Chem 345 Reaction List: Chem 343 Reactions: Page 1 (You do not need to know the mechanism for the reactions in the boxes). Nuc-
LG Nuc SN2 optically optically active active
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-, TsO-, etc... More hindered the alpha carbon or the more basic the nucleophile, the more likely
that E2 outcompetes SN2.
Nuc-
LG Nuc SN1 optically racemic active
Alpha carbon (carbon attached to leaving group) must be tertiary or secondary. Primary alpha carbons can undergo SN1 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-, TsO-, etc... Can undergo rearrangements to give a more stable carbocation.
Chem 345 Reaction List: Chem 343 Reactions: Page 2 (You do not need to know the mechanism for the reactions in the boxes).
H2SO4
LG E1 optically active
Alpha carbon (carbon attached to leaving group) must be tertiary or secondary. Primary alpha carbons can undergo SN1 if a resonance stabilized carbocation is involved. The most substituted alkene is the major product (Saitzev's rule) Non-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
NOT E2 optically LG active
The strength of the base necessary is dependent on the hindrance of the alpha carbon due
to competition from the SN2 reaction. Tertiary alpha carbons (no competition with SN2): a moderate base (conj. pKa 10) can be used Secondary alpha carbons: a strong base (conj. pKa 15 or higher necessary) Primary alpha carbons: a strong, bulky base such as KOtBu necessary. Major product dependent on base used. Small base->more substituted alkene. Bulky base (KOtBu)->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-, TsO-, etc... HO's cannot be eliminated by an E2 mechanism.
Chem 345 Reaction List: Chem 343 Reactions: Page 3 (You do not need to know the mechanism for the reactions in the boxes).
PCC (Primary alcohol becomes aldehyde OH CH Cl secondary alcohol becomes ketone. 2 2 O 343 reaction)
OH PBr3 Br (Works for methyl, primary, and secondary alcohols via SN2 reaction. Does not react with tertiary R R alcohols. 343 reaction)
O R O H2CrO4 (Secondary alcohols are converted or into ketones) 343 Reaction
H2O R OH R OH
Chem 345 Reaction List: Exam I Reactions: Page 4 (You do not need to know the mechanism for the reactions in the boxes). O RO OR cat. H2SO4 Acid catalyst should be a strong one like TsOH, H SO , or HCl. ROH 2 4
RO OR cat. H SO O 2 4 Acid catalyst should be a strong one like TsOH, H SO , or HCl. H2O 2 4
O R N cat. H2SO4 Acid catalyst can be a weak acid like AcOH. RNH2 R group ends up cis to the smaller substituent on the aldehyde R or ketone. N O cat. H2SO4
RNH2 H2O Acid technically not needed for imine cleavage O cat. NaOH NC OH
HCN
O KCN NC OH
AcOH
O acid or base O HO OR acid or base
ROH Hemiacetals are mechanistic intermediates only. Very few are stable enough to be synthetic products.
Chem 345 Reaction List: Exam I Reactions: Page 5 (You do not need to know the mechanism for the reactions in the boxes). O RMgBr + H3O R OH
O
O + RLi H3O R OH Organolithiums behave just like Grignards O
O NaBH4 H OH EtOH
NaBH4 R EtOH R N N H RNH2 cat. AcOH Reductive amination NaBH3CN O R N H
O NC OH cat. NaOH About any base capable of pulling a proton off an OH can be used. (conj. pKa 10 or more)
O KCN NC NH2
NH Cl 4
Chem 345 Reaction List: Exam I Reactions: Page 6 (You do not need to know the mechanism for the reactions in the boxes).
PPh3 (Just an SN2 Reaction)
Br PPh3
Base Wittig Reagent
PPh3 (Base needs to be strong like PPh3 KOtBu, NaH, NaNH2, or BuLi) O
PPh3
Nonstabilized Wittig Nonstabilized Wittigs typically give Z Stabilized Wittigs typically give E
O
O O PPh3
O O
Stabilized Wittig Nonstabilized Wittigs typically give Z Stabilized Wittigs typically give E
Mg X MgX (X can be I, Br, or Cl) O
2.0 eq. Li X Li (X can be I, Br, or Cl) (LiX is byproduct) O
It is okay if you do not mention 2.0 eq.
