SN2 Reaction

10 Key excerpts on "SN2 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)
  • 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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  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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  Klein's Organic Chemistry

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

    (Publisher)

  This type of process, in which an alcohol is used as a substrate in an S N 2 reaction, has very limited utility and is generally only utilized in certain FIGURE 7.23 The one concerted step of an S N 2 process. Nuc attack loss of LG + FIGURE 7.24 The concerted step and the two possible additional steps of an S N 2 process. Nuc attack loss of LG Proton transfer Proton transfer + But it is possible for the leaving group to leave as a result of a methyl shift: Br Tertiary carbocation Br ⊝ ⊕ + This is essentially a concerted process in which loss of the leaving group occurs simultaneously with a carbocation rearrangement. Examples like this are less common. In the vast majority of cases, each step of an S N 1 process occurs separately. 7.8 DRAWING THE COMPLETE MECHANISM OF AN S N 2 REACTION In the previous section, we analyzed the additional steps that can accompany an S N 1 process. In this section, we analyze the additional steps that can accompany an S N 2 process. Recall that an S N 2 reaction is a concerted process in which nucleophilic attack and loss of the leaving group occur simultaneously (Figure 7.23). No carbocation is formed, so there can be no carbocation rearrangement. In an S N 2 process, the only two possible additional steps are proton transfers (Figure 7.24). There can be a proton transfer before and/or after the concerted step. Proton transfers will accompany S N 2 processes for the same reasons that they accompany S N 1 processes. 302 CHAPTER 7 Substitution Reactions industrial applications. Methyl chloride is prepared commercially by such a process (using aqueous HCl as the source of H 3 O + and Cl − ): CH 3 Cl CH 3 OH HCl Proton Transfer at the End of an S N 2 Process S N 2 –H + A proton transfer will occur at the end of an S N 2 process if the nucleophile is neutral.

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  eBook - ePub

  Principles of Organic Chemistry

  • Robert J. Ouellette, J. David Rawn(Authors)
  • 2015(Publication Date)
  • Elsevier

    (Publisher)

  N 2 reaction.

  When (R) -2-bromobutane reacts with sodium hydroxide, the substitution product is (R) -2-butanol. The reaction occurs with inversion of configuration. Thus, the nucleophile approaches the electrophilic carbon atom from the back and the leaving group simultaneously departs from the front of the substrate in the SN 2 mechanism.

  The SN 1 Mechanism

  A nucleophilic substitution reaction that occurs by an SN 1 mechanism proceeds in two steps. In the first step, the bond between the carbon atom and the leaving group breaks to produce a carbocation and, most commonly, an anionic leaving group. In the second step, the carbocation reacts with the nucleophile to form the substitution product.

  The formation of a carbocation is the slow, or rate-determining, step. The subsequent step, formation of a bond between the nucleophile and the carbocation, occurs very rapidly. Because the slow step of the reaction involves only the substrate, the reaction is unimolecular. Because only the substrate is present in the transition state, the rate of the reaction depends only on its concentration, and not on the concentration of the nucleophile.

  Figure 7.3 shows an energy diagram tracing the progress of a reaction that occurs by an SN 1 mechanism. The rate of the reaction reflects the activation energy required to form the carbocation intermediate. The activation energy required for step 2, addition of the nucleophile to the carbocation, is much smaller, so step 2 is very fast. The rate of step 2 has no effect on the overall rate of the reaction.

  Figure 7.3 Activation Energy and the SN 1 Reaction

  The reaction of 2-bromo-2-methylpropane occurs in two steps with formation of an intermediate carbocation. It forms in the rate-determining step, which does not involve the nucleophile. In the second, fast step, the carbocation reacts with a nucleophile such as water to form the product.

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  Organic Chemistry

  • T. W. Graham Solomons, Craig B. Fryhle, Scott A. Snyder(Authors)
  • 2016(Publication Date)
  • Wiley

    (Publisher)

  SUMMARY OF S N 1 VERSUS S N 2 REACTIONS S N 1: The Following Conditions Favor an S N 1 Reaction 1. A substrate that can form a relatively stable carbocation (such as a substrate with a leaving group at a tertiary position) 2. 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 [ HELPFUL HINT ] S N 1 versus S N 2 272 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

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

    (Publisher)

