SNi Reaction

11 Key excerpts on "SNi 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)

  Table 6.8 , with secondary substrates being able to participate in either type of process.

  The most distinguishing feature of the SN 1 mechanism is the intermediate carbocation. Formation of the carbocation is the rate-determining step, and this is more favourable in polar solvents that are able to assist in facilitating the charge separation/ionization. A useful, though not always exact, guide is that SN 1 reactions are going to be favoured by an acidic/positive environment, and are less likely to occur under basic/negative conditions. Since good nucleophiles are often also strong bases, this does tend to limit the applicability of SN 1 reactions. Indeed, under strongly basic conditions, side-reactions such as elimination (see Section 6.4.1) are more likely to occur than nucleophilic substitution reactions. However, all is not lost, because the carbocation is a particularly good electrophile and can be used with relatively poor nucleophiles. This is illustrated in the following examples.

  Table 6.8 Occurrence of SN 1 or SN 2 reactions according to substrate

  Class of substrate	SN 1	SN 2
  Tertiary	Common	Never
  Secondary	Sometimes	Sometimes
  Primary	Never	Common

  Finally, do appreciate that, depending upon conditions, it is quite possible that both SN 1 and SN 2 mechanisms might be operating at the same time, with each contributing its own stereochemical characteristics upon the product.

  Box 6.4

  Biological SN 1 reactions involving allylic cations

  The leaving groups most commonly employed in nature are phosphates and diphosphates. These good leaving groups are anions of the strong acids phosphoric (pK a 2.1) and diphosphoric (pK a 1.5) acids respectively. The pK a

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  Klein's Organic Chemistry

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

    (Publisher)

  As a result, the rate of an S N 1 process will only be affected by factors that affect the rate of that step. Increasing the concentration of the nucleophile has no impact on the rate at which the leaving group leaves. It is true that the nucleophile must be present in order to obtain the product, but an excess of nucleophile will not speed up the reaction. A unimolecular substitution reaction is therefore consis- tent with a stepwise mechanism in which the first step is the rate-determining step. Conceptual CHECKPOINT 7.15 The following reaction occurs via an S N 1 mechanistic pathway: NaCl Na Cl + (a) What happens to the rate if the concentration of tert-butyl iodide is doubled and the concentration of sodium chloride is tripled? (b) What happens to the rate if the concentration of tert-butyl iodide remains the same and the concentration of sodium chloride is doubled? FIGURE 7.12 An energy diagram of an S N 1 process. Reaction coordinate Nuc LG ⊕ Potential energy 7.6 The S N 1 Mechanism 289 FIGURE 7.14 Electrostatic potential maps of various carbocations. The alkyl groups help spread the positive charge, thereby stabilizing the charge. Methyl Least stable Most stable Primary (1°) Secondary (2°) Tertiary (3°) H H H H 3 C H H CH 3 H H 3 C CH 3 CH 3 H 3 C ⊕ ⊕ ⊕ ⊕ Tertiary carbocations are more stable than secondary carbocations, which are more stable than primary carbocations. Therefore, formation of a tertiary carbocation will have a smaller E a than formation of a secondary carbocation (Figure 7.15). The larger E a associated with formation of a secondary carbocation can be explained by the Hammond postulate (Section 6.6). Specifically, the transition state for formation of a tertiary carbocation will be close in energy to a tertiary carboca- tion, while the transition state for formation of a secondary carbocation will be close in energy to a secondary carbocation. Therefore, formation of a tertiary carbocation will involve a smaller E a .

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  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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  Reaction Mechanisms in Organic Chemistry

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

    (Publisher)

  Under the steric conditions in which S N 2 is inhibited, a S N 2 ′ reaction can be a dominant one or it can be an exclusive reaction. The presence of alkyl groups at the α-carbon atom will hinder the S N 2 reaction, but S N 2 ′ can still take place. Larger nucleophiles can also increase the amount of S N 2 ′ reaction at the expense of the S N 2 reaction. The reaction of 3-chloro-3-methylbut-1-ene with benzene thiolate exclusively forms the S N 2 ′ product because the attack is sterically hindered because of the crowding at the α-carbon atom. C CH H 2 C CH 3 Cl CH 3 S C CH CH 2 CH 3 CH 3 S S N 2′ 3-chloro-3-methylbut-1-ene – Cl In recent years, allylic substitution reactions have been successfully applied to form a carbon–carbon bond using various copper catalysts [17, 18]. Copper-catalyzed allylic substitution typically occurs to form products from the addition of copper alkyl compounds (hard nucleophiles) at the γ-position to the leaving group to form the rearranged product exclusively. OAc Cu-catalyst Ether/toluene n-Bu n-BuMgI 2.3.3.1 Stereochemistry in Allylic Substitution Reactions The stereochemistry of the normal products formed by allylic substitution reactions is similar to that of the products formed by S N 1 and S N 2 reactions. If the reaction proceeds by the S N 1 mechanism, the bond between the carbon and the leaving group breaks to form a carbocation as an intermediate. Because of the planar structure, the carbocation will be attacked at either side to form a racemic mixture. In S N 2-type reactions, the nucleophile attacks the back of the carbon atom that is bonded to the leaving group, forming a product with configuration inversion. 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.

