CH 3 CHCH 3 CH 3 CHCH 3 Isopropyl cation. Oxomium ion intermediate. intermediate (an electrophile)

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1 Understanding (as opposed to memorizing) mechanisms is critical to mastering organic chemistry. Although the mechanisms you encounter throughout the course may seem entirely different, they are actually related in fundamental ways. In fact, almost all of the organic reaction mechanisms you will learn are composed of only a few different individual elements (steps) that are put together in various combinations. Your job is to learn these individual mechanism elements, and then understand how to assemble them into the steps of the correct mechanism for the reactions you will see. The KEY idea is that each mechanism step should be thought of as a MULTIPLE IE situation in which you evaluate the structures and reactivities of the molecules involved then rule out inappropriate elements on the way to deducing the appropriate element for each step of the mechanism. Polar Reaction Mechanisms: Polar reactions are most of what you will see in organic chemistry, amounting to greater than 95% of cases we will discuss. There are only a few different mechanistic elements that combine to make up the different steps of almost all the mechanisms you saw in 320M. Better yet, in 320 the following four mechanistic elements are pretty much all you need to think about until we get to electrophilic aromatic substitution near the end of the semester. 1. Make a new bond between a nucleophile (source for an arrow) and an electrophile (sink for an arrow). Use this element when there is a nucleophile present in the solution as well as an electrophile suitable for reaction to occur. Water (a nucleophile) Isopropyl cation xomium ion intermediate intermediate (an electrophile) 2. Break a bond so that relatively stable molecules or ions are created Use this element when there is no suitable nucleophile-electrophile or proton transfer reaction, but breaking a bond can create neutral molecules or relatively stable ions, or both. Br Br 3 2-Bromo-2-methylpropane 3 Bromide ion (relatively stable anion) tert-butyl cation intermediate (stabilized by inductive and hyperconjugation effects. See Section 6.3A)

2 3. Add a proton Use this element when there is no suitable nucleophile-electrophile reaction, but the molecule has a strongly basic functional group or there is a strong acid present Ethyl acetate (a carboxylic ester) ydronium ion (a strong acid) A protonated intermediate Water 4. Take a proton away Use this element when there is no suitable nucleophile-electrophile reaction, but the molecule has a strongly acidic proton or there is a strong base present. 3 3 xomium ion intermediate (strongly acidic) 3 3 Water (can act as abase) 2-Propanol Water The situation is even simpler than you might expect because 1. and 2. are the functional reverse of each other, as are 3. and 4. in many cases. Useful Definitions: Mechanism A scheme that illustrates all reaction intermediates, as well as the flow of electrons and movement of atoms during bond breaking and bond making processes. Remember that arrows are used only to indicate the movement of electrons. Movement of atoms is assumed, but not explicitly indicated, by the arrows. ucleophile An electron-rich species such as an atom with a lone pair or the pi bond of an alkene that reacts with an electrophile to make a new covalent bond. The nucleophile is the source for the arrow that indicates the new covalent bond being made. Electrophile A molecule that is the sink for the arrow that indicates a new covalent bond. Electrophiles often have a full or partial positive charge as well as possessing a relatively weak bond that can be broken to accommodate the new covalent bond. Brønsted-Lowry Base A molecule containing a lone pair (or pi bond) that will accommodate binding to a proton in a proton transfer reaction. Brønsted-Lowry Acid A molecule that can donate a proton in a proton transfer reaction. Leaving group A group that will be relatively stable when it departs, such as a small neutral species like 2 or 2, or a group such as a halide atom that departs as a relatively stable ion.

