{"id":2624,"date":"2018-06-19T20:38:19","date_gmt":"2018-06-19T20:38:19","guid":{"rendered":"https:\/\/courses.lumenlearning.com\/suny-potsdam-organicchemistry\/chapter\/6-1-a-first-look-at-reaction-mechanisms-2\/"},"modified":"2018-08-06T13:54:59","modified_gmt":"2018-08-06T13:54:59","slug":"7-5-reaction-mechanisms","status":"publish","type":"chapter","link":"https:\/\/courses.lumenlearning.com\/suny-potsdam-organicchemistry\/chapter\/7-5-reaction-mechanisms\/","title":{"raw":"7.5. Reaction mechanisms","rendered":"7.5. Reaction mechanisms"},"content":{"raw":"
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An acid-base (proton transfer) reaction<\/h3>\r\nFor our first example of chemical reactivity, let\u2019s look at a very simple reaction that occurs between hydroxide ion and hydrochloric acid:\r\n\r\n\\[HCl\u00a0 + OH^- \\rightarrow\u00a0 H_2O + Cl^\u2013 \\tag{6.1.1}\\]\r\n\r\nThis is an acid-base reaction: a proton is transferred from HCl, the acid, to hydroxide, the base. The product is water (the conjugate acid of hydroxide)\u00a0 and chloride ion (the conjugate base of HCl). You have undoubtedly seen this reaction before in general chemistry.\u00a0 Despite its simplicity (and despite the fact that the reactants and products are inorganic<\/em> rather than organic), this reaction allows us to consider for the first time many of the fundamental ideas of organic chemistry that we will be exploring in various contexts throughout this text.\r\n\r\nOne very important key to understanding just about any reaction\u00a0 mechanism is the concept of electron density<\/strong>, and how it is connected to the electron movement<\/strong> (bond-breaking and bond-forming) that occurs in a reaction. The hydroxide ion \u2013 specifically, the electronegative oxygen atom in the hydroxide ion \u2013 has high electron density due to the polarity of the hydrogen-oxygen bond.\u00a0\u00a0 The hydroxide oxygen is electron-rich<\/strong>.\r\n\r\n\"image002.png\"\r\n\r\nThe hydrogen atom in HCl, on the other hand, has low electron density: it is electron-poor<\/strong>.\u00a0 As you might expect, something that is electron-rich is attracted to something that is electron-poor.\u00a0 As hydroxide and HCl move closer to each other, a lone pair of electrons on the electron-rich hydroxide oxygen is attracted by the electron-poor proton of HCl, and electron movement occurs towards the proton.\u00a0 The two electrons in the hydrogen-chlorine s bond are repelled by this approaching hydroxide electron density, and therefore move even farther away from the proton and towards the chlorine nucleus.\u00a0 The consequence of all of this electron movement is that the hydrogen-chlorine bond is broken, as the two electrons from that bond completely break free from the 1s orbital of the hydrogen and become a lone pair in the 3p orbital of a chloride anion.\r\n\r\n\"image004.png\"\r\n\r\nAt the same time that the hydrogen-chlorine bond is breaking, a new sigma bond forms between hydrogen and oxygen, containing the two electrons that previously were a lone pair on hydroxide.\u00a0 The result of this bond formation is, of course, a water molecule.\r\n\r\nPreviously (section 6.1.<\/a>) , we saw how curved arrows were used to depict \u2018imaginary\u2019 electron movement when drawing two or more resonance contributors for a single molecule or ion.\u00a0 These same curved arrows are used to show the very real electron movement that occurs in chemical reactions,\u00a0 where bonds are broken and new bonds are formed.\u00a0 The HCl + OH-<\/sup> reaction, for example, is depicted by drawing two curved arrows.\r\n\r\n\"image006.png\"\r\n\r\nThe first arrow originates at one of the lone pairs on the hydroxide oxygen and points to the \u2018H\u2019 symbol in the hydrogen bromide molecule, illustrating the \u2018attack\u2019 of the oxygen lone pair and subsequent formation of the new hydrogen-oxygen bond.\u00a0 The second curved arrow originates at the hydrogen-bromine bond and points to the \u2018Br\u2019 symbol, indicating that this bond is breaking - the two electrons are \u2018leaving\u2019 and becoming a lone pair on bromide ion.\r\n
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Exercise<\/h3>\r\nDraw electron movement arrows to illustrate the acid-base reaction between acetic acid, CH3<\/sub>COOH, and ammonia, NH3<\/sub>.\u00a0 Draw out the full Lewis structures of reactants and products.\r\n\r\n[reveal-answer q=\"251097\"]Show Solution[\/reveal-answer]\r\n[hidden-answer a=\"251097\"]\r\n

