Ch 12 reagents and rxns.

TBAF (tetra-n-butylammonium fluoride)

Tetrabutylammonium fluoride (TBAF) is a source of fluoride ion. It is used to cleave silyl ethers, which are common protecting groups for alcohols.

1.)R-Mg-X + Electrophile (Grignads mechanism) 2.) H2O

(Aldehyde or Ketone typically) 1.) Grignards reagent acts as a *nucleophile* which attacks the *electrophile* in the case of a carbonyl it attacks the carbon on the C=O causing the *addition of the R- group* and formation of an *alkoxide*. 2.) Addition of a protic reagent such as *water* serves to *protonate the alkoxide* and form the *OH* group OUTCOMES : *addition of R group* on the carbonyl C=O, as well as the *formation of OH* Note: If protic solvent is around before the grignards electrophile reaction an acid base reaction is more likely to occur, this is why H2O is added after the grignards reaction

NaBH4, MeOH,H2O,EtOH vs. 1.) LAH, 2.) H2O vs. H2, (Pt,Pd,Ni)

*NaBH4* is a mild reducing agent and will reduce aldehydes and ketones *LAH* is a strong reducing agent and will reduce Ketones, Aldehydes and Esters as well as Carboxylic acids. *H2* with high pressure and temperature will convert ketones and aldehydes into alcohols. will also reduce alkenes into alkanes. This uses forceful conversion which is not desirable, thus is not often used by synthetic chemists.

examples of grignards (R-MG-X, R-MgX) reactions (aldehyde and ketones) - picture on the back

- Use of a Grignards reagent with R- as the nucleophile on a *ketone* yeilds a *tertiary alcohol* with the R group attached at the once carbonyl carbon and OH in place of the =O double bond. note: does not replace O is protonated forming OH - Use of a Grignards reagent with R- as the nucleophile on a *aldehyde* yields a *secondary alcohol* with the R group attached at the once carbonyl carbon and OH in place of the =O double bond. note: does not replace O is protonated forming OH

1.)LiAlH4 2.) H2O (Aldehyde) ------------->

Addition of LAH to an Aldehyde converts it into a *primary alcohol*

1.)LiAlH4 (excess) 2.) H2O (Ester) ---------------------->

Addition of LAH to an ester generates a *primary alcohol* on carbonyl α carbon (C=O) and a second OH group on secondary oxygen (R(α)-*O*-R) in ester.

1.)LiAlH4 (excess) 2.) H2O (Carboxylic acid) -------------------->

Addition of LAH to carboxylic acid generates a *primary alcohol*.

1.)LiAlH4 2.)H2O (Ketone) -------------->

Addition of LAH to ketone converts it into a *secondary alcohol*. When added to a non symmetrical ketone we expect a stereo-center to be generated and a pair of enantiomers to form, the mixture will be racemic because the H- (nuc:) may add on either side of the trigonal planar ketone.

1.)RCO3H 2.) H3O+ Alkene ------------------->

Addition of peroxy acid and source of H3O + yeilds an anti dihydroxylation through the formation of an epoxide. forming a trans-diol

Formation of chromic acid used in oxidation reactions

Chromium trioxide + Acid and acetone yields chromic acid. Sodium dichromate + acid and water makes chromic acid

Oxidation state increase, oxidation possibilities of varying substrates. (primary, secondary, tertiary alcohols)

If we increase the number of bonds to a hetero atom we generally increase the oxidation state. and conversely if we decrease the number of binds to hydrogen we also increase the oxidation state. - *Primary alcohols* can be oxidized twice as shown in the picture. Forming, *aldehyde* and *carboxylic acid* - *Secondary alcohols* can be oxidized a single time to yield a *ketone* - *Tertiary alcohols* are generally considered *un-reactive* in these oxidation pathways.

1.)LiAlH4 2.) H2O (overall and mechanism.)