3 Putting it All Together: The preceding discussion can be applied to all of the polar reaction mechanisms you will see in organic chemistry. For example, the following equation describes the conversion of a tertiary alcohol into a haloalkane under acidic conditions. Br Br Alcohol Each step of the correct three-step mechanism for this process can be deduced by choosing the appropriate mechanistic element (1-7) based on the structures and reactivities of the molecules present. Step 1: Add a Proton - There is no suitable nucleophile-electrophile reaction, the molecule has no good leaving groups, but there is a proton source present in the solution such as a strong acid. The alcohol oxygen atom lone pairs can accept the proton from a strong acid like Br. 3 3 Br Strong Acid Br 3 3 Step 2: Break a bond so that relatively stable molecules or ions are created There is no suitable nucleophile-electrophile* or proton transfer reaction, but the molecule has a good leaving group attached. *There is no suitable nucleophile-electrophile reaction despite the presence of a good leaving group and a good nucleophile (Br - ) in the solution because of the steric hindrance caused by the three methyl groups around the tertiary carbon atom, preventing a backside attack required for an S 2 reaction. Good Leaving Group These Methyl Groups Block ucleophiles From Reacting

4 Step 3: Make a new bond between a nucleophile and an electrophile There is a nucleophile present in the solution (water) and the molecule has an electrophilic atom (an atom with a positive charge). The nucleophile-electrophile reaction takes place because the electrophilic carbon atom is sp 2 hybridized (trigonal planar geometry), and the Br - can approach from either the top or bottom without interference from the methyl groups. Br 3 3 Br Electrophile ED F MEAISM ucleophile 3 ote that steps 2 and 3 above correspond to an S 1 mechanism, and that E1 was suppressed in this case because of the presence of the strong acid (never have a step involving base when the reaction is run in acid). Sometimes to save space, mechanisms are written in a more condensed format such as the following: Br Br 3 3 Add a Break a proton bond 3 Step 1 Step Br Make a bond Step 3 3 Br 3 3

5 In second semester organic chemistry, the mechanisms get more complicated, but not the multiple choice type of analysis used to deduce appropriate mechanism elements for each mechanism step. For example, the following equation describes the acid-catalyzed hydrolysis of an acetal to give an aldehyde and two equivalents of alcohol l Acetal 3 The following seven-step mechanism for acetal hydrolysis may look complicated, but it is actually a relatively straightforward sequence of mechanism elements 1-4 that can be deduced by analyzing each step according to the structures and reactivities of the molecules present. Step 1: Add a Proton - There is no suitable nucleophile-electrophile reaction, the molecule has no good leaving groups, but there is a proton source present in the solution such as a strong acid. 3 l Strong Acid l Step 2: Break a bond so that relatively stable molecules or ions are created There is no suitable nucleophile-electrophile or proton transfer reaction, but the molecule has a good leaving group attached. Good Leaving Group Resonance Delocalization Stabilization 3

6 Step 3: Make a new bond between a nucleophile and an electrophile There is a nucleophile present in the solution (water) and the molecule has an electrophilic atom (an atom with a positive charge). 3 ucleophile 3 3 Electrophile 3 Step 4: Take a Proton Away There is no suitable nucleophile-electrophile reaction, but the molecule has an acidic proton. Strongly Acidic 3 l 3 + l 3 3 emiacetal Intermediate ote that the 2 group is a good leaving group as well as being strongly acidic, but having it depart would simply reverse the previous step, so that is not a productive choice. Step 5: Add a Proton - There is no suitable nucleophile-electrophile reaction, the molecule has no good leaving groups, but there is a proton source present in the solution such as a strong acid. 3 Strong Acid l 3 + l 3 3 emiacetal Intermediate

7 Step 6: Break a bond so that relatively stable molecules or ions are created There is no suitable nucleophile-electrophile or proton transfer reaction, but the molecule has a good leaving group attached Good Leaving Group Resonance Delocalization Stabilization ote that the 3 group is strongly acidic as well as being a good leaving group, but taking a proton away would simply reverse the previous step, so that is not a productive choice. Step 7: Take a Proton Away There is no suitable nucleophile-electrophile reaction, the molecule has no good leaving groups, but it has an acidic proton. Strongly Acidic 3 l 3 + l ED F MEAISM omplex mechanisms such as this are often written in one of several condensed formats. ere is one such format in which is the mechanism is drawn in a linear fashion: 3 l l 3 3 Add a proton Step 1 l 3 Break a bond Step 2 3 Resonance Delocalization Stabilization Make a bond Step Take a Proton Away Step emiacetal Intermediate l Add a proton Step Break a bond Step Resonance Delocalization Stabilization l Take a Proton Away Step l + l + l + 3