BuLi RLi RX Lithium Halogen Exchange O (Don't make BuLi this way)
Chem 345 Reaction List: Exam II Reactions: Page 7 (You do not need to know the mechanism for the reactions in the boxes). O O (This works when R is methyl or primary sp3 carbon). S 2 reaction RBr R N O O
O O cat. H2SO4 (Fisher esterification: This works for methyl, primary, or secondary ROH R OH alcohols but not tertiary alcohols) O
O O NaOH OR O
O O cat. H2SO4 or cat. NaOR ROH R O O
O O cat. H2SO4 Works for tertiary esters (carbonyl oxygen bond remains intact) O OH
O O SOCl2
R OH R Cl
O O RNH2 R Et3N R N R Cl H
O ROH O
NEt3 R R Cl R O
Chem 345 Reaction List: Exam II Reactions: Page 8 (You do not need to know the mechanism for the reactions in the boxes).
DCC O O NEt3 R RNH N OH 2 H
O HCl R R H3N O N H
O H2/Pd R R H2N O N H
O R R H H2N O N N H
O O H2/Pd
O R HO R
Chem 345 Reaction List: Exam II Reactions: Page 9 (You do not need to know the mechanism for the reactions in the boxes). BocCl
NHBoc NH2 NEt3
FmocCl
NHFmoc NH2 NEt3
ZCl NHZ NH2 NEt3
O O cat. H2SO4
OH O
O O
H2SO4 N OH H H2O
O + O NaOH H3O
N H2O H OH
O O O NH2
O O N O H O O OH
Cl O
Chem 345 Reaction List: Exam II Reactions: Page 10 (You do not need to know the mechanism for the reactions in the boxes). O + RMgBr H3O R OH
OMe O R
O RLi + H3O R OH
OMe O R
O O excess RMgBr + RH
OH O O
O excess + O RLi H3O
OH O R
O + LiAlH4 H3O H OH
O
excess RMgBr + O H3O CO2 O R OH excess + O RLi H3O CO2 O R R
Chem 345 Reaction List: Exam II Reactions: Page 11 (You do not need to know the mechanism for the reactions in the boxes).
O LiAlH + 4 H3O
OH O OH
O LiAlH + 4 H3O
O ROH OR OH
O + LiAlH4 H3O
R R O N N H H
LiAlH H O+ N 4 3
O NH2
N RLi + O H3O
O R
N + RMgBr H3O O
O R
N O H2SO4
H2O OH Chem 345 Reaction List: Exam II Reactions: 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. Reactions on this page only work on ketones and aldehydes
Baeyer-Villiger O O Migration Order: mcpba H>3°C>2°>1°C>Me R' R R' R O
O O O O
mcpba mcpba H OH O
Beckmann HO TsO O NH OH N N O 2 TsCl, NEt HCl 3 Δ R' R R' R R' R N R R' H2O oxime H Migration Order: Whichever group is opposite the O migrates so 3°C>2°>1°C>Me>H O
1.) NH2OH, HCl H 2.) TsCl, NEt3 N H H 3.) Δ, H2O
O
O O O O Δ 1.) NH2OH, HCl 2.) TsCl, NEt3 NH2OH, HCl 3.) Δ, H2O H2SO4, H2O NH NH
Reaction can also be done in a single step. Chem 345 Reaction List: Exam III Reactions: Page 13 OH OD O O excess D D DCl excess DCl
D D D
NO2 H2SO4 HNO3
O
O
Cl (Reaction does not work when the ring AlCl3 is strongly deactivated) It can work with halobenzenes, but not anything more deactivated)
Cl Br
Cl2 Br2
AlCl3 FeBr3
Δ SO H H2SO4 3 H2SO4 SO3 H2O
useful way to make ortho substituted benzene rings
Chem 345 Reaction List: Exam III Reactions: Page 14 R RCl
AlCl3
excess Have to use large excess, otherwise multiple alkylations occur. R is an alkyl group (sp3C). Not a particularly clean reaction as rearrangements occur quite frequently as well.
Clemmenson Reduction O HCl ZnHg
Ph Ph Reduces ketones and Wolff-Kishner Reduction aldehydes KOH O NH2NH2 Δ
Vilsmeier-Haack Reaction
POCl3 H2O O DMF O DMF= N H
(Reaction does not work when the ring is strongly deactivated) It can work with halobenzenes, but not anything more deactivated) Chem 345 Reaction List: Exam III Reactions: Page 15 Sandmeyer Sequence:
H2/Pd/C
NH NO2 2
NaNO2, HBr CuBr
H2O
Br NH 2 N2 Br When using CuBr or CuCl, the acid used in the first step should match.
