Chem 345 Reaction List: Chem 343 Reactions: Page 1 (You do not need to know the mechanism for the reactions in the boxes).

Transcription

1 Chem 345 eaction List: Chem 343 eactions: Page 1 (You do not need to know the mechanism for the reactions in the boxes). uc - optically active LG 2 optically active uc Alpha carbon (carbon attached to leaving group) must be unhindered. Alpha carbon inverted in the reaction. Leaving group must be good (conjugate pka less than or equal to 0) Good LG's: I -, Br -, Ts -, etc... More hindered the alpha carbon or the more basic the nucleophile, the more likely that E2 outcompetes 2. uc - optically active LG 1 racemic uc Alpha carbon (carbon attached to leaving group) must be tertiary or secondary. Primary alpha carbons can undergo 1 if a resonance stabilized carbocation is involved. Alpha carbon scrambled in the reaction. Leaving group must be good (conjugate pka less than or equal to 0) Good LG's: I -, Br -, Ts -, etc... Can undergo rearrangements to give a more stable carbocation.

2 Chem 345 eaction List: Chem 343 eactions: Page 2 (You do not need to know the mechanism for the reactions in the boxes). 2 4 optically active LG E1 Alpha carbon (carbon attached to leaving group) must be tertiary or secondary. Primary alpha carbons can undergo 1 if a resonance stabilized carbocation is involved. The most substituted alkene is the major product (aitzev's rule) on-nucleophilic acids like sulfuric acid work best Alcohols are commonly used as leaving groups as sulfuric acid can protonate them to turn them into good leaving groups. Base LG optically active E2 T The strength of the base necessary is dependent on the hindrance of the alpha carbon due to competition from the 2 reaction. Tertiary alpha carbons (no competition with 2): a moderate base (conj. pka 10) can be used econdary alpha carbons: a strong base (conj. pka 15 or higher necessary) Primary alpha carbons: a strong, bulky base such as KtBu necessary. Major product dependent on base used. mall base->more substituted alkene. Bulky base (KtBu)->less substituted alkene. Leaving group and beta hydrogen must be anticoplanar. Leaving group must be good (conjugate pka less than or equal to 0) Good LG's: I -, Br -, Ts -, etc... 's cannot be eliminated by an E2 mechanism.

3 Chem 345 eaction List: Chem 343 eactions: Page 3 (You do not need to know the mechanism for the reactions in the boxes). PCC C 2 2 secondary alcohol becomes ketone. 343 reaction) (Primary alcohol becomes aldehyde PBr 3 Br (Works for methyl, primary, and secondary alcohols via 2 reaction. Does not react with tertiary alcohols. 343 reaction) or 2 Cr 4 2 (econdary alcohols are converted into ketones) 343 eaction

4 Chem 345 eaction List: Exam I eactions: Page 4 (You do not need to know the mechanism for the reactions in the boxes). cat. 2 4 Acid catalyst should be a strong one like Ts, 2 4, or. cat Acid catalyst should be a strong one like Ts, 2 4, or. cat Acid catalyst can be a weak acid like Ac. group ends up cis to the smaller substituent on the aldehyde or ketone. 2 cat. a C cat Acid technically not needed for imine cleavage C KC C Ac acid or base acid or base emiacetals are mechanistic intermediates only. Very few are stable enough to be synthetic products.

5 Chem 345 eaction List: Exam I eactions: Page 5 (You do not need to know the mechanism for the reactions in the boxes). MgBr 3 + Li 3 + rganolithiums behave just like Grignards ab 4 Et ab 4 Et 2 cat. Ac ab 3 C eductive amination C cat. a About any base capable of pulling a proton off an can be used. (conj. pka 10 or more) KC 4 C 2

6 Chem 345 eaction List: Exam I eactions: Page 6 (You do not need to know the mechanism for the reactions in the boxes). PPh 3 (Just an 2 eaction) Br PPh 3 Base PPh 3 PPh 3 Wittig eagent (Base needs to be strong like KtBu, a, a 2, or BuLi) PPh 3 onstabilized Wittig onstabilized Wittigs typically give Z tabilized Wittigs typically give E PPh 3 tabilized Wittig onstabilized Wittigs typically give Z tabilized Wittigs typically give E X Mg MgX (X can be I, Br, or ) X 2.0 eq. Li Li (X can be I, Br, or ) (LiX is byproduct) It is okay if you do not mention 2.0 eq. X BuLi Li Lithium alogen Exchange (Don't make BuLi this way)