8 ere is an alternative format that is similar to the one we will use in class: l Add a proton Step l Break a bond Step Resonance Delocalization Stabilization 3 Make a bond Step 3 l l l l 3 Breack a bond 3 Step 6 Add a proton Step emiacetal Intermediate Take a Proton Away Step Resonance Delocalization Stabilization l Take a Proton Away Step 7 3 l

9 ere are the keys to understanding mechanisms in 320!! 1) There are basically four different mechanisms elements that make up the steps of carbonyl reactions. A) Make a bond between a nucleophile and an electrophile B) Break a bond to give stable molecules or ions ) Add a proton D) Take a proton away 2) These same four mechanism elements describe most of the other mechanisms you have/will learn!!! (Yes, organic chemistry really is this simple if you look at it this way!!) There are basically four different mechanisms that describe the vast majority of carbonyl reactions, which are different combinations/ordering of the four mechanism elements listed above. In this class, I have termed them "Mechanism A", "Mechanism B", "Mechanism ", and "Mechanism D". They all involve a nucleophile attacking the partially positively charged carbon atom of the carbonyl to create a tetrahedral intermediate. Different reaction mechanisms are distinguished by the timing of protonation of the oxygen atom as well as the presence or absence of a leaving group attached to the carbonyl.

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11 Grignard Reagent Reacting with an Epoxide MgBr 2 2) l / 2 hemist opens flask and adds acidic water Key Recognition Element (KRE): Products 1) 3 2 MgBr 2) l / ) 3 2 MgBr 2) l / ) 3 2 MgBr 2) l / 2

12 Grignard Reagent Reacting with an Aldehyde or Ketone MgBr Tetrahedral Intermediate 2) l / 2 Key Recognition Element (KRE): Products 1) 3 2 MgBr 2) l / 2 1) 3 2 MgBr 3 2) l / 2 1) 3 2 MgBr 3 3 2) l / 2 1) 3 2 MgBr 2) l / 2

13 Alkyne Anion Reacting with an Aldehyde or Ketone 3 + a a Tetrahedral Intermediate 2) l / 2 Key Recognition Element (KRE): Products

14 Reacting with an Aldehyde or Ketone 3 + Tetrahedral Intermediate Key Recognition Element (KRE): Products

15 Wittig Reaction S 2 P + Br Phosphonium salt n-butyl lithium (n-buli) Li Phosphonium ylide P + 3 Betaine intermediate Products xaphosphetane intermediate Key Recognition Element (KRE):

16 Acid atalyzed emiacetal and Acetal Formation From an Aldehyde or Ketone emiacetal intermediate 3 3 Key Recognition Element (KRE): Products

17 Formation if an Imine (Schiff Base) From an Aldehyde or Ketone Reacting with an Amine 3 Proton Transfer* 3 2 Imine (aka Schiff Base) Products Key Recognition Element (KRE): ote: this last step might actually occur as two steps in some cases. * "Proton Transfer" refers to a situation in which a proton moves from one part of a molecule to another on the SAME MLEULE. We do not draw arrows for proton transfer steps because that would be deceptive. In some cases, the same proton may move from one part of the molecule to the other directly, but in other cases, solvent molecules may be involved as indicated in the following scheme. To make things even more interesting, the following two steps might even be reversed in some cases. Becuase of all the ambiguity, we just write "Proton Transfer" and do not bother with arrows. "Proton Transfer"

18 Wolff-Kishner Reduction of an Aldehyde or Ketone Imine formation mechanism Several steps Resonance Stabilized Anion Key Recognition Element (KRE): Products

19 Keto-Enol Equilibrium atalyzed by Acid or Base Acid A A 3 Keto form Enol Base 3 Keto form Resonance Stabilized Enolate Anion α-hydrogen pk a = Enol For both aldehydes and ketones, the keto form predominates at equilibrium, because bonds are stronger than bonds. Enols are significant, however, because they react like, not carbonyls, and this is important in certain situations.