NaNO2, HCl CuCl
H2O
Cl
NH2 N2 Cl
CuCN H3PO2
H2O H2O
Cl Cl
N2 CN N2 H
Cu2O KI
H2O H2O
Cl Cl I N2 OH N2
Chem 345 Reaction List: Exam III Reactions: Page 16
R R N R N R R R > > O O N N O O > > C N C N > > O O directors S S HO meta HO O O > > Deactivating O O R R ~ ~ O O RO > RO I > I Br, Br, Reactivity Br, Br, X Cl, Cl, X Cl, Cl, > X=F, X=F, > X=F, X=F, H Approximate Approximate H the > > aryl of aryl R R favored nature nature Substitution: Substitution: strongly R=alkyl, R=alkyl, directors > R=alkyl, R=alkyl, in in > the the para para typically typically group, O O para para ortho ortho Aromatic Aromatic R R (changing (changing protonated protonated > Activating > carbonyl carbonyl be be R a R media media N can can N isn't N R R Electrophilic Electrophilic R the the If group) acidic acidic Chem 345 Reaction List: Exam III Reactions: Page 17
Nucleophilic aromatic substitution
NO NO2 2
NaOEt
EtOH
Cl O
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 N 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. Nucleophiles can be primary or secondary amines, hydroxide, etc... If Hydroxide is the nucleophile, and acid workup step is needed.
1 6 N 2 R2NH 5 No detectable reaction
3 Cl 4 R 1 6 N Cl N N 2 R2NH R 5 3 4
Chem 345 Reaction List: Exam III Reactions: Page 18
Cl NH2
NaNH2 via benzyne NH3
Cl NH2
NaNH2 NH2 + NH3
Chem 345 Reaction List: Exam III Reactions: Page 19
You do not have to memorize the Suzuki/Heck mechanisms. You do need to understand what is happening in the main steps and identify them.
Suzuki Reaction R
Pd Base R OH X B
OH X can be Br or I Base can be NaOH, Na2CO3, NaOMe, NEt3, etc... R R
B(OMe) NH4Cl 3 H O Boronic acids can react with a lot of THF or Et2O 2 reagents, so it is best to use it right away in a Suzuki reaction and not carry it through a OH bunch of steps. Li B
OH
Heck Reaction Pd Base R
R
X Works best with monosubstituted alkenes Product is often the E (trans) alkene X can be Br or I Base can be NaOH, Na2CO3, NaOMe, NEt3, etc...
Grubbs Ring Closing Metathesis PCy3 Cl R
Ru C H 4 Cl 5 7 1 3 5 PCy3 3 6
2 4 6 2 7 1
In the mechanism, the Grubbs Catalyst can be abbreviated as: CH2 Ru The mechanism is akin to the Wittig mechanism, but all of the steps are reversible.
Chem 345 Reaction List: Exam IV Reactions: Page 20 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. NaOH
O If you want to stop at the 3-hydroxycarbonyl, (Or other strong you should use the LDA method. alkoxide base) O ROH
O Li LDA LDA N
O
OLi LDA steals the proton to give the less substituted enolate.
O 1.) O You stop at the 3-hydroxycarbonyl R 2.) H O+ Method works best if the electrophile R H 3 is an aldehyde. OLi O OH
O O O
H KOH
(Or other strong alkoxide base) ROH
(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.
7 O 4 2 1 7 KOH 6 1 H O 6 5 (Or other strong 2 5 3 alkoxide base) O ROH 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.
Chem 345 Reaction List: Exam IV Reactions: Page 21 Claisen 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 Claisen 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 KOtBu and tBuOH which are too hindered for transesterification. Hydroxide or water cannot be used.
O O O + NaOEt H3O O O
EtOH OEt OEt OEt O O cat. NaOMe H
OEt MeOH OMe Crossed Claisen or Mixed Claisen condensations can be done using LDA or you can use an electrophile that does not have an enolizable proton. O O O OLi O O + OEt H3O
O
O H O O O + NaOEt H3O OEt EtO OEt EtOH
O Here the base/solvent does not match, but it does not matter. O O O + NaOEt H3O H H OMe EtOH
Here the base/solvent does not match, but it does not matter. O O 6 4 2 1 OEt NaOEt H O+ 3 1 5 3 EtOH 2 6
O O 3 5 4
Chem 345 Reaction List: Exam IV Reactions: Page 22 You can use these reactions in predict the product type and synthesis questions. O O O O O O NaOMe MeI
MeOH OMe OMe OMe Base must match ester or use KOtBu, HOtBu 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. O O O O O O EtI KOtBu
OMe OMe tBuOH OMe
For the second deprotonation, a nonnucleophilic base like KOtBu in tBuOH or LDA in ether. If a nucleophilic base like a primary or secondary alkoxide could result in the reverse Claisen reaction, and a lower yield. The alkyl halide could be a methyl, primary, or secondary halide/tosylate. O O O O O O + NaOH H3O
O O OH
O O OH O Δ
OH
O O O Δ You can combine the three cat. H2SO4 steps above in one step. H O O 2
1.) NaOMe, MeOH O O O 2.) MeI 3.) KOtBu, tBuOH If you start with a malonic ester, then the product is a substituted HO carboxylic acid. MeO OMe 4.) EtI 5.) Δ dimethyl malonate cat. H2SO4, H2O
Chem 345 Exam IV Reaction List Page 23 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. R O O AcOH O HN
RNH2
R H R
Need an aldehyde, primary or secondary amine, and a ketone. Cat. AcOH is used to catalyze the imine formation.