7 Chem 345 eaction List: Exam II eactions: Page 7 (You do not need to know the mechanism for the reactions in the boxes). Br (This works when is methyl or primary sp 3 carbon). 2 reaction cat. 2 4 (Fisher esterification: This works for methyl, primary, or secondary alcohols but not tertiary alcohols) a cat. 2 4 or cat. a cat. 2 4 Works for tertiary esters (carbonyl oxygen bond remains intact) 2 2 Et 3 Et 3

8 Chem 345 eaction List: Exam II eactions: Page 8 (You do not need to know the mechanism for the reactions in the boxes). DCC Et /Pd /Pd

9 Chem 345 eaction List: Exam II eactions: Page 9 (You do not need to know the mechanism for the reactions in the boxes). Boc 2 Et 3 Boc Fmoc 2 Et 3 Fmoc Z 2 Et 3 Z cat a

10 Chem 345 eaction List: Exam II eactions: Page 10 (You do not need to know the mechanism for the reactions in the boxes). MgBr 3 + Me Li 3 + Me excess MgBr + excess Li 3 + LiAl C 2 excess MgBr 3 + C 2 excess Li 3 +

11 Chem 345 eaction List: Exam II eactions: Page 11 (You do not need to know the mechanism for the reactions in the boxes). LiAl LiAl LiAl LiAl Li 3 + MgBr

12 Chem 345 eaction List: Exam II eactions: Page 12 (You do not need to know the mechanism for the reactions in the boxes). The mechanisms of these reactions are fair game for exam III. eactions on this page only work on ketones and aldehydes ' Baeyer-Villiger mcpba ' Migration rder: >3 C>2 >1 C>Me mcpba mcpba ' Beckmann 2 oxime Migration rder: Whichever group is opposite the migrates so 3 C>2 >1 C>Me> ' Ts, Et 3 Ts ' Δ 2 ' 1.) 2, 2.) Ts, Et 3 3.) Δ, 2 1.) 2, 2.) Ts, Et 3 3.) Δ, 2 Δ 2, 2 4, 2 eaction can also be done in a single step.

13 Chem 345 eaction List: Exam III eactions: Page 13 D excess D D D excess D D D D Al 3 (eaction does not work when the ring is strongly deactivated) It can work with halobenzenes, but not anything more deactivated) 2 Br 2 Br Al 3 FeBr Δ useful way to make ortho substituted benzene rings

14 Chem 345 eaction List: Exam III eactions: Page 14 Al 3 excess ave to use large excess, otherwise multiple alkylations occur. is an alkyl group (sp 3 C). ot a particularly clean reaction as rearrangements occur quite frequently as well. emmenson eduction Zng Ph Wolff-Kishner eduction K 2 2 Δ Ph educes ketones and aldehydes Vilsmeier-aack eaction P 3 2 DMF DMF= (eaction does not work when the ring is strongly deactivated) It can work with halobenzenes, but not anything more deactivated)

15 Chem 345 eaction List: Exam III eactions: Page 15 andmeyer equence: 2 /Pd/C 2 2 a 2, Br CuBr Br Br When using CuBr or Cu, the acid used in the first step should match. a 2, Cu CuC 2 3 P C 2 Cu 2 2 KI I

16 Chem 345 eaction List: Exam III eactions: Page 16 Electrophilic Aromatic ubstitution: Approximate eactivity X C > > > > > ~ > > > > =alkyl, aryl If isn't a carbonyl group, the can be protonated in strongly acidic media (changing the nature of the group) Activating X=F,, Br, I Deactivating X C > > > > > ~ > > > > =alkyl, aryl ortho para directors para typically favored X=F,, Br, I meta directors

17 Chem 345 eaction List: Exam III eactions: Page 17 ucleophilic aromatic substitution 2 2 aet Et If the ring is benzene, then a nitro group has to be present in the ortho or para position to the leaving group. The ring can be a heterocycle as well. Especially if there is a present in the ring and there is a pi bond to it. For example: If the ring is a pyridine ring, the leaving group is in the 2,4,or 6 position. ucleophiles can be primary or secondary amines, hydroxide, etc... If ydroxide is the nucleophile, and acid workup step is needed o detectable reaction

