Nucleophilic Addition Reaction

7 Key excerpts on "Nucleophilic Addition Reaction"

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  Biochemistry

  An Organic Chemistry Approach

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

    (Publisher)

  3  Nucleophiles and Electrophiles

  Aliphatic substitution reactions are early examples of organic chemical reactions in a typical undergraduate organic chemistry course. Such reactions involve the reaction of nucleophilic species with an electrophilic species, and for the most part they follow first-order or second-order kinetics. There are nucleophiles that are prevalent in biochemical reactions, including alcohols, amines, and thiols. Substitution reactions in a typical organic chemistry course involve reactions at carbon that is connected to a heteroatom moiety such as a halogen leaving group. In biochemistry the leaving group is often a phosphonate ester or another biocompatible group. Another type of nucleophilic reaction involves carbonyl compounds, including acyl addition of ketone and aldehyde moieties and acyl substitution reactions of carboxylic acid derivatives.

  This chapter will briefly review the SN 2 and SN 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

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  Computational Organic Chemistry

  • Steven M. Bachrach(Author)
  • 2014(Publication Date)
  • Wiley

    (Publisher)

  Chapter 6 Organic Reactions of Anions This chapter presents computational studies of organic reactions that involve anions. These reactions are usually not grouped together in textbooks. However, these reactions are fundamentally variations on a theme. Anions, acting as nucleophiles, can attack sp 3 carbon atoms; we call these as nucleophilic substitution reactions that follow either the S N 1 or S N 2 mechanism. Reactions where the nucleophile attacks sp 2 or sp carbon atoms are addition reactions. The 1,2- and 1,4-addition reactions follow the classic addition mechanism, where the nucleophile adds first followed by the addition of an electrophile. Other nucleophilic reactions at carbonyl compounds, especially carboxylic acid derivatives, follow the addition–elimination pathway. In a sense, these reaction mechanisms differ simply in the timing of the critical steps: the formation of the new C-nucleophile bond and the cleavage of a carbon-leaving group (C-LG) bond. In the S N 1 mechanism, cleavage occurs prior to bond formation. The opposite order characterizes the addition–elimination mechanism—bond formation precedes bond breaking. Lastly, the two bond changes occur together in one step in the S N 2 mechanism. In this chapter, we present the contributions of computational chemistry toward understanding the mechanism and chemistry for three reactions involving nucleophilic attack. The S N 2 reaction, with emphasis on the gas versus solution phase, is presented first. Next, we describe the critical contribution that computational chemists made in developing the theory of asymmetric induction at carbonyl and vinyl compounds

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  The Organometallic Chemistry of the Transition Metals

  • Robert H. Crabtree(Author)
  • 2019(Publication Date)
  • Wiley

    (Publisher)

  8.9 ) show examples of the four types of reaction.

  1. Nucleophilic addition[1 ]:
     8.1
     8.2
  2. Nucleophilic abstraction[2 ]:
     8.3
     8.4
     8.5
  3. Electrophilic addition[3 ]:
     8.6
     8.7
  4. Electrophilic abstraction[4 ]:
     8.8
     8.9

  In Eqs. (8.1 ) and (8.2 ), the reaction reduces the hapticity of the ligands because the metal is displaced from the carbon that the nucleophile attacks. In Eq. (8.2 ), for example, an η5 ‐L2 X ligand converts into an η4 ‐L2 ligand with a one‐unit decrease in the net ionic charged but a zero net change in the metal electron count. In general, an L

  n

  X ligand is converted to an L

  n

  ligand, and an L

  n

  ligand is converted to an L

  (n−1)

  X ligand. Electrophilic reagents, in contrast, tend to increase the hapticity of the ligand to which they add (Eqs. (8.6 ) and (8.7 )). Electrophilic attack on a ligand depletes the electron density on that ligand, often compensated for by the attack of a metal lone pair on the ligand. For instance, in Eq. (8.7 ), an η4 ‐L2 diene ligand becomes an η5 ‐L2 X pentadienyl. At the same time, a net positive ionic charge appears on the complex, which leaves the overall electron count unchanged. In general, an L

  n

  X ligand converts to an L

  (n+1)

  ligand and an L

  n

  ligand to an L

  n

  X ligand. Equations (8.3 ) and (8.4 ) show that nucleophilic abstraction of H+ is simply ligand deprotonation. Nucleophilic abstraction of a methyl cation from Pt(IV) by iodide was the key step in the reductive elimination mechanism of Fig. 6.2.

  Attack often occurs at the metal rather than at the ligand. For a nucleophile, this is simply associative substitution (Section 4.5 ) and can lead to the displacement of an existing ligand. If the original metal complex is 16e, nucleophilic attack may take place directly on the metal; if 18e, a ligand must usually dissociate first. In a coordination‐inert 18e complex, a nucleophile is therefore likely to attack a ligand, rather than the metal. The pyridine in Eq. (8.1

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  The Chemistry of Carbonyl Compounds and Derivatives

  • Paulo Costa, Ronaldo Pilli, Sergio Pinheiro, Peter Bakuzis(Authors)
  • 2022(Publication Date)
  • Royal Society of Chemistry

    (Publisher)

  Scheme 10.8 Nucleophilic addition (1,2- and 1,4-addition) to diastereotopic faces of C=C and C=O bonds of α,β-unsaturated carbonyl compounds.