\"image312.png\"<\/p>\r\n[\/hidden-answer]\r\n\r\n<\/div>\r\n<\/div>\r\n<\/div>\r\n<\/div>\r\n

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A one-step nucleophilic substitution reaction (SN<\/sub>2)<\/h3>\r\nThe reaction between hydroxide and HCl is a simple example of a Br\u00f8nsted acid-base (proton transfer) reaction, and we will look at this reaction type in much more detail in Chapter 7<\/a>.\u00a0 For now, however, let\u2019s continue our introduction to the basic ideas of organic reactivity with a real organic reaction.\u00a0 Consider what might happen if a hydroxide ion encounters a chloromethane molecule instead of HCl.\u00a0 The hydroxide is still an electron-rich species, and thus might again be expected to act as a base and \u2018attack\u2019 a hydrogen. But in this case, the three hydrogens on the second reactant are not very electron-poor, as they are bound not to chlorine but to carbon, which is not very electronegative. However, there is<\/em> a relatively electron-poor atom in chloromethane: the carbon.\r\n\r\n\"image010.png\"\r\n\r\nBecause of the relative electronegativity of chlorine, the carbon-chlorine bond is polar. It stands to reason that a lone pair of electrons on the electron-rich hydroxide oxygen will be attracted to the electron-poor carbon.\r\n\r\n\"image012.png\"\r\n\r\nHowever, in order for a new bond to form between the hydroxide oxygen and the carbon, one of the bonds already on the carbon must break - otherwise, there will be five bonds to carbon and the octet rule will be violated. The C-Cl bond breaks as the new C-O bond forms, and the chlorine leaves along with its two electrons.\r\n\r\nThe reaction mechanism we see here is called a nucleophilic substitution<\/strong>, and is abbreviated SN<\/sub>2. The 'substitution' term is easy to understand: just recognize how hydroxide substitutes for bromine as the fourth bond to the central carbon.\u00a0 The term 'nucleophilic' means 'nucleus-loving' and refers to the electron-rich species, the hydroxide oxygen.\u00a0 This oxygen is a nucleophile<\/strong>: it is attracted to the (positively-charged) nucleus of the central carbon atom, and 'attacks' with a lone pair of electrons to form a new covalent bond. The number \u20182\u2019 refers to the fact that this reaction is bimolecular, and has second order kinetics.\r\n\r\nThe carbon is referred to in this context as an electrophile<\/strong>.\u00a0 The chlorine, because it leaves with its two electrons to become a chloride ion, is termed a leaving group<\/strong>.\u00a0 Notice that the three players in a nucleophilic substitution reaction - the nucleophile, the electrophile, and the leaving group - correspond conceptually to the three players in an acid-base reaction: the base, the acidic proton, and the conjugate base of the acid, respectively.\r\n\r\n\"image014.png\"\r\n\r\nIn many ways, the proton transfer process of an acid-base reaction can be thought of as simply a special kind of nucleophilic substitution reaction, one in which\u00a0 the electrophile is a hydrogen rather than a carbon.\r\n
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Exercise<\/h3>\r\nIn each of the reactions below, identify the nucleophile, electrophile, and leaving group (assume in each case that a basic group is available to accept a hydrogen from the nucleophilic atom).\"image016.png\"\r\n\r\n[reveal-answer q=\"786672\"]Show Solution[\/reveal-answer]\r\n[hidden-answer a=\"786672\"]\"image314.png\"\r\n\r\n[\/hidden-answer]\r\n\r\n<\/div>\r\n<\/div>\r\n<\/div>\r\n<\/div>\r\n<\/div>\r\n
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A two-step nucleophilic substitution reaction (SN<\/sub>1)<\/h3>\r\nReaction\u00a0 mechanisms describe not only the electron movement that occurs in a chemical reaction, but also the order<\/em> in which bond-breaking and bond-forming events occur.\u00a0 Nucleophilic substitution reactions, for example, can occur by a second, alternative mechanism that is different from the mechanism above in terms of the order of events.\u00a0 A simple illustration is provided by the reaction of hydroxide with a tertiary alkyl chloride, such as 2-chloro-2-methyl propane.\r\n\r\n\"image018.png\"\r\n\r\nUnlike the chloromethane plus hydroxide reaction, in which the substitution process took place in a single, concerted step, this mechanism involves two separate steps.\u00a0 The leaving group, chloride anion, leaves first, before<\/em> the hydroxide nucleophile approaches.\r\n\r\n\"image020.png\"\r\n\r\nWhat is left behind after the leaving group leaves is a carbocation: a planar, sp2<\/sup>-hybridized carbon center with three bonds, an empty 2pz<\/sub> orbital, and a full positive charge. In the language of organic mechanisms, this carbocation is referred to as a reaction<\/strong> intermediate<\/strong>.\r\n\r\nA positively charged carbon is (obviously) very electron-poor, and thus the reactive intermediate is a powerful electrophile.\u00a0 It is quickly attacked by the hydroxide nucleophile to form the substitution product.\r\n\r\n\"image022.png\"\r\n\r\nWe will see later that other products are possible for this combination of reactants, but we will not worry about that for now.\r\n
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Note: Intermediates<\/strong><\/p>\r\n\r\n