18 Chem 345 eaction List: Exam III eactions: Page 18 2 a 2 3 via benzyne 2 a

19 Chem 345 eaction List: Exam III eactions: Page 19 You do not have to memorize the uzuki/eck mechanisms. You do need to understand what is happening in the main steps and identify them. uzuki eaction Pd Base X B X can be Br or I Base can be a, a 2 C 3, ame, Et 3, etc... Li B(Me) 3 TF or Et B Boronic acids can react with a lot of reagents, so it is best to use it right away in a uzuki reaction and not carry it through a bunch of steps. eck eaction Pd Base X can be Br or I X Works best with monosubstituted alkenes Base can be a, a 2 C 3, ame, Et 3, etc... Product is often the E (trans) alkene Grubbs ing osing Metathesis PCy u PCy 3 C In the mechanism, the Grubbs Catalyst can be abbreviated as: u C 2 The mechanism is akin to the Wittig mechanism, but all of the steps are reversible.

20 Chem 345 Exam IV eaction List Page 20 2 Br 2, a Br 2, a' ' ' ofmann earrangement via isocyanate Br 2 ame Me C 2 Me a 3 Δ Curtius earrangement C isocyanate C 2 2 via Carbamic Acid (Very unstable) C Carbamate ester Also known as urethane C 2 Urea

21 Chem 345 eaction List: Exam IV eactions: Page 21 Aldol reactions are tricky due to multiple products depending on time, temperature, and exact reagent/solvent. They can also depend on how much of each starting material. Aldol reactions can be acid or base catalyzed. In a synthetic laboratory setting, base catalyzed reactions are far more prevalent than acid catalyzed aldol reactions. The acid catalyzed reactions typically use complex Lewis Acids that I have not talked about. The following reactions are reliable enough to be used in synthesis type questions and predict the products. a (r other strong alkoxide base) If you want to stop at the 3-hydroxycarbonyl, you should use the LDA method. LDA Li LDA Li LDA steals the proton to give the less substituted enolate. Li 1.) 2.) 3 + You stop at the 3-hydroxycarbonyl Method works best if the electrophile is an aldehyde. K (r other strong alkoxide base) (You do not stop at the 1,3-hydroxycarbonyl) You can use this reaction, as long as an aldehyde and a ketone are used and the aldehyde does not have an enolizable proton K (r other strong 5 3 alkoxide base) 4 3 Intramolecular aldols are clean if a five or six-member ring can be formed. Aldehydes make better electophiles than ketones. It is helpful to start the numbering at the electrophile. 2

22 Chem 345 eaction List: Exam IV eactions: Page 22 aisen reactions are base mediated only. There is not an acid version. Also, you need a full equivalent of base to get these to work. If you write cat. base, that will be counted wrong. In the case of the first reaction, a catalytic amount of alkoxide in alcohol will give the transesterification product. The following reactions are okay for you to use during synthesis and predict the products. The aisen product needs a proton on the carbon between the two carbonyls, otherwise the reaction will not work. If the final product contains an ester, than the base/solvent must match the end ester. Exceptions include the use of KtBu and tbu which are too hindered for transesterification. ydroxide or water cannot be used. aet 3 + Et Et cat. ame Et Et Et Me Me Crossed aisen or Mixed aisen condensations can be done using LDA or you can use an electrophile that does not have an enolizable proton. Li Et 3 + Et Et aet Et 3 + Et ere the base/solvent does not match, but it does not matter. aet 3 + Me Et ere the base/solvent does not match, but it does not matter aet Et Et

23 Chem 345 eaction List: Exam IV eactions: Page 23 You can use these reactions in predict the product type and synthesis questions. ame MeI Me Me Me Base must match ester or use KtBu, tbu or LDA and ether Instead of MeI, you can use any primary or methyl halide or tosylate. The conjugate acid of the anion has a pka of approximately 10, so secondary alkyl halides can be used, but the yield will be lower due to competition with elimination. Tertiary halides are too hindered and end up giving E2 products. KtBu EtI Me Me tbu Me Me For the second deprotonation, a nonnucleophilic base like KtBu in tbu or LDA in ether. If a nucleophilic base like a primary or secondary alkoxide could result in the reverse aisen reaction, and a lower yield. The alkyl halide could be a methyl, primary, or secondary halide/tosylate. a 3 + Δ Δ cat You can combine the three steps above in one step. Me Me dimethyl malonate 1.) ame, Me 2.) MeI 3.) KtBu, tbu 4.) EtI 5.) Δ cat. 2 4, 2 If you start with a malonic ester, then the product is a substituted carboxylic acid.

