicity, including the presence of a charge and polarizability. • Protic solvents contain a hydrogen atom connected directly to an electronegative atom, while polar aprotic solvents lack such a hydrogen atom. A polar aprotic solvent will speed up the rate of an S N 2 process by many orders of magnitude. SECTION 7.5 • The transfer of an alkyl group is called alkylation. If the alkyl group is a methyl group, the process is called methylation. • In the laboratory, methylation is accomplished via an S N 2 process using methyl iodide. In biological systems, a methylating agent called SAM (S-adenosylmethionine) is employed. SECTION 7.6 • A weak base is a stabilized base, and a strong base is an unstable base. • There is an inverse relationship between the strength of a base and the strength of its conjugate acid. • When treated with a strong base, an alkyl halide can undergo a type of elimination process, called beta elimination, also known as 1,2-elimination. • Bimolecular elimination reactions are called E2 reactions. SECTION 7.7 • In addition to their systematic and common names, alkenes are also classified by their degree of substitution, which refers to the number of alkyl groups connected to a double bond. • A cis alkene will generally be less stable than its stereoiso- meric trans alkene. This can be verified by comparing heats of combustion for isomeric alkenes. • A trans π bond cannot be incorporated into a small ring.

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  Klein's Organic Chemistry

  • David R. Klein(Author)
  • 2020(Publication Date)
  • Wiley

    (Publisher)

  • This reaction proceeds with inversion of configuration, as expected for an S N 2 process. • The solvent used for this reaction, acetonitrile (CH 3 CN), is a polar aprotic solvent, and it is used to speed up the rate of the process (as described in Section 7.8). • Notice that the OH groups (normally found in glucose) have been converted into acetate groups (OAc). This was done in order to minimize side reactions. These acetate groups can be removed easily upon treatment with aqueous acid (we will explore this process, called hydrolysis, in more detail in Section 21.11). O Ac O Ac O Ac O 18 F OAc O HO HO HO OH 18 F H 3 O + The effective application of FDG in PET scans certainly requires the contribution from many different disciplines, but organic chemistry has played the most critical role: The synthesis of FDG is achieved via an S N 2 process! 306 CHAPTER 7 Substitution Reactions The Substrate The identity of the substrate is the most important factor in distinguishing between S N 2 and S N 1. Earlier in the chapter, we saw different trends for S N 2 and S N 1 reactions. These trends are compared in the charts in Figure 7.26. The trend in S N 2 reactions is due to issues of steric hindrance in the transition state, while the trend in S N 1 reactions is due to carbocation stability. The bottom line is that methyl and primary substrates favor S N 2, while tertiary substrates favor S N 1. Secondary substrates can proceed via either mechanism, so a secondary substrate does not indicate which mechanism will predominate. In such a case, you must move on to the next factor, the nucleophile (covered in the next section). FIGURE 7.26 Substrate effects on the rates of S N 2 and S N 1 processes.

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  Organic Reaction Mechanisms 2018

  An Annual Survey Covering the Literature Dated January to December 2018

  • Mark G. Moloney(Author)
  • 2021(Publication Date)
  • Wiley

    (Publisher)

  11 S N 2 Mechanistic Studies The variation of nucleophiles, substrates and solvents and the way they may affect activation entropy in S N 2 processes has been studied; the changes of the activation entropy suggest that they are related to changes of isokinetic temperature ( T iso ) values. 12 The importance of the nucleophile, leaving group, substrate and solvent on the mechanism of bimolecular nucleophilic substitution ( S N 2) reactions is well known; a detailed review covering recent developments in the understanding of this interplay, and especially for the behaviour of lower row elements, has appeared. 13 Key conclusions include that, in the absence of an elimination pathway, stronger bases are better nucleophiles; leaving groups with a weak bond are more reactive (I ≫ F); electropositive central atoms are more electrophilic and give faster reactions; lower steric bulk around the central atom lowers reaction barriers; and sterically bulky substituents and solva-tion can change the potential energy reaction surface. The effect of polar and apolar solvents on the potential energy surface profile of nucleophilic substitution reactions at carbon, silicon, phosphorus and arsenic using density functional theory at the OLYP/TZ2P level has been elab-orated. The polarity of the solvent and its solvation behaviour readily modifies the shape of their reaction potential energy surface profile and therefore the reaction rate. In the gas phase, all of the model S N 2 reactions at various Group 14 (C, Si) and Group 15 (P, As) electrophilic centres, have single-well profiles, except for that at carbon, which has a double-well energy profile. 14 The pre-orientation of reactants (“stereodynamics”), and the impact that this has on S N 2 pro-cesses, has been studied using crossed-beam velocity map imaging; the model reactions of Cl – and CN – with increasingly methylated alkyl iodides were used.