\r\n\r\nIn biological chemistry, the term 'intermediate' is also used to refer to compounds that are part of a metabolic pathway.\u00a0 In the general scheme below, compounds B, C, D, E, and F are all intermediate compounds in the metabolic pathway in which compound A is converted to compound G.\r\n\r\n\"image024.png\"\r\n\r\nPathway<\/em> intermediates are often relatively stable compounds, whereas reaction<\/em> intermediates (such as the carbocation species that plays a part in the two-step nucleophilic substitution) are short-lived, high energy species.\r\n\r\n<\/div>\r\n<\/div>\r\nThis mechanism is referred to by the abbreviation SN<\/sub>1: a nucleophilic substitution that is unimolecular, with first order kinetics.\r\n\r\nAlthough nucleophilic substitutions at carbon are not terribly common in biochemistry, there are nevertheless some very important biological examples.\u00a0 One of these is DNA methylation.\u00a0 In the reaction below, the nucleophile is an amino nitrogen on adenosine (one of the four DNA building blocks).\u00a0 The electrophile is a methyl carbon on a molecule called S-adenosylmethionine (usually abbreviated \u2018SAM\u2019).\r\n\r\n\"image026.png\"\r\n\r\nNotice that the leaving group in this reaction is a neutral sulfide, and that this is a single-step nucleophilic substitution (SN<\/sub>2), like our chloromethane example.\r\n\r\nWe will have much more to say about nucleophilic substitutions, nucleophiles, electrophiles, and leaving groups in chapter 8, and we will learn why<\/em> some substitutions occur in a single step and some occur in two steps with a carbocation intermediate.\u00a0 For now, however, we need to review the convention of energy diagrams and some of the basic concepts of thermodynamics and kinetics in order to continue our introduction to organic reactivity.\r\n\r\n\"\"\r\n\r\n[embed]https:\/\/www.youtube.com\/watch?v=7ljWcombzmE[\/embed]\r\n\r\n<\/div>\r\n<\/section>","rendered":"
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An acid-base (proton transfer) reaction<\/h3>\n

For our first example of chemical reactivity, let\u2019s look at a very simple reaction that occurs between hydroxide ion and hydrochloric acid:<\/p>\n

\\[HCl\u00a0 + OH^- \\rightarrow\u00a0 H_2O + Cl^\u2013 \\tag{6.1.1}\\]<\/p>\n

This is an acid-base reaction: a proton is transferred from HCl, the acid, to hydroxide, the base. The product is water (the conjugate acid of hydroxide)\u00a0 and chloride ion (the conjugate base of HCl). You have undoubtedly seen this reaction before in general chemistry.\u00a0 Despite its simplicity (and despite the fact that the reactants and products are inorganic<\/em> rather than organic), this reaction allows us to consider for the first time many of the fundamental ideas of organic chemistry that we will be exploring in various contexts throughout this text.<\/p>\n

One very important key to understanding just about any reaction\u00a0 mechanism is the concept of electron density<\/strong>, and how it is connected to the electron movement<\/strong> (bond-breaking and bond-forming) that occurs in a reaction. The hydroxide ion \u2013 specifically, the electronegative oxygen atom in the hydroxide ion \u2013 has high electron density due to the polarity of the hydrogen-oxygen bond.\u00a0\u00a0 The hydroxide oxygen is electron-rich<\/strong>.<\/p>\n