  Similarly, the conjugate addition step leads to intermediate diastereomeric enolates 1 and 2 that are formed in different amounts (Scheme 10.8b). From these enolates, protonation can occur either at the Si or Re faces of Cα, leading to the formation of four diastereomeric products (C, D, E, and F).

  10.2 Heteroatoms as Nucleophiles

  In Figure 10.7 , we show several nucleophiles where a heteroatom is the nucleophilic site. Phosphines and phosphites (Figure 10.7a ) show high nucleophilicity due to the polarizability of the phosphorus atom. The nitrogen atom also occupies a prominent position due to the variety of nitrogenated compounds that can be used as nucleophiles (Figure 10.7b ). Primary and secondary amines, hydroxylamines, hydrazines, imidazoles, and carbamates, in addition to the azide and amide anions, are the most used nitrogen-centered nucleophilic species. It is worth mentioning that for the nitrite anion, while the negative charge is located at the oxygen atom in the resonance structure shown, it is the nitrogen with a lone electron pair that acts as the nucleophilic site (more polarizable, larger HOMO atomic coefficient). Similarly, in the sulfinate anion it is not the negatively charged oxygen atom, but rather the more polarizable sulfur atom that acts as the nucleophilic center (Figure 10.7c ). Alcohols, thiols, and selenols, as well as their respective anions, are the most widely used nucleophiles among the chalcogens.

  Figure 10.7 Representative heteronucleophiles in conjugate addition to α,β-unsaturated carbonyl compounds.

  10.2.1 Nitrogen as Nucleophile

  The 1,4-addition of ammonia to crotonic acid was the first conjugate addition involving a nitrogen nucleophile to be described, in 1911. Due to the importance of nitrogen derivatives and the key role played in the formation of C–N bonds, the scope of this reaction has been extensively studied, and we currently have a wide range of conjugated carbonyls and nucleophilic species available to carry out this transformation, as we will see throughout this section.

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  Organic Chemistry

  A Mechanistic Approach

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

    (Publisher)

  421 11.1 INTRODUCTION In this chapter, we will be studying addition reactions to carbon–carbon multiple bonds; this is the converse process of the eliminations that we studied in the previous chapter. Addition to carbon–heteroatom multiple bonds is coming up in Chapter 14. Nucleophiles, electrophiles, and radicals can all add across double bonds; first, we will concentrate on electrophiles and radicals, as nucleophiles only add readily when the double bond bears a group (such as a carbonyl, nitro, or nitrile; Chapter 17) capable of accepting electron density. Reactions with electrophiles or radicals add two moieties, atoms or groups, by a stepwise process; the two atoms or groups are not added simultaneously. However, there is another class of reactions where the two new bonds are made simultaneously—these are called concerted reactions. We should first recall the electronic structure of alkenes, with carbon atoms sp 2 hybridized and a sigma framework of bonds at approximately 120 ° to each other. Above and below the plane of the molecule is a π-orbital, derived from the two remaining p z orbitals ( 11.1). 11.1 The addition of two atoms or groups to an alkene is the most important reaction for this type of com- pound. The two electrons of the π-bond provide two of those needed to make the two new σ-bonds. 11.2 ELECTROPHILIC REACTIONS 11.2.1 REACTION MECHANISM This reaction is typified by the addition of a hydrogen halide, HX, or water, to an alkene. The process involves two steps, with a carbocation as the intermediate. In the first step (Figure 11.1), an electrophile, for example, a proton, is added to the carbon–carbon bond to form a carboca- tion. Notice how the curly arrow is drawn—the proton is being added to the “upper” carbon of the double bond and the electrons are “taken away” from the “lower” carbon, leaving it positively charged. In the second step, the counterion, for example, bromide, attacks the carbocation to give a saturated product.

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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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  Organic Reaction Mechanisms 2015

  An annual survey covering the literature dated January to December 2015

  • A. C. Knipe(Author)
  • 2019(Publication Date)
  • Wiley

    (Publisher)

  CHAPTER 10 Addition Reactions: Polar Additions A. C. Knipe School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland Reviews . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 430 Electrophilic Additions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 430 Halogenation and Related Reactions . . . . . . . . . . . . . . . . . . . . . . . 430 Additions of Electrophilic S and Se . . . . . . . . . . . . . . . . . . . . . . . . 437 Additions of Brønsted Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . 440 Additions of Electrophilic Nitrogen . . . . . . . . . . . . . . . . . . . . . . . . 441 Additions Initiated by Metal Ions as Electrophiles . . . . . . . . . . . . . . . . 442 (i) Boron . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 442 (ii) Silicon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 444 (iii) Iron and Ruthenium . . . . . . . . . . . . . . . . . . . . . . . . . . 447 (iv) Cobalt, Rhodium, and Iridium . . . . . . . . . . . . . . . . . . . . 448 (v) Nickel, Palladium, and Platinum . . . . . . . . . . . . . . . . . . . 455 (vi) Copper, Silver, and Gold . . . . . . . . . . . . . . . . . . . . . . . 463 (vii) Miscellaneous metal catalysts . . . . . . . . . . . . . . . . . . . . 471 Miscellaneous Electrophilic Additions . . . . . . . . . . . . . . . . . . . . . . 472 Nucleophilic Additions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 473 Additions of Multiple Bonds Conjugated with C=O . . . . . . . . . . . . . . . 473 (i) Boron nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . 473 (ii) Sulfur nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . 473 (iii) Oxygen nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . 473 (iv) Phosphorus nucleophiles . . . . . . . . . . . . . . . . . . . . . . . 473 (v) Nitrogen nucleophiles .

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