LAH is a source of H- but is far stronger than NaBH4. a protic solvent must be introduced in a separate step. mechanism: 1.) LAH is added and H- acts as a nucleophile, attacking the carbonyl carbon causing the electrons in the oxygen carbon double bond to go onto the oxygen 2.)the generated alkoxide ion now can be protonated by the second step addition of water or protic solvent 3.) an OH is on same carbonyl carbon (type of OH (sec,prim...etc) depends on the substrate to which it was added (ketone, aldehyde, ester... etc)

Conc. H2SO4, heat alcohol elimination ---------------------------->

Lone pairs on the oxygen serve as a nucleophile to deprotonate generated H3O+forming R-H2O+ on the alcohol. this makes the alcohol a good lg (as H2O). this can leave generating a carbocation and later an H is abstracted forming an alkene (E1) or a hydrogen can be abstracted and immediate formation of the alkene and loss of the leaving group can be initiated in a concerted mechanism (E2) - a mixture of alkene products may be formed but as a general rule the more substituted alkene is the more stable and will make up the majority of the products - E1 mechanism shown,

PCC, CH2Cl2 Primary Alcohols ---------------->

PCC is a milder oxidizing agent which in the case of primary alcohols can prevent the full oxidation to carboxylic acids and instead produce the intermediate oxidation product of an aldehyde.

PCC, CH2Cl2 Secondary Alcohols ----------------->

PCC will oxidize secondary alcohols into ketones. this reaction only has one oxidation possibility. thus, Chromic acid could also be used having the same result as a secondary OH being oxidized into a ketone.

PBr3 alcohols ------------------->

Primary and secondary alcohols react with PBr3 via an Sn2 style reaction exchanging the OH with a Bromine via substitution

SOCl2 alcohols -----------------> py

Primary and secondary alcohols react with SOCl2 via an Sn2 reaction exchanging the OH with a Cl via substitution

NaBH4, MeOH,H2O,EtOH (only one of the polar solvents) (Aldehyde) ----------------------------------------------->

Sodium Boro-hydride acts as a _source of H-_, and the solvent a source of H+ for protonation of the alkoxide. H- acts as a nucleophile attacking the carbonyl carbon. Reduced aldehyde yields a *primary Alcohol*.

NaBH4, MeOH,H2O,EtOH (only one of the polar solvents) (Ketone) -------------------------------------------------->

Sodium Boro-hydride acts as a _source of H-_, and the solvent a source of H+ for protonation of the alkoxide. H- acts as a nucleophile attacking the carbonyl carbon. we expect a mixture of enantiomers because nuc: can attack from both side of the sp2 carbonyl carbon. ketones are converted into secondary alcohols. watch for stereochemical outcomes

TMSCI

TMSCl is a protecting group for alcohols. When added to alcohols, it forms a silyl ether, which is inert to most reagents except for fluoride ion and acid. Note that the reagent can be written two ways (CH3)3SiCl and TMSCl.

1)TsCl, py 2) NaBr alcohols ------------------>

Treatment of TsCl and pyridine converts alcohols or hydroxl groups into good leaving groups which are detonated as (OTs) by making the OH into a good leaving group it makes it susceptible to back side attack by Br- in solution yielding a bromine substitution at the OH spot and an inversion of stereochemistry

H2, (Pt,Pd,Ni) high P,T (Ketone, Aldehyde) ----------------------->

Use of these reagents under forced conditions leads to the reduction of aldehydes and ketones to alcohols.... high temperature and pressure are required and thus thus set of reagents is not often used. will also convert alkenes into alkanes. Note : alkene ---> alkane reduction may occur at lower temperature and pressure. however, to reduce a ketone very high temperature and pressure are required.

primary alcohols and chromic acid

because Chromic acid is a very potent oxidizing agent. When fully treated primary alcohols produce carboxylic acids rather than aldehydes

Alternative oxidation methods

other oxidation methods which are chemically greener and potentially fit for other scenarios exist but we are not expected to know them. 1.) swern oxidation 2.) DMP, CH2Cl2

H2/LAH/NaBH4 (diketones)

production of Diol (two OH groups) via reduction pathways.

plethora of reaction grignards, diversity array and bond formations

selection of the carbonyl (ketone, aldehyde, ester) R groups and the r groups on grignards reagents have a great diversity of the types of molecules we are able to make and arrange.

Formation of Grignards with intramolecular OH

similarly we can not prepare a grignards on a substrate which has an acidic protons such as that with an alcohol group... the generated R- would react intramolecularly to de-protonate the alcohol forming an alkoxide and protonated carbanion.

Terminal alkene + n Butyl lithium

this forms a organolithium reagent which can act as a nucleophile

1.) TSCl, py 2.) NaOEt alcohol elimination ------------------------------>

when we first convert the OH into a good leaving group then treat it with a strong non bulky base, we expect to have a concerted mechanism of elimination. And formation of the most stable and substituted alkene.