\"image002.png\"<\/p>\n

The hydrogen atom in HCl, on the other hand, has low electron density: it is electron-poor<\/strong>.\u00a0 As you might expect, something that is electron-rich is attracted to something that is electron-poor.\u00a0 As hydroxide and HCl move closer to each other, a lone pair of electrons on the electron-rich hydroxide oxygen is attracted by the electron-poor proton of HCl, and electron movement occurs towards the proton.\u00a0 The two electrons in the hydrogen-chlorine s bond are repelled by this approaching hydroxide electron density, and therefore move even farther away from the proton and towards the chlorine nucleus.\u00a0 The consequence of all of this electron movement is that the hydrogen-chlorine bond is broken, as the two electrons from that bond completely break free from the 1s orbital of the hydrogen and become a lone pair in the 3p orbital of a chloride anion.<\/p>\n

\"image004.png\"<\/p>\n

At the same time that the hydrogen-chlorine bond is breaking, a new sigma bond forms between hydrogen and oxygen, containing the two electrons that previously were a lone pair on hydroxide.\u00a0 The result of this bond formation is, of course, a water molecule.<\/p>\n

Previously (section 6.1.<\/a>) , we saw how curved arrows were used to depict \u2018imaginary\u2019 electron movement when drawing two or more resonance contributors for a single molecule or ion.\u00a0 These same curved arrows are used to show the very real electron movement that occurs in chemical reactions,\u00a0 where bonds are broken and new bonds are formed.\u00a0 The HCl + OH–<\/sup> reaction, for example, is depicted by drawing two curved arrows.<\/p>\n

\"image006.png\"<\/p>\n

The first arrow originates at one of the lone pairs on the hydroxide oxygen and points to the \u2018H\u2019 symbol in the hydrogen bromide molecule, illustrating the \u2018attack\u2019 of the oxygen lone pair and subsequent formation of the new hydrogen-oxygen bond.\u00a0 The second curved arrow originates at the hydrogen-bromine bond and points to the \u2018Br\u2019 symbol, indicating that this bond is breaking – the two electrons are \u2018leaving\u2019 and becoming a lone pair on bromide ion.<\/p>\n

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Exercise<\/h3>\n

Draw electron movement arrows to illustrate the acid-base reaction between acetic acid, CH3<\/sub>COOH, and ammonia, NH3<\/sub>.\u00a0 Draw out the full Lewis structures of reactants and products.<\/p>\n

Show Solution<\/span><\/p>\n
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\"image312.png\"<\/p>\n<\/div>\n<\/div>\n<\/div>\n<\/div>\n<\/div>\n<\/div>\n

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A one-step nucleophilic substitution reaction (SN<\/sub>2)<\/h3>\n

The reaction between hydroxide and HCl is a simple example of a Br\u00f8nsted acid-base (proton transfer) reaction, and we will look at this reaction type in much more detail in Chapter 7<\/a>.\u00a0 For now, however, let\u2019s continue our introduction to the basic ideas of organic reactivity with a real organic reaction.\u00a0 Consider what might happen if a hydroxide ion encounters a chloromethane molecule instead of HCl.\u00a0 The hydroxide is still an electron-rich species, and thus might again be expected to act as a base and \u2018attack\u2019 a hydrogen. But in this case, the three hydrogens on the second reactant are not very electron-poor, as they are bound not to chlorine but to carbon, which is not very electronegative. However, there is<\/em> a relatively electron-poor atom in chloromethane: the carbon.<\/p>\n

\"image010.png\"<\/p>\n

Because of the relative electronegativity of chlorine, the carbon-chlorine bond is polar. It stands to reason that a lone pair of electrons on the electron-rich hydroxide oxygen will be attracted to the electron-poor carbon.<\/p>\n

\"image012.png\"<\/p>\n

However, in order for a new bond to form between the hydroxide oxygen and the carbon, one of the bonds already on the carbon must break – otherwise, there will be five bonds to carbon and the octet rule will be violated. The C-Cl bond breaks as the new C-O bond forms, and the chlorine leaves along with its two electrons.<\/p>\n

The reaction mechanism we see here is called a nucleophilic substitution<\/strong>, and is abbreviated SN<\/sub>2. The ‘substitution’ term is easy to understand: just recognize how hydroxide substitutes for bromine as the fourth bond to the central carbon.\u00a0 The term ‘nucleophilic’ means ‘nucleus-loving’ and refers to the electron-rich species, the hydroxide oxygen.\u00a0 This oxygen is a nucleophile<\/strong>: it is attracted to the (positively-charged) nucleus of the central carbon atom, and ‘attacks’ with a lone pair of electrons to form a new covalent bond. The number \u20182\u2019 refers to the fact that this reaction is bimolecular, and has second order kinetics.<\/p>\n