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  Solomons' Organic Chemistry

  • T. W. Graham Solomons, Craig B. Fryhle, Scott A. Snyder(Authors)
  • 2017(Publication Date)
  • Wiley

    (Publisher)

  A relatively weak nucleophile 3. A polar, protic solvent such as EtOH, MeOH, or H 2 O The S N 1 mechanism is, therefore, important in solvolysis reactions of tertiary alkyl halides, especially when the solvent is highly polar. In a solvolysis reaction the nucleophile is weak because it is a neutral molecule (of the polar protic solvent) rather than an anion. S N 2: The Following Conditions Favor an S N 2 Reaction 1. A substrate with a relatively unhindered leaving group (such as a methyl, primary, or secondary alkyl halide). The order of reactivity is R CH 3 —X > R—CH 2 —X > R—CH—X > > 2° 1° Methyl Tertiary halides do not react by an S N 2 mechanism. 2. A strong nucleophile (usually negatively charged) 3. High concentration of the nucleophile 4. A polar, aprotic solvent S N 1 versus S N 2 HINT PRACTICE PROBLEM 6.18 List the following compounds in order of decreasing reactivity toward CH 3 O − in an S N 2 reaction carried out in CH 3 OH: CH 3 F, CH 3 Cl, CH 3 Br, CH 3 I, CH 3 OSO 2 CF 3 , 14 CH 3 OH. 272 CHAPTER 6 NUCLEOPHILIC REACTIONS: Properties and Substitution Reactions of Alkyl Halides The trend in reaction rate for a halogen as the leaving group is the same in S N 1 and S N 2 reactions: R − l > R − Br > R − Cl S N 1 or S N 2 Because alkyl fluorides react so slowly, they are seldom used in nucleophilic substitution reactions.

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  Organic Chemistry

  An Acid-Base Approach, Third Edition

  • Michael B. Smith(Author)
  • 2022(Publication Date)
  • CRC Press

    (Publisher)

  N 1 reaction can rearrange if the charge can be shifted to an adjacent carbon to give a potentially more stable carbocation. An example is the reaction of 2-chloro-3-methylpentane with KI in aq THF.

  Rearrangement and SN 1 Reactions

  In the presence of water, ionization of the chloride will give the secondary carbocation, 12, but the final product, 3-iodo-3-methylpentane does not arise from this intermediate. A 1,2-hydride shift gives the more stable tertiary carbocation, 13, which reacts with iodide to give the observed product. Because a carbocation is an intermediate, skeletal rearrangement is a potential issue in any SN 1 reaction. If a primary or secondary cation is generated on a carbon adjacent to a carbon that give a more stable cation rearrangement will occur.

  • 11.14. Draw the mechanism and the final product formed when (2S)-bromo-2-phenylpentane is treated with KI in aq THF.

  Alkyl halides undergo SN 1 reactions to give an alcohol by heating in an aqueous medium. If 2-bromo-2-methylpentane is heated in anhydrous ethanol (no water) for several hours, or for several days there is a reaction and a poor yield of 2-ethoxy-2-methypentane is obtained. This tertiary halide cannot react by an SN 2 mechanism because the activation energy barrier for that transition state is too high. There is no water in this medium, but ethanol is a protic solvent.

  Although ionization and stabilization of charge (solvation) is not as facile in ethanol as in water (i.e., it is slow), it does occur. Prolonged heating leads to slow ionization of the halide to a tertiary carbocation, which reacts quickly with ethanol to yield an oxonium ion intermediate. Loss of the proton to ethanol in an acid-base reaction yields the ether product, 2-ethoxy-2-methylpentane. Replacement of alkyl halides with solvent in this way is called solvolysis , and it occurs most often with protic solvents (e.g., alcohols). This reaction is a reminder that water is not

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