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  Biochemistry

  An Organic Chemistry Approach

  • Michael B. Smith(Author)
  • 2020(Publication Date)
  • CRC Press

    (Publisher)

  N 1 reactions and then describe nucleophiles that are common in biochemical applications and the substitution reactions that are common for these nucleophiles. Nucleophilic reactions require electrophilic species. Electrophiles or electrophilic substrates are common in biochemistry, including phosphonate derivatives, carbonyl compounds and imine compounds. Any discussion of typical nucleophilic reactions also requires an understanding of such electrophilic substrates. The fundamentals of both acyl addition and of acyl substitution reactions will be presented for carbonyl electrophilic centers and the reactions of these electrophilic centers with nucleophiles.

  3.1 Nucleophiles and Bimolecular Substitution (the SN 2 Reaction)

  The SN 2 reaction is one of the seminal reactions in a typical undergraduate organic chemistry course. The reaction of 1-bromo-3-methylbutane with sodium iodide (NaI) using acetone as a solvent gave 1-iodo-3-methylbutane, in 66% yield.1 In terms of the structural changes, the iodide ion substitutes for the bromine, producing bromide ion (Br– ). Iodide reacted as a nucleophile in the reaction at Cδ+ of the alkyl bromide, breaking the C—Br bond and transferring the electrons in that bond to bromine. In molecules that contain the C—Br bond, or indeed a C—C bond, where X is a heteroatom-containing group, the carbon will have a δ+ dipole. In other words, the carbon atom is electrophilic, and the substrate that reacts with the nucleophile is called an electrophile. The reaction of a nucleophile with an aliphatic electrophile is formally called nucleophilic aliphatic substitution , illustrated in Figure 3.1 . The displaced atom or group (e.g., chloride), departs (leaves) to become an independent ion. Displacement of chlorine leads to the chloride ion (Cl– ), but the bromide ion, iodide ion, or a sulfonate anion also correlates to X, which is referred to as a leaving group . In many biochemical reactions, the leaving group is a phosphate, —O–PO2 –O—.

  1 Furniss, B.S.; Hannaford, A.J.; Smith, P.W.G.; Tatchell, A.R. (eds.), Vogel’s Textbook of Practical Organic Chemistry , 5th ed. Longman, Essex, UK, 1994 , Exp. 5.62, p. 572.

  FIGURE 3.1 Nucleophilic attack at a sp3 carbon bearing a leaving group.

  A leaving group does not spontaneously “fly off” or “leave,” it is displaced by the nucleophile after collision with the electrophilic carbon atom. In other words, the incoming nucleophile effectively “kicks out” the leaving group, but only after collision with the electropositive carbon. The rate of the SN 2 reaction (the speed at which the reactants are converted into products) is proportional to the concentration of both the nucleophile and the electrophilic substrate. The rate at which this reaction occurs is proportional to the concentration of the nucleophile and also the concentration of the alkyl halide, and this type of rate expression is second-order . To change the proportionality to an equality, the expression must contain a proportionality constant, k

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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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  Organic Mechanisms

  Reactions, Methodology, and Biological Applications

  • Xiaoping Sun(Author)
  • 2020(Publication Date)
  • Wiley

    (Publisher)

  This steric hindrance (characteristic of a tertiary‐butyl group or any tertiary substrate) makes an S N 2 reaction extremely slow (Fig. 6.5). On the other hand, because a tertiary carbocation, such as (CH 3) 3 C +, is relatively stabilized, an S N 1 reaction for a tertiary substrate can take place in a relatively fast rate (Fig. 6.17). In general, the nucleophilic substitution reaction of a tertiary (3°) substrate always follows the S N 1 mechanism. The reaction can be effected by a weak nucleophile (mostly neutral molecules). The type of solvents can change the reaction rate, but does not change the mechanism. For a secondary (2°) substrate such as 2‐halopropane (CH 3) 2 CHX, as the number of methyl groups on the central electrophilic carbon increases, the steric hindrance to the nucleophilic attack from the opposite side of the leaving group is getting more severe. This disfavors an S N 2 reaction, but does not completely prevent it from happening (Fig. 6.5). On the other hand, the stability of a secondary (2°) carbocation allows the S N 1 reaction of a 2° substrate to take place in an appreciable rate (see Fig. 6.17). In addition, a primary substrate which contains an unsaturated group (such as phenyl and vinyl) on the electrophilic carbon can also have both S N 1 and S N 2 reactions. In general, the nucleophilic substitution reactions of a secondary (2°) substrate and a primary (1°) benzylic or allylic substrate can follow either the S N 2 or S N 1 mechanism, depending on the nature of the nucleophile and solvent. Usually, when a reaction is performed with a strong nucleophile (mostly, an anion) in an aprotic solvent, it follows the S N 2 mechanism. If a reaction is performed with a weak nucleophile (mostly, a neutral molecule) in a protic solvent, it follows the S N 1 mechanism. Now, let us look at nucleophilic substitution reactions of (R)‐2‐bromobutane, a secondary haloalkane, performed in different conditions (Fig