24 Chem 345 Exam IV eaction List Page 24 You can use these reactions in predict the product type and synthesis questions. You do not need to know the mechanisms for the reactions in the rectangles. Mannich: cat. Ac 2 eed an aldehyde, primary or secondary amine, and a ketone. Cat. Ac is used to catalyze the imine formation. Knoevenagel Condensation: The nucleophile comes from a C 2 sandwiched between two electron withdrawing groups. Possible EWG's include C, 2, and Carbonyls.

25 Chem 345 Exam IV eaction List Page 25 You can use these reactions in predict the product type and synthesis questions. You do not need to know the mechanisms for the reactions in the rectangles. LDA C 3 I Deprotonation occurs at the least hindered acidic proton. A primary halide can also be used. econdary and tertiary halides will give too much E2 products to be useful. 2.0 eq. LDA or 2.0 eq. a C 3 I You need two equivalents of a strong base, otherwise deprotonation stops at the middle proton. A primary halide can also be used. econdary and tertiary halides will give too much E2 products to be useful. 3 + LDA LDA LDA is strong enough to doubly deprotonate 1,3 dicarbonyls which can do 2 reactions The more reactive enolate reacts first. 1.0 eq. Br Me or primary halide Br Me, primary, or secondary halide

26 Chem 345 eaction List: Exam IV eactions: Page 26 You can use these reactions in predict the product type and synthesis questions. Michael eaction: 1,5 dicarbonyls are the product when a Michael acceptor is used as the electrophile. Though the carbonyl can compete as an electrophile, the major product is typically the addition to the alkene. Lecture Videos: Michael Breakdown, Michael eaction, obinson Annulation a (r other strong base) LDA 3 + LDA can be used to pull off the least hindered acidic proton. Common Michael Acceptors Me C Me Methyl vinyl ketone will often result in the obinson Annulation when an alkoxide is used as the base. Me K Et racemic

27 Chem 345 eaction List: Exam IV eactions: Page 27 You can use these reactions in predict the product type and synthesis questions. Umpolung reaction where an aldehyde carbon acts like a nucleophile. Unlike the dithiane reactions earlier, the steps in these mechanisms are all reversible. We should cover these on Wed. ov. 23. Lecture Videos: Umpolung Breakdown, Benzoin Condensation, tetter eaction Benzoin condensation KC Et You cannot have acid present, otherwise a cyanohydrin may form. For this reaction to work with cyanide, the aldehyde may not have an enolizable proton. Et 3 2-hydroxycarbonyl In the thiazolium catalyzed version, the aldehyde can have an enolizable proton. tetter eaction: If a Michael acceptor is present, then a 1,4-dicarbonyl is formed instead of the 2-hydroxycarbonyl. Et 3

28 Chem 345 eaction List: Exam IV eactions: Page 28 You can use these reactions in predict the product type and synthesis questions. You do not need to know the mechanisms for the reactions in the rectangles. We should cover these on Wed. ov. 23. Lecture Videos: Corey-eebach Dithiane Chemistry pka ~30 BuLi Acid base reaction Can undergo reactions like any organolithium Li Li 3 + racemic Li optically active 3 + optically active Li EtBr Unlike normal organolithiums, deprotonated dithianes can be nucleophiles in 2 reactions with methyl and primary halides. econdary halides give elimination products in large quantities. Tertiary halides only give E2 products. g 2 2 The dithiane can be thought as a protecting group that can be removed with g 2 and water. 2 aney i The dithiane can be replaced with two hydrogens by using 2 and aney ickel

29 Chem 345 eaction List: Exam IV eactions: Page 29 You can use these reactions in predict the product type and synthesis questions. We will hopefully cover these reactions on Wednesday. Their mechanisms are doable and not difficult, but I will not put them on this exam due to time. These reactions will not be on the exam. Lecture Videos: Enamine synthesis Enamine formation: eaction works best with secondary amines, but can work with primary amines and ammonia. Typically, secondary amines are used for the alkylation reactions below. Br should be sp 2 C

30 Chem 345 eaction List: Exam IV eactions: Page 30 You can use these reactions in predict the product type and synthesis questions. We covered cuprates on Monday, ov. 28. If they appear on Exam IV, it will be minor (four points at most). 2.0 eq. Li CuI 2 CuLi 2 CuLi 3 + Li Et EtBr racemic enolate intermediate can be alkylated by a primary or Me halide in an 2 reaction 2 CuLi Cuprates react with acid chlorides to give ketones or attack Michael acceptors to give enolates, which can be protonated.