Knoevenagel Condensation:
O O O O O
H H N
The nucleophile comes from a CH2 sandwiched between two electron withdrawing groups. Possible EWG's include CN, NO2, and Carbonyls.
Chem 345 Exam IV Reaction 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. O
LDA CH3I
O O O Deprotonation occurs at the least hindered acidic proton. A primary halide can also be used. Secondary and tertiary halides will give too much E2 products to be useful.
O O 2.0 eq. LDA O O O O or 2.0 eq. NaH CH3I
O
+ H3O You need two equivalents of a strong base, otherwise deprotonation stops at the middle proton. O O A primary halide can also be used. Secondary and tertiary halides will give too much E2 products to be useful.
O O O O O O LDA LDA
O O
LDA is strong enough to doubly deprotonate 1,3 dicarbonyls 1.0 eq. Me or which can do SN2 reactions Br primary The more reactive enolate reacts first. halide
O O O O Br
Me, primary, or secondary halide
Chem 345 Reaction List: Exam IV Reactions: Page 25 You can use these reactions in predict the product type and synthesis questions. Michael Reaction: 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 Reaction, Robinson Annulation
O O O O NaOH O
(Or other strong base)
O O O + O O LDA H3O
O O
LDA can be used to pull off the least hindered acidic proton. Common Michael Acceptors H OMe R N H
O O O O
O CN N
O
Me Methyl vinyl ketone will often result in the Robinson Annulation when an alkoxide is used as the base. O O
R Me KOH racemic O EtOH O
R Chem 345 Reaction List: Exam IV Reactions: Page 26 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. Lecture Videos: Umpolung Breakdown, Benzoin Condensation, Stetter Reaction
Benzoin condensation O O KCN You cannot have acid present, otherwise a R cyanohydrin may form. For this reaction to EtOH work with cyanide, the aldehyde may not have R H R an enolizable proton.
OH H O S O
N H NEt3 R OH 2-hydroxycarbonyl
In the thiazolium catalyzed version, the aldehyde can have an enolizable proton. Stetter Reaction: If a Michael acceptor is present, then a 1,4-dicarbonyl is formed instead of the 2-hydroxycarbonyl. H S O N O R
R H O NEt3 R
O
Chem 345 Reaction List: Exam IV Reactions: Page 27 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. Lecture Videos: Corey-Seebach Dithiane Chemistry
O HS SH S S pKa ~30 HCl H H
BuLi Acid base reaction S S S S O Can undergo reactions like any organolithium H Li O
H racemic S S S S + H3O O Li
OH
O
optically active OH S S S S + H3O O Li optically active
EtBr Unlike normal organolithiums, deprotonated S S S S dithianes can be nucleophiles in SN2 reactions with methyl and primary halides. Secondary halides give elimination products in large quantities. Tertiary halides only give E2 products. Li
HgCl2 The dithiane can be thought as a protecting group O that can be removed with HgCl and water. S S 2 H2O
H2 Raney Ni The dithiane can be replaced with two hydrogens by using H2 and Raney Nickel S S
Chem 345 Reaction List: Exam IV Reactions: Page 28 You can use these reactions in predict the product type and synthesis questions. We will likely cover these on Monday.
H O N N Enamine formation: Reaction works best with secondary amines, but can work with primary amines and ammonia. Typically, secondary amines are used for the alkylation reactions below.
O R Br N N + H3O H2O R R should be sp2 C. R
O O O N N O + H3O R Cl H2O R R
O O N N + H3O H2O
O O
Chem 345 Reaction List: Exam IV Reactions: Page 29 You can use these reactions in predict the product type and synthesis questions.
2.0 eq. CuI Li R CuLi R 2 O
R CuLi + 2 H3O R R
O O O OLi Et EtBr R
O racemic O enolate intermediate can be alkylated by a primary or Me halide in an SN2 reaction
O Cuprates react with acid chlorides to give ketones R CuLi O 2 or attack Michael acceptors to give enolates, which can be protonated. Cl O R