The carbon is referred to in this context as an electrophile<\/strong>.\u00a0 The chlorine, because it leaves with its two electrons to become a chloride ion, is termed a leaving group<\/strong>.\u00a0 Notice that the three players in a nucleophilic substitution reaction – the nucleophile, the electrophile, and the leaving group – correspond conceptually to the three players in an acid-base reaction: the base, the acidic proton, and the conjugate base of the acid, respectively.<\/p>\n

\"image014.png\"<\/p>\n

In many ways, the proton transfer process of an acid-base reaction can be thought of as simply a special kind of nucleophilic substitution reaction, one in which\u00a0 the electrophile is a hydrogen rather than a carbon.<\/p>\n

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Exercise<\/h3>\n

In each of the reactions below, identify the nucleophile, electrophile, and leaving group (assume in each case that a basic group is available to accept a hydrogen from the nucleophilic atom).\"image016.png\"<\/p>\n

Show Solution<\/span><\/p>\n
\"image314.png\"<\/p>\n<\/div>\n<\/div>\n<\/div>\n<\/div>\n<\/div>\n<\/div>\n<\/div>\n
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A two-step nucleophilic substitution reaction (SN<\/sub>1)<\/h3>\n

Reaction\u00a0 mechanisms describe not only the electron movement that occurs in a chemical reaction, but also the order<\/em> in which bond-breaking and bond-forming events occur.\u00a0 Nucleophilic substitution reactions, for example, can occur by a second, alternative mechanism that is different from the mechanism above in terms of the order of events.\u00a0 A simple illustration is provided by the reaction of hydroxide with a tertiary alkyl chloride, such as 2-chloro-2-methyl propane.<\/p>\n

\"image018.png\"<\/p>\n

Unlike the chloromethane plus hydroxide reaction, in which the substitution process took place in a single, concerted step, this mechanism involves two separate steps.\u00a0 The leaving group, chloride anion, leaves first, before<\/em> the hydroxide nucleophile approaches.<\/p>\n

\"image020.png\"<\/p>\n

What is left behind after the leaving group leaves is a carbocation: a planar, sp2<\/sup>-hybridized carbon center with three bonds, an empty 2pz<\/sub> orbital, and a full positive charge. In the language of organic mechanisms, this carbocation is referred to as a reaction<\/strong> intermediate<\/strong>.<\/p>\n

A positively charged carbon is (obviously) very electron-poor, and thus the reactive intermediate is a powerful electrophile.\u00a0 It is quickly attacked by the hydroxide nucleophile to form the substitution product.<\/p>\n

\"image022.png\"<\/p>\n

We will see later that other products are possible for this combination of reactants, but we will not worry about that for now.<\/p>\n

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Note: Intermediates<\/strong><\/p>\n

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In biological chemistry, the term ‘intermediate’ is also used to refer to compounds that are part of a metabolic pathway.\u00a0 In the general scheme below, compounds B, C, D, E, and F are all intermediate compounds in the metabolic pathway in which compound A is converted to compound G.<\/p>\n

\"image024.png\"<\/p>\n

Pathway<\/em> intermediates are often relatively stable compounds, whereas reaction<\/em> intermediates (such as the carbocation species that plays a part in the two-step nucleophilic substitution) are short-lived, high energy species.<\/p>\n<\/div>\n<\/div>\n

This mechanism is referred to by the abbreviation SN<\/sub>1: a nucleophilic substitution that is unimolecular, with first order kinetics.<\/p>\n

Although nucleophilic substitutions at carbon are not terribly common in biochemistry, there are nevertheless some very important biological examples.\u00a0 One of these is DNA methylation.\u00a0 In the reaction below, the nucleophile is an amino nitrogen on adenosine (one of the four DNA building blocks).\u00a0 The electrophile is a methyl carbon on a molecule called S-adenosylmethionine (usually abbreviated \u2018SAM\u2019).<\/p>\n

\"image026.png\"<\/p>\n

Notice that the leaving group in this reaction is a neutral sulfide, and that this is a single-step nucleophilic substitution (SN<\/sub>2), like our chloromethane example.<\/p>\n

We will have much more to say about nucleophilic substitutions, nucleophiles, electrophiles, and leaving groups in chapter 8, and we will learn why<\/em> some substitutions occur in a single step and some occur in two steps with a carbocation intermediate.\u00a0 For now, however, we need to review the convention of energy diagrams and some of the basic concepts of thermodynamics and kinetics in order to continue our introduction to organic reactivity.<\/p>\n

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