20 α-alogenation of an Aldehyde or Ketone atalyzed by Acid Keto form Enol Br Br 3 Products

21 Fischer Esterfication Products

22 Reaction with Thionyl hloride l S l Several Steps hlrorosulfite intermediate l Products Decarboxylation of a β-keto Acid β α Reactive onformation Products

23 The aloform Reaction 3 Keto form Resonance Stabilized Enolate Anion α-hydrogen pk a = Br Br Two more times Acid-base reaction Products

24 Keto-Enol Tautomerization vs. Enolate Resonance Keto-Enol Tautomerization Acid or Base 3 Keto form Enol Enolate Resonance 3 Keto form α-hydrogen pk a = Resonance Stabilized Enolate Anion Diazomethane reaction 3 Diazomethane contributing structures Amide Resonance VERY IMPRTAT!!!!!! 3 3

25 Interconversion of arboxylic Acid Derivatives

26 Acid atalyzed Anhydride ydrolysis Products

27 Acid atalyzed Ester ydrolysis Products

28 Microscopic Reversibilty: Acid atalyzed Ester ydrolysis-fischer Esterification * Racemic

29 Microscopic Reversibilty: Acid atalyzed Ester ydrolysis-fischer Esterification * Racemic

30 Microscopic Reversibilty: Acid atalyzed Ester ydrolysis-fischer Esterification Racemic *

31 Microscopic Reversibilty: Acid atalyzed Ester ydrolysis-fischer Esterification Racemic *

32 Base-Promoted Ester ydrolysis - Saponification 2) l Products

33 Acid Promoted Amide ydrolysis Products

34 Acid Promoted itrile ydrolysis tautomerization several steps (see amide hydrolysis mechanism) Products

35 Acid hlorides Reacting with Amines l 2 3 Proton transfer 2 3 Products

36 Grignard Reacting with Esters MgBr MgBr hemist pens Flask 2) Products

37 Grignard Reacting with Esters MgBr Make a bond * MgBr Racemic MEAISM B Break a bond MgBr MgBr Make a bond MgBr hemist pens Flask 2) Add a proton MEAISM A Mg Salts Products

38 Reduction of Esters with LiAl 4 Li Al Li Al hemist pens Flask 2) Products

39 Reduction of Esters with LiAl 4 Li Al 3 Li Make a bond Racemic * Al MEAISM B Break a bond Li Li Al Al 3 Make a bond Li 3 Al hemist pens Flask 2) MEAISM A The second alcohol comes from this alkoxide that is also protonated in water Aluminum salts Products

40 Reduction of Amides with LiAl 4 Li Al Li Al Products ote: In this reaction the chemist opens the flask and adds water in a second step that quenches any excess LiAl 4. Therefore, you need a second step to add water when using this reaction in synthesis even though it is not shown in the mechanism above.

41 Interconversion of arboxylic Acid Derivatives

42 Aldol Reaction Products Draw both enantiomers

43 Acid catalyzed dehydration Aldol product tautomerization Products

44 laisen ondensation o chiral centers in this case 3 Draw both enantiomers (hemist opens flask and adds a mild acid) 2) Mild Initial Products Final Products

45 Enamine Formation proton transfer slightly acidic p Products

46 Michael Reaction 1 Equivalent (aet) tautomerization Initial Products 2) Mild (hemist opens flask and adds a mild acid) Finall Products

47 β-substituted aldehydes, nitriles, ketones, or esters α,β-unsaturated, nitriles, ketones, or esters α,β-unsaturated aldehydes β-keto esters β-ydroxy aldehydes Acid hlorides Aldehydes Ketones arboxylic esters β-ketoaldehyde β-diketone arboxylic acids Substituted aldehyde Substituted ketone β-diester

48 Enolate KRE s. Identify the KRE s and the new - bonds * Racemic * Racemic * * Racemic * Racemic 2 * Racemic * * Racemic Racemic * Racemic

49 -X reacting with conjugated dienes Br major contributing structure minor contributing structure Allylic cation intermediate Br Br 1,2 Addition 1,4 Addition - more stable, more highly substituted = Products Products