1.) (Excess) R-Mg-X 2.) H2O (Ester) ------------------------> (mechanism as well)

- addition of a grignards reagent with an *ester* will add the R- onto the Carbonyl carbon twice with the second oxygen on the ester (*O*-R) acting as a leaving group. Mechanism : 1.) Gringards reagent acts as a nucleophile (R-) attacking the carbonyl carbon 2.)alkoxide lg forms causing the C=O double bond to reform 3.) a second gringards reagent (R-) attacks the carbonyl carbon causing the second addition of R group. this forms an alkoxide ion 4.)addition of H2O or protic reagent causes the protonation of the alkoxide forming an alcohol OUTCOMES: - two alkyl substituents are added onto the carbonyl carbon and the carbonyl oxygen is converted into an OH group, *tertiary alcohol*

Alcohol group protection

- if we do not want to affect an OH already on a substrate we can use protecting groups to prevent any reactions from taking place. - Further, because grignards reagents can not be created in the presence of acidic protons protection groups can be used on existing OH groups.

1.)LiAlH4 (excess) 2.) H2O (Ester mechanism.) ------------------->

1.) LAH is added and H- acts as a nucleophile, attacking the carbonyl carbon causing the electrons in the oxygen carbon double bond to go onto the oxygen 2.) Carbon oxygen double bond (carbonyl group) reforms. with second oxygen on the ester (R(α)-*O*-R) acting as a leaving group, generating carbonyl + alkoxide ion 3.) Second molecule of LAH delivers H- to the carbonyl group generating alkoxide on carbonyl oxygen from double bond electrons. 4.) Alkoxide ion protonation occurs when protic agent such as water is introduced forming a primary alcohol. 5.) as a note ( *O*-R) which acted as a leaving group and was an alkoxide will be protonated forming ( *OH*-R)

1.) (Excess) R-Mg-X 2.) H2O Carboxylic acid ------------------------>

An acid base reaction will take place instead of the Grignards reagent attacking the electrophilic carbonyl carbon. --- formation of a grignards reagent or reaction of grignards reagents in the presence of even mildly acidic protons will not happen because acid base equilibria will be the main driving force of the reaction similarly we can not prepare a grignards on a substrate which has an acidic protons such as that with an alcohol group... the generated R- would react intramolecularly

H-Cl ZnCl2 primary/secondary alcohols --------------------->

Because of ZnCl2 ionic nature this is limited to alcohols which are water soluble... ZnCl2 converts OH into a reasonable leaving group allowing Cl- anions in solution to initiate backside attack. (Ask about sec alcohols) --- are they sn2 restrictive ??

H-X Primary/secondary alcohols ------------------->

addition of H-X into a secondary or primary alcohol yields an Sn2 style of reaction 1.) the lone pair on the oxygen deprotonates H-X converting the alcohol into an excellent leaving group 2.) X- generated from the previous step now is able to initiate backside attack replacing the OH with X and generating H2O - note: for non symmetrical secondary alcohols we expect to generate a stereocenter and thus expect a racemic formation of products.

H-X Tertiary alcohol ---------------->

addition of H-X into a tertiary alcohol yields an Sn1 style reaction 1.) Lone pairs on oxygen deprotonate H-X. this converts the R-OH into R-H2O which acts as a good lg and leaves 2.) This leaves behind a tertiary carbocation which is susceptible to back side attack from the generted X- from the previous step. 3.) if the R groups are not degenerate we expect to form a stereocenter where we expect to see a racemic mixture of products.

Li, or Na Alcohol ----------------->

addition of alkaline earth metals especially to primary alcohols forms an alkoxide and dissolved metal. ---> essentially liberated hydrogen from the Alcohol.

R-X + Mg

addition of alkyl halide with magnesium produces a Grignards reagent Grignards reagents are effectively sources of carbon anions which act as nucleophiles and can attack a wide range of electrophiles.

1.)OsO4 (catalytic), NMO Alkene ------------------------------>

addition of osmium tetroxide yields a syn dihydroxylation leading to the formation of a cis-diol.

R-Br ---------> R-Li

addition of two equivalents of Li to R-Br leads to R-Li + LiBr

organometallic + formaldehyde eg. R-MgBr, R-Li

leads to the formation of primary alcohols.