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  Organic Chemistry

  A Mechanistic Approach

  • Penny Chaloner(Author)
  • 2014(Publication Date)
  • CRC Press

    (Publisher)

  Zinc chloride, a Lewis acid, is sometimes added to facilitate the reaction (Figure 9.32). Key Points from Sections 9.6 through 9.9 • Tertiary substrates react by the S N 1 mechanism, primary (unconjugated) substrates by S N 2 processes. Secondary substrates may follow either mechanism, depending on the sub- strate and the nucleophile. Any type of steric hindrance slows S N 2 reactions. • Substrates with an adjacent double bond, especially α-haloketones, react more rapidly in S N 2 processes. • Polar protic solvents favor ionization and hence S N 1 reactions. Polar aprotic solvents, unable to solvate nucleophiles, favor S N 2 processes. • Elimination processes compete with both types of substitution. • Carbocation rearrangements compete with S N 1 processes. In allylic systems, allylic trans- position may occur in either S N 1 or S N 2 reactions. • S N 1 reactions are favored by good carbocations, good leaving groups, polar protic sol- vents, weak nucleophiles. S N 2 reactions are favored by low steric hindrance, good nucleo- philes and leaving groups, and polar aprotic solvents. Br Br EtNH 2 Br NHEt Br Br Br Br PhCH 2 O – Na + (XS) Br Br OCH 2 Ph OCH 2 Ph FIGURE 9.29 Neither.S N 1.nor.S N 2.substitution.occurs.at.sp 2 .or.sp.centers. Chapter 9 – Nucleophilic Substitution at Saturated Carbon 337 Although the reactions with acids are easy, and inexpensive, not all molecules can tolerate the harsh conditions involved. Another method for turning OH into a leaving group, and then displacing it with halide, involves the reaction of the alcohol with PX 3 (X = Cl or Br; PI 3 can be formed and used in situ). The lone pair of electrons on oxygen attacks phosphorus, displacing bromide. All three bromides can be displaced. The bromide ions then attack at carbon to give the alkyl bromide and eventually P(OH) 3 , which rearranges to HP( =O)(OH) 2 (Figure 9.33).

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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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  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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  Synthesis of Aromatic Compounds

  • Kenneth E. Maly, Kenneth Maly(Authors)
  • 2022(Publication Date)
  • De Gruyter

    (Publisher)

  3  Nucleophilic aromatic substitution reactions

  3.1  Introduction

  In the previous chapter, we saw that aromatic rings themselves are usually nucleophiles, reacting with electrophiles in electrophilic aromatic substitution reactions. Furthermore, SN 2 reactions cannot take place at the sp2 hybridized carbon atoms of an aromatic ring. Nonetheless, as we will see in this chapter, nucleophilic displacements on aromatic rings can occur. We will explore the mechanistic scenarios for nucleophilic aromatic substitution with particular attention to the addition–elimination mechanism. We will also consider the chemistry of aryl diazonium salts, which bear superficial resemblance to nucleophilic aromatic substitution.

  3.2  Addition–elimination of nucleophiles (SN Ar)

  The most common type of nucleophilic aromatic substitution at an aromatic ring proceeds first by nucleophilic addition to the carbon bearing the leaving group to form a delocalized carbanion intermediate, followed by expulsion of the leaving group and rearomatization [1 ]. Because the reaction proceeds by an anionic intermediate, it usually involves electron-deficient aromatic rings. The rate-determining step is typically nucleophilic addition and the reaction usually requires electron withdrawing groups ortho or para to the site of nucleophilic attack (Figure 3.1 ).

  Figure 3.1: Generalized SN Ar mechanism.

  As shown in Figure 3.1 , initial nucleophilic attack at the carbon bearing the leaving group results in a delocalized carbanion intermediate, referred to as a Meisenheimer complex. The reaction often requires electron-withdrawing groups ortho or para to the leaving group in order to stabilize the negative charge of the intermediate. The most common electron-withdrawing groups used to activate compounds toward nucleophilic aromatic substitution are nitro groups, but other frequently used groups include cyano, carbonyl, and sulfonate groups. All of these groups can stabilize the negative charge by resonance. This direct resonance stabilization explains the importance of having electron-withdrawing at the ortho- and/or para-positions – groups in the meta-positions can only stabilize the negative charge inductively. As strong support for this mechanism, several Meisenheimer intermediates have been isolated and characterized (Figure 3.2 ) [2

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