  If they react rapidly by an S N 1 mechanism, then the reactants will follow an S N 1 pathway. • A number of factors affect the relative rates of S N 1 and S N 2 reactions. The most important factors are: 1. The structure of the substrate 2. The concentration and reactivity of the nucleophile (for S N 2 reactions only) 3. The effect of the solvent 4. The nature of the leaving group 6.13A The Effect of the Structure of the Substrate S N 2 Reactions Simple alkyl halides show the following general order of reactivity in S N 2 reactions: Methyl > primary > secondary > (tertiary—unreactive) Methyl halides react most rapidly, and tertiary halides react so slowly as to be unreactive by the S N 2 mechanism. Figure 6.9 shows some example structures and their relative rates of S N 2 reaction. The important factor behind this order of reactivity is a steric effect, specifically steric hindrance. > H H C (~0) 3° H H H C H H H H C Nu X C H (0.00001) Neopentyl Structural Class: Methyl Relative Rate: (30) (0.03) 2° (1) 1° H H H C H H H C X C Nu H H H H H H H H H H H X C C C C C Nu H H H C H H X C Nu H H H X C Nu FIGURE 6.9 Steric effects and relative rates in the S N 2 reaction. 6.13 Factors Affecting the Rates of S N 1 and S N 2 Reactions 269 • Steric hindrance is when the spatial arrangement of atoms or groups at or near a react- ing site of a molecule hinders or retards a reaction. For particles (molecules and ions) to react, their reactive centers must be able to come within bonding distance of each other. Although most molecules are reasonably flexible, very large and bulky groups can often hinder the formation of the required transition state. In some cases they can prevent its formation altogether. An S N 2 reaction requires an approach by the nucleophile to a distance within the bonding range of the carbon atom bearing the leaving group. Because of this, bulky substituents on or near that carbon atom have a dramatic inhibiting effect (Figure 6.9).

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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)

  6.14 ORGANIC SYNTHESIS 273 Alkyl chlorides and bromides are also easily converted to alkyl iodides by nucleophilic substitution reactions. or R Cl R Br R I ( + Cl or Br ) I − − − One other aspect of the S N 2 reaction that is of great importance is stereochemistry (Section 6.8). S N 2 reactions always occur with inversion of configuration at the atom that bears the leaving group. This means that when we use S N 2 reactions in syntheses we can be sure of the configuration of our product if we know the configuration of our reactant. For example, suppose we need a sample of the following nitrile with the (S ) configuration: N C CH 3 H CH 2 CH 3 C (S)-2-Methylbutanenitrile If we have available (R )-2-bromobutane, we can carry out the following synthesis: − Br + H CH 3 CH 2 CH 3 C (S)-2-Methylbutanenitrile C N (R)-2-Bromobutane H 3 CH 2 C H H 3 C (inversion) C S N 2 Br + − C N PRACTICE PROBLEM 6.19 Starting with (S )-2-bromobutane, outline syntheses of each of the following compounds: (c) SH ( R )-CH 3 CHCH 2 CH 3 (a) OCH 2 CH 3 ( R )-CH 3 CHCH 2 CH 3 (d) SCH 3 ( R )-CH 3 CHCH 2 CH 3 (b) OCCH 3 ( R)-CH 3 CHCH 2 CH 3 O THE CHEMISTRY OF... Biological Methylation: A Biological Nucleophilic Substitution Reaction The cells of living organisms synthesize many of the compounds they need from smaller molecules. Often these biosynthe- ses resemble the syntheses organic chemists carry out in their laboratories. Let us examine one example now. Many reactions taking place in the cells of plants and animals involve the transfer of a methyl group from an amino acid called methionine to some other compound. That this transfer takes place can be demonstrated experimentally by feeding a plant or animal methionine containing an isotopically labeled carbon atom (e.g., 13 C or 14 C) in its methyl group. Later, other compounds containing the “labeled” methyl group can be isolated from the organism. Some of the compounds that get their methyl groups from methionine are the following.

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  Organic Chemistry

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

    (Publisher)

  Two variations of the proposed synthesis are shown below: ONa O Cl OLi O OTs In each of these variations, there is a strong nucleophile (alkoxide) displacing a leaving group on an unhindered carbon atom, so we expect the S N 2 mechanism to proceed smoothly to give the desired target molecule as the major product. When considering a synthetic transformation, it also doesn’t 7.11 Synthesis Strategies 333 matter which of the starting materials is called the “substrate” and which is called the “reagent,” because either way, the nucleophile and electrophile will react with each other when mixed together. OLi O Substrate T arget molecule Reagent (Nucleophile) Br (Electrophile) Target molecule O OLi (Nucleophile) Br (Electrophile) Target molecule It is important to note that a suitable solvent (polar aprotic) would be selected to facilitate the S N 2 mechanism when we move from planning a synthesis to actually implementing the experimental procedure in the laboratory. In many cases, you will find that solvents are omitted from the prob- lems found in textbooks, but your instructor may expect you to include solvents in your answers, for a more complete solution (pun intended!). SKILLBUILDER 7.8 PERFORMING A RETROSYNTHESIS AND PROVIDING A SYNTHESIS OF A TARGET MOLECULE Provide a synthesis for the given target molecule. Show your retrosynthetic analysis, and then provide a complete synthesis, showing all necessary reagents. O O SOLUTION We focus our attention on the bonds around the ester functional group, because these are the most likely bonds to be formed in the synthesis. There are three possible disconnections to be considered, as shown here: O O a b c Disconnection b is between an oxygen atom and an sp 2 hybridized atom.

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