50 Aromatic resonance stabilization of charged species Phenoxide anion Benzyl cation Benzyl radical

51 E E E E. E E

52 Fe X X X X X S S S Fe X X X X X S X FeX 4 X S E Reagents X = Br, l alogenation X 2, FeX 3 itration 2 S 4 / 3 Sulfonation 2 S 4 /S 3 Fuming sulfuric acid contains both of the above reagents, the S 3 is the important one Wicked strong electrophile

53 Reagents Friedel-rafts Alkylation R-X, AlX 3 Wicked strong electrophile E X Al X X X R X Al X R AlX 4 R X R X = Br, l Friedel-rafts Acylation Rl, All 3 l X ote this is a carbocation, so it will rearrange if it is a primary or a rearrangmentprone secondary cation l Al l l R R l l Al l AlX 4 l R Acylium ion R ther notes: 1) It is hard to stop the Friedel-rafts alkylation after one alkyl group adds (because alkyl groups are "good", that is, activating), but it can be done. 2) either Friedel- rafts reaction works if there is already an electron withdrawing (bad) group on the ring.

54 Arenium ion stabilizing interactions A) Pi donation, a resonance effect for atoms with lone pairs attached to the ring Electrophile Electrophile B) yperconjugation for alkyl groups attached to the ring Electrophile Electrophile Side view Arenium ion destabilizing interaction A) Inductive effect of electronegative atoms or groups attached to the ring Electrophile

55 RT GD or UGLY GD or UGLY GD or UGLY GD or UGLY Electrophile Electrophile Electrophile Electrophile META GD or UGLY GD or UGLY GD or UGLY Electrophile Electrophile Electrophile PARA GD or UGLY GD or UGLY GD or UGLY GD or UGLY Electrophile Electrophile Electrophile Electrophile

56 RT BAD Electrophile BAD Electrophile BAD Electrophile META BAD BAD BAD Electrophile Electrophile Electrophile PARA BAD BAD BAD Electrophile Electrophile Electrophile

57 ucleophilic Aromatic Substitution F Meisenheimer complex Products

58 Preparation of Diazoniums, The "Mr. Bill" Reaction a + al l The Mr. Bill reagent 2 Several Steps tautomerization l Products

59 3 R 3 R 3 R R 3 R R R R R emiacetal (not a stable species) R 3 R Acetal product

60 This can be another sugar! R R yclic hemiacetal (a stable species) 1 R Acetal product (A glycosidic bond if this were a carbohydrate) !-(D)-Glucose yclic hemiacetal (a stable species) "-(D)-Glucose yclic hemiacetal (a stable species) 1

61 Solid Phase Peptide Synthesis R' PLYMER BEAD R 2 PyBP Prot.Grp. R' PLYMER BEAD Prot.Grp. R Wash beads with solvent Add base to remove protecting group R' PLYMER BEAD R PyBP 2 Prot.Grp. R" Wash beads with solvent Add base to remove protecting group R' PLYMER BEAD 2 R R" Repeat as necessary then remove from resin. an add up to 100 amino acids this way.

62 R 2 R' PyBP :Base R R' P PyBP :Base R R R P R 2 R' P R R'

63 Solid Phase Synthesis of DA Prot.Grp. BASE' BASE (ipr) 2 P PLYMER BEAD Mix then wash beads Prot.Grp. BASE' P BASE PLYMER BEAD Add I 2 to oxidize P atom Wash resin Remove protecting group BASE' P BASE PLYMER BEAD

64 Substrate R Empty enzyme active site R 1 Aspartic Acid 25 Aspartic Acid 25' Aspartic Acid 25 Aspartic Acid 25' R R R R R 1 R 1 R 1 R 1 Aspartic Acid 25 Aspartic Acid 25' Aspartic Acid 25 Aspartic Acid 25' Aspartic Acid 25 Aspartic Acid 25' Aspartic Acid 25 Aspartic Acid 25' R R 1 R R 1 R R 1 Aspartic Acid 25 Aspartic Acid 25' Aspartic Acid 25 Aspartic Acid 25' Aspartic Acid 25 Aspartic Acid 25'

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